Bullet of Experimental Therapies for AIDS (BETA) No. - June 1995; Published by the San Francisco AIDS Foundation, San Francisco, California Contents -------- BETA News Briefs Treatment for HIV-Related Fungal Infections The CD8 Cell Antiviral Factor: An Interview with Immunologist Jay Levy, MD A Positive View of Safe Sex Long-Term Non-Progressors, Survivors and HIV Positives Turning the Corner on Wasting? A Symposium on Wasting Disorders State of the Art in Wasting: An Interview with Carl Grunfeld, MD, PhD Reform at FDA: Faster Access To Promising Drugs? AZT Use by Pregnant Women Stirs Policy Debate Research Notes The National Task Force on AIDS Drug Development: A Progress Report A Letter to Abbott Laboratories The Inter-Company Collaboration for AIDS Drug Development: Boon or Bust? Selected Open Clinical Trials for HIV/AIDS Treatments Glossary --------------------------- BETA News Briefs Ronald Baker, PhD Ronald Baker is Editor-in-Chief of BETA and Director of the Department of Treatment Education and Advocacy at the San Francisco AIDS Foundation. Cidofovir (Vistide) for CMV Retinitis Injections into the eye of small amounts (20 micrograms) of the antiviral drug cidofovir (Vistide) may successfully control the progression of cytomegalovirus (CMV) retinitis in people with AIDS for an extended time. Two recently published reports suggest that cidofovir is effective when injected directly into the eye (see Research Notes, p. 52). Two major advantages of cidofovir are (1) in vitro the drug has a longer half-life in cells than either ganciclovir or foscarnet, allowing for less frequent dosing and eliminating the need for an indwelling catheter; and (2) in vitro cidofovir is 10 times more potent against CMV than ganciclovir. A single injection with cidofovir into the eye following initial IV therapy for CMV retinitis appears to be effective for maintenance treatment for 55 days. Time-released ganciclovir implants also have been shown effective for maintenance treatment of CMV retinitis (see BETA. March 1995. p. 73). For injecting cidofovir, the procedure used is to anesthetize the eye, followed by injecting the drug directly into the retina. The authors of the cidofovir study published in the journal Ophthalmology conclude that a single 20 microgram dose of cidofovir injected into the eye safely prevented progression of CMV retinitis for 55 days, without IV therapy. In addition, they say, this effect can be sustained after a second injection with the drug. Thus far CMV has not developed resistance to cidofovir. These encouraging results give people new hope for improved management of their CMV retinitis. The standard of care for the treatment and prevention of CMV disease is changing rapidly. There are important new therapeutic options that may slow disease progression as well as significantly improve the quality of life of individuals with CMV disease, in particular those with CMV retinitis. These new options include: 1. cidofovir by injection into the eye for maintenance treatment; 2. ganciclovir eye implants for maintenance treatment; and 3. oral ganciclovir for primary prophylaxis of CMV disease and maintenance treatment. The San Francisco AIDS Foundation has asked Gilead Sciences to implement as soon as possible a compassionate use (expanded access) program for cidofovir for people who have failed on ganciclovir and foscarnet. Gilead Sciences is located in Foster City, CA. New Treatment for HIV-related ITP The FDA in March approved WinRho SD, a virally inactivated immune globulin product, for the treatment of children and adults with HIV-related immune thrombocytopenic purpura (ITP). ITP is an autoimmune disease in which the immune system attacks and destroys blood platelets which are necessary for blood clotting. Left untreated, ITP may lead to excessive bruising, uncontrolled bleeding and death. WinRho SD can be administered by either intravenous or intramuscular injection. The drug likely will be available to physicians in June 1995. The average wholesale cost for a single 300 microgram vial of WinRho SD is $160. The average wholesale cost for a course of treatment for an individual weighing 150 pounds is approximately $1,600 (ten 300 microgram vials). For more information about the drug, physicians may call 1-800-494-6746. For reimbursement information, call 1-800-789-2099. WinRho SD is marketed and distributed by Univax Biologics of Rockville, MD. Religious Groups Oppose Patenting of Human and Animal Genes A coalition of religious groups representing most major religions are asking Congress to ban patents on human and animal genes. If Congress agrees, it would reverse existing policy that allows patent holders the right to exclusively manufacture or sell their product for 20 years following the granting of the patent. Religious leaders say they do not oppose biotechnology and genetic engineering per se, but rather the patenting of human genes or organisms. They argue that life is a gift from God, and that the patenting of life forms reduces life to a commercially marketable commodity, thus violating its sanctity. Biotechnology companies contend that without patent rights for their products, they cannot secure the investment funds necessary to develop new treatments for life-threatening and debilitating diseases such as heart disease, multiple sclerosis, Alzheimer's, cystic fibrosis, cancer and AIDS. According to biotechnology spokespersons, companies will not develop drugs for these and other serious human diseases if they cannot obtain patent rights on genetically engineered products that help to bring them a financial return on their investment in research and development. FDA Grants Extended Patents to Brand Name Drug Makers FDA in May granted 3 additional years of patent protection for pharmaceutical companies before their products can be "copied" and marketed by generic firms, according to an article by Carl Hall (San Francisco Chronicle. May 27, 1995. B1). Previous FDA policy had granted companies 17 years of patent protection. The new ruling was intended to bring U.S. patent laws in line with the terms of the General Agreement on Tariffs and Trade (GATT). The action was prompted by a petition from Glaxo Wellcome. For generic drug makers and for consumers, the ruling was a clear negative, since drug prices tend to fall dramatically once they are off patent. One market analyst estimated that the ruling will give brand name drug makers an additional $6 billion in sales. Radical New View on HIV Pathogenesis Researchers at the Stanford University School of Medicine have published 2 papers in the Journal of Clinical Investigation (May 1995) that outline a radical new view of HIV disease pathogenesis. The Stanford team's work suggests that the immune cells most devastated by HIV are not CD4 T-cells (helper T-cells), but rather a group of T-cells known as "naive" T-cells (see Research Notes, p. 44). Naive T-cells are "immature" immune cells in the bloodstream that search for new, never before encountered microbial threats. They are critically important because they form a defense against new invading microbes. When naive T-cells encounter an unknown antigen, they are activated to battle that particular antigen, and become "memory" T-cells. The Stanford scientists report that naive T-cells are a prime target for HIV, and over the course of HIV disease progression the virus destroys them in vast numbers. With this loss of naive T-cells, the immune system is much less capable of fighting off new microbes. The massive loss of naive T-cells may explain why HIV positive individuals eventually become susceptible to opportunistic infections. In healthy adults the ratio of naive T-cells to memory T-cells is about 50-50, but in HIV positive individuals with fewer than 200 CD4 cells/mm3, about 80% of the T-cells are memory cells. Stanford immunologist Mario Roederer, MD, says there are 2 types of naive T-cells, naive CD4 cells and naive CD8 cells. Both types decrease in number as HIV disease progresses. In the future, a new objective of anti-HIV treatment may be to find a way to prevent loss of the naive CD4 and CD8 cell subsets. The Stanford researchers' work could have an immediate impact on AIDS vaccine trials. Based on their findings, investigators should consider the naive T-cell count in addition to the CD4 count. "We'd predict that those individuals with few or no naive T-cells won't respond to vaccination," said Roederer. "The whole basis of vaccination requires that you have naive cells to respond." Switch From AZT to d4T Brings Clinical Benefit A study comparing d4T (stavudine) monotherapy to AZT (zidovudine) monotherapy among 822 patients who had taken AZT for at least 6 months showed that those switching to d4T did better than those remaining on AZT. While there was no survival benefit from the switch to d4T, clinical progression in the d4T group was delayed by about 3 months longer than in the AZT arm. Patients on d4T also had CD4 counts about 40 cells/mm3 higher than those continuing on AZT. These study results were presented at the 8th International Conference on Antiviral Research in Santa Fe, New Mexico, held April 23-28, 1995. None of the study participants had previously used ddI or ddC; all were clinically stable at study entry, with CD4 cell counts between 50 and 500 cells/mm3. Both drugs caused adverse side effects. Predictably, the most commonly reported adverse effect from d4T use was peripheral neuropathy, which was more frequent among those with lower CD4 counts. The FDA approved d4T (Zerit) last year under its accelerated approval mechanism, with the proviso that the study described here (Bristol-Myers Squibb 019) be completed, and that its results confirm a clinical benefit from the drug. Bristol-Myers Squibb is now expected to ask FDA to grant d4T "official" status as a second-line treatment for individuals who have taken AZT for at least 6 months. HHV-6 May Cause AIDS-Related Dementia Human herpes virus type 6 (HHV-6) may infect the brains of some people with AIDS and cause dementia, according to a report in the Journal of Acquired Immune Deficiency Syndromes and Retrovirology (April 26, 1995). HHV-6 may destroy the brain's myelin (white matter) that surrounds nerve fibers, according to Konstance Knox, MD, and Donald Carrigan, MD, of the Medical College of Wisconsin. The researchers said they discovered active HHV-6 in the brains of 4 of 6 people with AIDS in a post mortem examination. Knox believes that HHV-6, a virus that harmlessly infects about 90% of the general population, activates to destroy brain tissue in people with HIV infection when their immune systems become seriously weakened (for a detailed report on HHV-6 infection and its potential role in AIDS, see BETA. June 1994. pp. 18-21). Oral Ganciclovir to Prevent CMV Disease Hoffmann-La Roche has submitted a supplemental New Drug Application (NDA) to FDA for clearance to market oral ganciclovir (Cytovene) to prevent cytomegalovirus (CMV) disease in immunocompromised individuals at risk for developing the debilitating opportunistic infection. Oral ganciclovir was approved by FDA last year for maintenance treatment (secondary prophylaxis) of CMV retinitis among immunocompromised patients (including those with AIDS) whose retinitis is stable following treatment with intravenous ganciclovir or foscarnet. FDA is expected to move quickly to approve oral ganciclovir for the prevention of CMV disease in patients at risk. However, prior to FDA approval, at-risk individuals may obtain the drug for prophylaxis free through an expanded access program sponsored by Hoffmann-La Roche (call 1-800-569-4630). Oral ganciclovir is also available free to qualified patients in California through the state's AIDS Drug Assistance Program (see news item below). Eighteen New AIDS Drugs Available Free in California Program In March 1995, 18 new drugs became available free to qualified individuals as a part of California's AIDS Drug Assistance Program (ADAP). The new medications are: oral ganciclovir, d4T (stavudine), doxorubicin, itraconazole, G-CSF (Filgrastim), alpha interferon, epoetin alpha, bleomycin sulfate, vinblastine sulfate, trimethoprim, megestrol acetate, cyclophosphamide, methotrexate, dexamethasone, prednisone, dronabinol, trimetrexate glucuronate and leucovorin calcium. Twenty-five other AIDS drugs are already available through the California ADAP program. FDA Approves Herpes Simplex Virus Diagnostic Test FDA has approved for marketing a new test kit for diagnosis of herpes simplex virus (HSV) infection from clinical specimens. The new ELVIS HSV test kit, manufactured by Diagnostic Hybrids, Inc. of Athens, OH, identifies both herpes simplex virus type 1, which usually causes cold sores, and herpes simplex virus type 2, which usually causes genital herpes. Both HSV-1 and HSV-2 also may cause debilitating infections of the eye and nervous system. The ELVIS HSV test kit provides highly accurate results, and reduces significantly the time and labor required to isolate and detect the viruses from conventional cell cultures. When using the new test kit, the presence of infectious virus is indicated by a change in color when viewed through a light microscope. Is Prophylaxis for MAC Appropriate? It is still unknown whether prophylaxis (preventive treatment) for Mycobacterium avium complex (MAC) is preferable to close monitoring and aggressive treatment of the disease, according to researchers at Vanderbilt University. Some physicians have chosen to recommend rifabutin (Mycobutin) monotherapy to their patients with advanced AIDS (fewer than 100 CD4 cells/mm3) as preventive treatment for MAC, an opportunistic infection that affects a significant number of people with AIDS who have low CD4 counts. Two studies of rifabutin, the only drug FDA-approved for prophylaxis for MAC, suggest that the drug may prevent the disease, but neither study shows a survival advantage for the patients on rifabutin. The antibiotics azithromycin (Zithromax) and clarithromycin (Biaxin) have demonstrated efficacy against MAC, and may be useful for MAC prophylaxis alone or in combination with each other or with rifabutin. Abbott Laboratories recently applied for FDA approval of clarithromycin as primary prophylaxis for MAC. Rifabutin is manufactured by Adria Laboratories of Columbus, OH; azithromycin is manufactured by Pfizer, Inc, of New York, NY; clarithromycin is manufactured by Abbott Laboratories of Abbott Park, IL. Glaxo Will Pace Access to 3TC Due to the dramatic increase in requests for enrollment in its 3TC (lamivudine) expanded access program, Glaxo Wellcome, Inc. has decided to "pace" enrollment of new participants worldwide. "Pacing" means that some eligible candidates for the 3TC expanded access program will experience a delay in receiving the drug for several weeks. Since April 1995, the company has limited new enrollment in the 3TC expanded access program to 350 patients per week. In addition, until September 1995, when drug supply is expected to increase, only those applicants with fewer than 100 CD4 cells/mm3 and who meet other entry criteria will be eligible for the program. Physicians seeking to enroll patients will be required to submit recent laboratory reports indicating the applicant's CD4 cell count. Glaxo Wellcome says the company will continue to supply 3TC to people already enrolled in the expanded access program (approximately 16,000 individuals worldwide), as well as to supply adequate drug for ongoing studies of 3TC. Glaxo Wellcome is expected to apply to FDA for accelerated approval of 3TC in combination with AZT by July 1, 1995. For more information about enrollment in the expanded access program, physicians may call 1-800-248-9757. Glaxo Wellcome is headquartered in London, England. Its U.S. company is located in Research Triangle Park, NC. FDA Approves New Mepron Formulation for PCP In April 1995, FDA approved a new suspension formulation of Mepron (atovaquone) for the treatment of mild to moderate cases of Pneumocystis carinii pneumonia (PCP) in individuals who fail on trimethoprim-sulfamethoxazole (Bactrim, Septra and others). The new suspension formulation of Mepron produces plasma levels of the drug that are 58% higher than those produced by the tablet formulation. The recommended dose and schedule of Mepron suspension is 750 mg (one teaspoonful) twice daily with meals for 21 days. Adverse events from the new formulation are the same as for Mepron tablets: rash, nausea, fever and diarrhea. Results of a study published in the Annals of Internal Medicine (August 1, 1994) show that Mepron is less toxic than intravenous pentamidine for individuals with mild to moderate PCP. Mepron appears to be a safe and reasonably effective alternative for people with mild to moderate PCP who cannot tolerate sulfa drugs such as Septra and dapsone. Mepron suspension also is being studied as prophylaxis for PCP and as a treatment for toxoplasmosis and microsporidiosis. Mepron is manufactured by Glaxo Wellcome, Inc. FDA Approves First Hepatitis A Vaccine In February 1995, FDA licensed Havrix (inactivated hepatitis A vaccine), the first vaccine for the disease. Hepatitis A is a highly contagious virus that may cause acute, life-threatening liver disease. Infected individuals may experience fatigue, jaundice (yellowing of the skin and eyes), fever, nausea, vomiting, abdominal pain and loss of appetite. Respiratory symptoms, rash and joint pain also may occur. Millions of travelers develop the disease in visits to South and Central America, Africa, Asia, Eastern Europe, the Middle East and parts of the Caribbean. Gay and bisexual men also are at high risk for hepatitis A, primarily from oral/anal contact either directly (through unprotected rimming) or indirectly. There is no effective treatment for the disease, which runs its course in several weeks to several months. Hepatitis A is transmitted through intimate contact with infected individuals or through ingestion of contaminated food or water. Possible sources of infection include contaminated water, ice, fruit, salad and shellfish. Manufactured by SmithKline Beecham, Inc., Havrix was studied in 4 clinical trials, including a trial of 40,000 children in Thailand. To prolong protection from hepatitis A, a "booster" injection with Havrix is recommended 6-12 months after the initial shot. Havrix does not contain any human blood or plasma-derived components. The vaccine appears to be well tolerated. The most commonly reported adverse side effects are soreness at the injection site (56%) and headache (14%). The wholesale cost for the vaccination and the booster shot is $43.75 each. Merck and Company has also developed a vaccine for hepatitis A called VAQTA. In April 1995 the company submitted an application to FDA for licensing of VAQTA, culminating almost 20 years of research to find a safe, effective vaccine against hepatitis A. The company hopes for swift regulatory approval. As with SmithKline Beecham's Havrix vaccine, a booster shot is recommended (6-18 months after initial vaccination with VAQTA). SmithKline Beecham is located in Philadelphia, PA; Merck and Company is located in Rahway, NJ. Varicella-Zoster (Chicken Pox) Vaccine Now Available Merck and Company manufactures and has begun distributing Varivax, the first vaccine developed against chicken pox. Every year in the U.S. over 4 million people (mostly children) develop chicken pox, a disease that usually takes a mild course, but which can be debilitating and even fatal. Chicken pox is most threatening to infants and to adults with weakened immune systems, such as people with AIDS or people taking immune-suppressive medications. In people with advanced HIV disease (fewer than 200 CD4 cells/mm3), the varicella-zoster virus (VZV) that causes chicken pox in childhood may reactivate to cause herpes zoster (shingles). Herpes zoster is a painful condition that may be difficult to treat in people with AIDS. The most effective treatments are acyclovir (Zovirax) and the recently FDA-approved antiviral famciclovir (Famvir). It is unknown whether people with HIV infection who have never contracted chicken pox would benefit from vaccination with Varivax. However, it is probably appropriate for all HIV negative adults who have never contracted the disease to be vaccinated, because chicken pox is much more severe in adults than when contracted in childhood. Some pediatric AIDS researchers have expressed interest in clinical trials of Varivax for HIV positive children with relatively normal immune systems. Varivax appears to be 90% effective in preventing chicken pox. If the disease occurs in spite of vaccination, it takes a much milder course than without vaccination. Studies suggest that Varivax protects against chicken pox for 6-10 years. Merck and Company is located in Rahway, NJ. Fungal Infections and AIDS Nearly 40% of all deaths from hospital-acquired infections are due not to bacteria or viruses, but to fungi, according to a report by Steve Sternberg in Science magazine (December 9, 1994). The fungal agent most responsible is Candida, says Sternberg. In people with AIDS, fungal infections such as candidiasis, histoplasmosis, cryptococcosis and aspergillosis can represent a serious threat to life. Concerns have arisen about the ability of people with AIDS and other immunocompromising conditions to defend themselves against fungal infections. These include a lack of safe and effective drugs, drug resistance and the slow pace of research on new agents. Amphotericin B, the mainstay of therapy for life-threatening fungal infections, has severe adverse side effects that limit its usefulness. Resistance to anti-fungal drug therapy also has emerged, e.g., some HIV positive individuals are infected with fluconazole (Diflucan)-resistant strains of Candida. In addition, research into the development of vaccines for certain fungal infections such as cryptococcosis are not moving forward on a fast track. For more information on treatment for AIDS-related fungal infections, see p. 10 in this issue of BETA. New Recommendations for PCP Prophylaxis in Children Data from a study published in the New England Journal of Medicine (March 23, 1995) suggest that current guidelines for Pneumocystis carinii pneumonia (PCP) prophylaxis are not effective for infants at the highest risk for the disease. A working group convened by the National Pediatric HIV Resource Center and the Centers for Disease Control (CDC) recently has formulated new guidelines for PCP prophylaxis in children. The new recommendation is to start prophylaxis for all infants born to HIV positive mothers, beginning at 4-6 weeks after birth. The guidelines suggest discontinuing preventive treatment in infants who test HIV negative at 6 months, but to continue treatment throughout the first year of life for those who are HIV positive. The recent finding that AZT can significantly reduce perinatal transmission of the virus presents an excellent reason for voluntary HIV antibody testing of pregnant women during pregnancy, according to the PCP Prophylaxis Evaluation Working Group. Diagnosis of HIV infection in women prior to or during pregnancy enables them to receive health improvement services, and allows AZT to be prescribed to reduce the risk of HIV infection in their unborn children. Diagnosis of HIV infection also makes possible PCP prophylaxis for the child. Counselling and voluntary testing for HIV infection in pregnant women could be the most important step to prevent PCP in infants, according to the working group. Weak Immunity Causes PCP Prophylaxis Failure Investigators at Johns Hopkins School of Public health believe they know why PCP occurs in HIV positive individuals despite their use of preventive treatment. Current treatments to prevent PCP are successful if the patient's CD4 cell count stays above 75 cells/mm3, says the Johns Hopkins team that studied 476 HIV positive men taking 1 of 3 drugs for PCP prophylaxis: dapsone, trimethoprim-sulfamethoxazole (Bactrim, Septra and others) and aerosolized pentamidine (Aeropent). "Once the immune system deteriorates further, however, none of the current forms of treatment is able to stave off P. carinii infections," according to Donald Hoover, PhD. The Johns Hopkins study appears in the Journal of the American Medical Association (April 19, 1995). Hoffmann-La Roche Postpones Genentech Takeover After paying $2.1 billion in 1990 for controlling interest in South San Francisco-based Genentech, Inc., Swiss pharmaceutical giant Hoffmann-La Roche (Roche) has opted not to buy out the remaining shares of the pioneer biotechnology firm, according to a report by Carl Hall in the San Francisco Chronicle (May 2, 1995). Instead, Roche has negotiated a 4-year "buyout option," an agreement that links Roche more closely with the biotech company, but allows Genentech to continue operating independently. The move also saves Roche about $2.3 billion it would otherwise have to spend to acquire the remaining Genentech shares. The new agreement gives Roche exclusive marketing rights outside the U.S. to Genentech's most promising new drugs, according to Hall. Both companies' primary drug development interests lie outside the AIDS drug market, but both have developed treatments for HIV infection and AIDS-related illnesses. Roche manufactures 6 drugs used in the treatment of HIV infection and AIDS: Bactrim, an antibiotic used as a first-line treatment for PCP prophylaxis and treatment; ddC (Hivid) and saquinavir (a protease inhibitor drug in Phase III trials), both antivirals for HIV infection; ganciclovir (Cytovene), an antiviral for cytomegalovirus (CMV) disease originally developed by Syntex Corporation (a biotech firm also recently acquired by Roche); and interferon alfa-2a (Roferon-A), for Kaposi's sarcoma. In addition, Roche is developing interleukin 12, a recombinant cytokine that has shown early promise as an AIDS and cancer therapy. Genentech manufactures Protropin, a genetically engineered human growth hormone that is FDA-approved for the treatment of dwarfism in children, but which may also be beneficial for AIDS-related wasting. A nearly identical recombinant human growth hormone has been developed for AIDS wasting by Serono Laboratories. Genentech also has developed a recombinant human nerve growth factor, a drug that may be useful in the treatment of the nerve damage caused by peripheral neuropathy, a common (and painful) condition among HIV positive individuals. Genentech recently ran afoul of AIDS activists when the company said it would stop supplying the drug for a government-sponsored study (ACTG 291) of its use for HIV-related neuropathy. After a national media blitz of Genentech officials coordinated by ACT-UP Golden Gate in San Francisco, the company relented and agreed to resupply the drug for the study. Hoffman-La Roche is headquartered in Basel, Switzerland; its U.S. company is located in Nutley, NJ. Genentech is located in South San Francisco, CA. Dronabinol (Marinol) for Anorexia and Poor Appetite in AIDS Dronabinol (Marinol), a drug derived from tetrahydrocannabinol (THC, the active ingredient in marijuana), produces significantly greater improvements among patients in appetite and nausea than placebo. These results emerged from a 6-week trial of the drug in 139 patients at 18 medical centers in the U.S. The patients on Marinol (2.5 mg twice daily) also showed a trend toward greater weight stabilization, according to a study published in the Journal of Pain Symptom Management (February 1995). Side effects from Marinol may include euphoria, dizziness, thinking abnormalities and sleepiness. The retail cost for 5 mg Marinol tablets from Walgreen's Pharmacy in San Francisco is $7 per tablet. Marinol tablets are manufactured by Unimed, Inc. of Somerville, NJ. Roxane Laboratories of Columbus, OH is licensed to market and distribute Marinol. Thalidomide and Weight Gain As outlined in previous issues of BETA, the drug thalidomide is now under investigation for the treatment of tuberculosis and a variety of HIV-associated conditions, including aphthous ulcers, HIV infection and wasting syndrome. Recently published results of a small, placebo-controlled, 2-week study at Rockefeller University in New York City suggest that daily use of thalidomide (300 mg daily at bedtime) produces significant weight gain in people with tuberculosis and HIV infection (Molecular Medicine. May 1995). Although the researchers did not measure whether weight gain was due to increased muscle, water or fat, they said they did not believe it was from water retention. For a detailed report on new studies of thalidomide, see p. 57 of Research Notes in this issue of BETA. "Underground" Thalidomide Compassionate Use Program The Healing Alternatives Buyers Club in San Francisco and the PWA Health Group in New York City are now selling thalidomide produced in Brazil to individuals for about $27 per ten 100 mg tablets. Buyers are limited to a maximum of 20 tablets per prescription. (The Rockefeller University study used cycles of 300 mg/day for 7 days followed by 7 days off drug). Using their dosing schedule, a month's supply of thalidomide would cost approximately $50. FDA is concerned that "underground" thalidomide may end up in the bodies of women of childbearing age. In the 1950's, thalidomide caused severe birth defects in the infants of women who were taking the drug as a sedative and for morning sickness. As a direct result of the thalidomide disaster, FDA dramatically increased its oversight of all drug manufacturing and testing. To receive thalidomide from an AIDS buyers' club, consumers must first obtain from the buyers' club a consent form and a brochure that discusses the potential toxicities of the drug. The next step is for the potential user to see his/her doctor to discuss the toxicity brochure and to sign a statement contained in the brochure to the effect that toxicity concerns have been discussed with the physician. Next, the consent form must be signed by the patient and physician. Finally, the patient obtains a written prescription for thalidomide from the physician and brings it along with the other 2 documents to the buyers' club. For complete information on obtaining thalidomide, call Healing Alternatives at 415-626-4053 (12-6 pm Tuesdays through Fridays and 12-5 on Saturdays, Pacific Time). In New York City, call the PWA Health Group at 212-255-0520. FDA has contacted both the San Francisco and New York buyers' clubs to warn them not to sell thalidomide. The agency also has invited representatives of both groups to attend a meeting in June at FDA to discuss the thalidomide situation. Matthew Sharp, manager of the Healing Alternatives Buyers' Club, told BETA: "If FDA agrees to establish a compassionate use program that provides thalidomide to people with wasting, we'll gladly stop selling the drug ourselves." Gallo To Leave NCI to Head Virus Study Center Robert Gallo, the government's best known and most controversial researcher, announced in May that he will leave the National Cancer Institute (NCI) after a career spanning 30 years. Gallo said he will head the new Institute of Human Virology in Baltimore, funded by a $12 million commitment from the state of Maryland. The Institute, planned as a new addition to the University of Maryland system, will focus on the study of viruses, in particular HIV. In an interview with USA Today, Gallo said, "AIDS is the primary target. There will be vaccine research We'll continue to study viruses related to cancer and we'll include some herpes virology." Joining Gallo at the new Institute will be epidemiologist William Blattner, MD, also from the NCI, and clinician Robert Redfield, MD, of the Walter Reed Army Research Institute. A number of people currently working in Gallo's NCI laboratory will also leave their government jobs to join Gallo in Baltimore. The Institute will conduct basic research, but will also operate a large treatment clinic, Gallo said. Medical Marijuana The California state Assembly passed a medical marijuana bill in May 1995 that allows people with AIDS, cancer, glaucoma and multiple sclerosis to grow and use marijuana with their doctor's approval. Many physicians treating these illnesses have long considered marijuana a valuable, effective and relatively inexpensive treatment for loss of appetite, nausea, muscle spasms, pain and the intraocular pressure that causes glaucoma. A similar bill passed by the Senate several years ago was vetoed by California Governor Pete Wilson. Wilson appears to be on the verge of announcing his candidacy for the Republican nomination for President of the United States. Political pundits say he likely will veto the bill once again. Human Growth Hormone (Serostim) T-IND Progress Report Results of a multicenter Phase III study among people with AIDS-related wasting demonstrate that human growth hormone (Serostim) produces significant weight gain as measured by lean body (muscle) mass (see BETA. September 1994. p. 10). Serostim also appears to provide a quality of life benefit to people with AIDS-related wasting syndrome. After reviewing the Phase III data, FDA granted Serono Laboratories a cost recovery Treatment Investigational New Drug (T-IND) for Serostim in February 1995. This FDA action allows Serono to charge $25 per milligram for the drug ($150 per day, $1,000 per week). A course of treatment involves daily injections for at least 3 months. There is no medical consensus on how often to use the drug after the initial 3 months of therapy. More than 400 individuals with AIDS have received Serostim through participation in studies of the drug. To date more than 110 people with AIDS-related wasting have started using Serostim, and over 260 people with wasting are "in the process" of enrolling in the expanded access program (T-IND), according to Gina Cella, communications director for Serono. About 100 patients have received full or partial assistance through the company's indigent patient program, which was established to provide drug for those with inadequate or no insurance coverage for Serostim. AIDS activists have criticized Serono strongly and repeatedly for not enrolling more people with AIDS-related wasting in the program for indigent patients. Proponents of Serostim point out that its ability to increase muscle mass with concomitant weight gain and a reduction in body fat makes it uniquely beneficial for people with wasting. Detractors say that Serostim's high cost makes it an impractical treatment for many if not most people with AIDS. In addition, they point out, the drug has not been shown to increase survival time among people with wasting. Serono has established a toll-free information hotline for patients, physicians and other caregivers. For more information on reimbursement issues and enrollment in the T-IND, call 1-800-714-2437. DOX-SL for Kaposi's Sarcoma BETA reported on the assessment of a study of DOX-SL by FDA (BETA. March 1995. p. 75). After analyzing data from 77 patients with an average CD4 cell count of 10 and advanced KS, FDA released a strongly negative press report on the drug's anti-KS activity. The agency said the data show that only 6 of 77 patients with advanced AIDS and KS experienced "some clinical benefit" from DOX-SL therapy. However, the drug's sponsor, Liposome Technology, presented a sharply different view of the same data. The company contends that 68% of those on drug showed at least a partial response rate (FDA found only a 27% partial response rate). Liposome Technology's presentation to FDA's Oncologic Drug Advisory Committee also emphasized DOX-SL's favorable safety profile compared to standard chemotherapy and its favorable impact on quality of life. The FDA Oncology Advisory Committee has recommended that DOX-SL receive accelerated approval, with the provision that the drug be evaluated in postmarketing studies. If FDA accepts the advisory panel's recommendations, DOX-SL could be available by prescription sometime in June 1995. Liposome Technology is located in Menlo Park, CA. AG-1343: Agouron's Protease Inhibitor Agouron Pharmaceuticals, Inc. of La Jolla, CA reports encouraging preliminary results from a Phase II pilot study in Great Britain of its oral protease inhibitor drug, AG-1343. In a small study of 8 people taking 300 mg AG-1343 three times daily the drug appears to be well-tolerated and active against HIV. The highest level of anti-HIV activity among study participants occurred in one patient whose viral burden (HIV load) dropped more than 99% (more than 2 logs) over 28 days with an accompanying increase of 116 CD4 cells/mm3. AG-1343 may be most useful in combination with another protease inhibitor and 1 or 2 of either: AZT; 3TC; d4T; nevirapine and other antiretrovirals. The drug shows reasonably good bioavailability (about 80%), and is best absorbed when taken with food. No significant adverse events have been reported by study volunteers, nor has the company noted any laboratory abnormalities at the doses studied (up to 900 mg/day). In addition, there have been no significant problems encountered in producing AG-1343. Relative ease of drug manufacturing usually translates into lower production costs and lower drug cost for consumers following approval for marketing. Agouron is now planning a Phase II/III study among antiretroviral- naive patients on 2 different doses of AG-1343 in combination with d4T. If, as expected, the AZT/3TC combination is approved for marketing by FDA this summer, Agouron intends to test AG-1343 as part of a triple combination with those agents as well. The company hopes to apply for accelerated approval of AG-1343 in 1996. The company already has begun discussions with community activists and treatment advocates regarding a compassionate use program for AG-1343 among people with AIDS and fewer than 50 CD4 cells/mm3. Convulsions From Kwell Scabies Treatment Due to the risk of drug-related seizures (convulsions), all HIV positive individuals should avoid using lindane (Kwell) for the treatment of scabies, according to a report in the Journal of Family Practice (March 1995). Doctors in Brooklyn, New York, described the case of an HIV positive man on Thorazine (for psychosis) who had no prior history of seizures. After a single application of Kwell to his skin for scabies, the patient developed a seizure lasting 30 minutes. Blood levels of Kwell were twice the toxic level 18 hours after his seizures. It has been noted that seizures occur over 5 times as often among HIV positive individuals than among those who are HIV negative. Topical lindane (Kwell) cream or lotion is the standard treatment for scabies. However, when absorbed through the skin, Kwell can affect the brain, causing effects such as drowsiness and convulsions. Kwell-related seizures also have been reported among HIV negative individuals, primarily infants, children and the elderly, or when the drug was not used properly. See Research Notes on page 60 for more information on Kwell-related seizures. Topical permethrin (RID, Elimite) for scabies is a safe and effective alternative to Kwell and carries no risk of causing seizures among HIV positives. ------------------------------------------------------------------ Treatment for HIV-Related Fungal Infections Leslie Hanna Leslie Hanna is Associate Editor of BETA. HIV positive individuals, in particular those with advanced HIV disease, are vulnerable to a host of infections caused by viruses, bacteria, protozoa, multicellular parasites and fungi. Fungal infections, in contrast to viral infections, are treatable with antibiotics, which inhibit some of the biochemical processes of the relatively simple fungal organisms. Of at least 100,000 known species of fungi, about 200 are known to cause disease in humans, and about 20 are considered capable of causing life-threatening infection. Fungi are widely found in nature in soil, animal (particularly bird and bat) excrement and the bark of some trees. Many fungi enter the body through inhalation. Others enter through breaks in the skin due to trauma (punctures or lacerations), burns, indwelling catheters (at the point of insertion) or surgery. Still other fungi (like Candida) commonly reside on and in healthy humans, on the skin and mucocutaneous surfaces in the mouth, gastrointestinal and reproductive tracts. Although many fungi have the potential to cause disease, few do so in people with relatively intact immune systems, for whom fungal infections may be bothersome but rarely serious. Athlete's foot (tinea pedis), caused by the fungal dermatophytes Trichophyton and/or Epidermophyton, is usually a relatively benign fungal infection. Vaginal candidiasis, caused by the yeast-like fungus Candida, is common in all women but does not usually cause serious disease. Mild or moderate mucous membrane or skin infections with Candida occur in several settings in addition to HIV: anemia, diabetes, the neonatal state and as a result of antibiotic or steroid therapies. Pregnancy increases women's risk for certain fungal infections. As immune function declines in an HIV-infected person, the risk of complicated or serious fungal conditions increases. Fungal infections such as oral candidiasis may be symptomatic of early-stage HIV disease progression. Esophageal candidiasis, an AIDS-defining condition, indicates more advanced HIV disease. For debilitating fungal disease, those at highest risk are people with AIDS and fewer than 100 CD4 cells/mm3 (as well as transplant recipients, diabetics, people receiving long-term antibiotic treatment or cancer treatment and those with severe burns). In these people, fungi may cause disease when a damaged immune system fails to keep their numbers in balance and permits fungal overgrowth. Proliferating resident fungi may enter the bloodstream and access multiple tissues and organs. Or, spores from inhaled fungi grow and proliferate in the hospitable environment of the lungs and, from there, gain access to the bloodstream and to virtually any organ. Dissemination throughout the body, uncommon in people with intact immune systems, may follow initial pulmonary (lung) infection in severely immunosuppressed HIV positive individuals. The following HIV-associated fungal infections will be discussed in this article: mucocutaneous candidiasis, cryptococcosis, histoplasmosis, coccidioidomycosis, aspergillosis and blastomycosis. Complications from these conditions range from mild discomfort to severe debilitation and death. Other fungal infections, including some that are less common or less invasive, will also be discussed. Candidiasis Candidiasis is most commonly caused by the yeast-like fungus Candida albicans. Other strains of Candida (C.) including C. glabrata, C. parapsilosis, C. tropicalis and C. krusei also cause disease. Candida are ubiquitous organisms, found in soil, food and hospitals. Skin and mucosal surfaces in all humans, regardless of their HIV status, are frequently colonized with Candida. In people with HIV, colonization levels of Candida in the mouth may rise as CD4 levels fall. However, rising colonization rates are not directly associated with the development of symptomatic disease. Other factors, such as the flow rate and constituents of saliva, and immune factors, determine a disease state. Mucocutaneous candidiasis refers to Candida infection of the skin and mucosal tissues in the body (e.g., mouth, throat, anus and vagina), and is extremely common in people with HIV. Since the presence or even a history of candidiasis (oral, vaginal or rectal) may indicate changes in immune status, some experts recommend that a thorough examination of a person with HIV include the mouth, skin, rectum and genitalia. Candida lesions usually appear as red tender patches in the groin, armpit or inframammary areas. In men, Candida can produce balanitis (inflammation of the glans penis) and distal urethritis. Candida can also produce acute or chronic paronychia (inflammation and redness of the skin around the nails). Oral candidiasis has been estimated to occur in up to 90% of men and women with HIV/AIDS. Since it is associated with CD4 cell deficiency, oral candidiasis is regarded as a marker for HIV disease progression. ("Oral" refers here to the mouth and the back of the throat.) It is more common and recurrent among people with advanced HIV disease, occurring in up to 60% of those with fewer than 200 CD4 cells/mm3. A recent Centers for Disease Control and Prevention (CDC) study in HIV positive men found that cigarette smoking increased the likelihood and rate of development of oral candidiasis, as well as of hairy leukoplakia and bacterial pneumonia. Symptoms of oral candidiasis are similar at early and later stages of HIV disease. While infection in some people is asymptomatic, burning pain, altered taste and difficulty swallowing (dysphagia) may occur. There are 4 types of oral candidiasis: 1. pseudomembranous (thrush), characterized by painless white spots on the tongue, gums, membranes of the inner cheek and/or throat. Plaques (spots) are composed of dead or dying tissue and are easily removable. 2. acute atrophic (erythematous), manifested in red patches on the tongue, gums and buccal membranes (inner cheeks). 3. chronic atrophic (e.g., angular cheilitis), signified by white or red fissures at the corners of the mouth, and 4. chronic hyperplastic candidiasis (leukoplakia). Leukoplakias are chronic, well-defined lesions of different sizes and appearances that cannot be removed by scraping. Candidiasis of the esophagus occurs in 10-20% of HIV positive people in the U.S., and in as many as 80% of people with AIDS living in the Third World. The esophagus is the portion of the gastrointestinal tract that links the pharynx to the stomach. In U.S. studies, women of all races and African-Americans appear to have higher incidence rates of esophageal candidiasis than men and Caucasians, respectively. (This is likely due to the high rates of Kaposi's sarcoma that are reported as the AIDS-defining condition in gay and bisexual men with AIDS in the U.S., a trend also observed in other developed countries.) As many as 40% of people with esophageal candidiasis experience no symptoms; however, ulcers and erosions on the esophagus commonly cause odynophagia (esophageal pain on swallowing) or dysphagia (general difficulty in swallowing). Sudden severe dysphagia in a person with oral candidiasis may indicate esophageal involvement, and eating solids may be difficult. Vaginal candidiasis is a frequent complication among HIV positive women, and may be a first indicator of immune dysfunction. Vaginal candidiasis usually is characterized by a creamy white vaginal discharge, although there may be marked swelling with scant discharge. Itchiness, burning and dyspareunia (painful sexual intercourse) may accompany the infection. Examination may reveal vaginal erythema (redness) and white plaques. Treatment for candidiasis Treatment with antifungal agents is usually successful for localized infection (e.g., oral, vaginal). A group of drugs referred to as the azoles are most commonly used. Used for a wide range of fungal infections, the azoles work by inhibiting the formation of ergosterol, a protein in fungal cell membranes. There are 2 classes of azole drugs, the imidazoles and the triazoles: the imidazole class is the original class, and includes clotrimazole (Lotrimin, Mycelex), miconazole (Monistat) and ketoconazole (Nizoral); the newer class of triazoles includes fluconazole (Diflucan) and itraconazole (Sporonox). For external Candida infection of the skin and/or nails, treatment includes drying out wet areas and applying antifungal powders (nystatin) and creams (clotrimazole). If topical (local) agents do not clear the infection, 100-200 mg of oral fluconazole daily for at least 14 days may be tried. For onychomycosis (fungal infection that causes nails to thicken and split) and paronychial (skin at the base of nails) infections, oral agents such as griseofulvin at 500 mg daily for at least 6 months are usually needed. Other regimens include pulsed itraconazole or ketoconazole therapy. Oral candidiasis may be treated locally (with troches or suspensions) or systemically (relating to the entire body, as with oral drugs); there are a variety of options [see chart on following page]. Troches (lozenges containing drug that are held in the mouth until dissolved) may be preferable to suspensions (liquid formulations). Systemic therapy is usually reserved for nonresponsive or noncompliant individuals. Symptoms generally begin to resolve within 7 days of beginning treatment. Studies comparing the efficacy of topical to systemic therapy suggest that clinical response rates are similar, although relapses occur more quickly and recurrences are found more often in those receiving topical treatment. Refractory (resistant to treatment) oral candidiasis necessitates systemic therapy. Studies indicate that fluconazole is superior to ketoconazole, which has similar efficacy to itraconazole. One advantage of fluconazole is that, unlike the other 2 agents, stomach acidity does not affect its absorption. Systemic antifungal therapy is required for esophageal candidiasis. Ketoconazole, itraconazole and fluconazole are all effective, although studies have suggested a slight superiority of fluconazole, compared to ketoconazole. For advanced disease, treatment with systemic amphotericin B (20-30 mg/day for 7-14 days) may be required. Considered the gold standard of antifungal therapy, amphotericin B, a broad-spectrum antifungal, is the only agent indicated for severe, life-threatening fungal infections. The standard formulation requires intravenous (IV) administration. At higher CD4 cell levels, even recurrent episodes of vaginal candidiasis respond well to local treatment. For vaginal candidiasis, topical agents (intravaginal creams or troches) are more or less equally effective. According to Judith Feinberg, MD, of Johns Hopkins University, if a standard topical therapy course fails, short-dose ketoconazole or fluconazole should be tried next. Several studies are underway for the treatment of candidiasis. A Phase II/III open-label safety and efficacy trial of an oral suspension formulation of fluconazole for the treatment of esophageal candidiasis is ongoing. Two Phase III trials involving itraconazole are also ongoing; an open-label safety and efficacy study for refractory oropharyngeal candidiasis (infection that extends through the mouth into the back of the throat) gives 100 mg oral itraconazole twice daily. The other study compares 2 doses of oral itraconazole to oral fluconazole (3 arms, randomized, double-blind). There also are ongoing trials of treatment and prophylaxis for vaginal candidiasis (see "Open Clinical Trials," p. 86). Prophylaxis for candidiasis Several small studies have examined the use of fluconazole to prevent recurrences of Candida (secondary prophylaxis). Antifungal prophylaxis with fluconazole, which one survey reported is routinely used by as many as 30% of HIV physicians, is fairly common in the U.S. There is no consensus on the appropriateness of prophylaxis to prevent recurrent mucosal candidiasis (oral, vaginal). Rather than recommending routine prophylaxis, some researchers have suggested that well-informed patients manage their recurrent candidiasis by having on hand a ready supply of antifungal medications in order to begin treatment as soon as symptoms appear. Candidates for prophylaxis may include people with frequent recurrences and those with complications of esophageal disease that result in malnutrition. For further discussion of antifungal prophylaxis and resistance, see the concluding section of this article. Cryptococcosis Cryptococcus neoformans, the organism that causes cryptococcosis, is a yeast-like fungus that is a significant cause of illness and death in people with AIDS. Of the 2 varieties of Cryptococcus neoformans, one (known as the neoformans variety) is ubiquitous, found in soil and the excrement of pigeons and other birds worldwide. The other type, known as the gattii variety, is found in warm climates in the bark of eucalyptus and red gum trees. AIDS-related cryptococcosis is almost exclusively due to infection with the neoformans variety. Even in regions where the gattii variety is found and where HIV negative people develop infection with it (e.g., California, Africa and Australia), cryptococcosis in HIV-infected persons is caused by the neoformans variety. Cryptococcosis is the most common life-threatening fungal infection in people with AIDS, and is mainly attributed to newly acquired (primary) infection, rather than to reactivation of a previous, latent infection. In people with AIDS, widespread dissemination of the infection to other areas of the body may follow initial pulmonary infection. Symptoms of initial pulmonary infection may resemble those of Pneumocystis carinii pneumonia (PCP) (such as coughing, fever, fatigue and shortness of breath). However, the first noticeable symptoms usually occur after infection has spread from the lungs to other sites in the body. The central nervous system (CNS) is particularly vulnerable to these fungi. Approximately 70-90% of people with AIDS and cryptococcosis develop meningitis, an inflammation of the meninges, the tissues that encase the brain. Cryptococcal meningitis is the third most common CNS disorder in people with AIDS, following toxoplasmosis and CNS lymphoma. Usually, cryptococcosis presents as low-grade meningitis. Fever, headache and mild central ataxia (difficulty with muscle coordination) are early symptoms. There also may be impairment of higher nervous system functions, such as short-term memory and concentration. Malaise, nausea and vomiting also may occur. Lethargy, personality changes, photophobia (abnormal sensitivity to light) and memory loss, overt symptoms of meningitis or brain disease, are far less common. The organism can also infect the liver, skin, lymph nodes, adrenal glands, bones, genitourinary tract, kidneys and prostate gland. Cryptococcal infection may cause skin lesions similar to molluscum contagiosum. The whitish, umbilicated papules (small, defined elevations on the skin) usually appear in groups, on the face. Cutaneous (relating to the skin) cryptococcosis always indicates systemic infection. According to Michael Saag, MD, of the University of Alabama, cryptococcosis is the fourth most common and serious opportunistic infection (OI) in people with AIDS, following PCP, cytomegalovirus disease (CMV) and mycobacterial disease (Mycobacterium avium complex, tuberculosis). Approximately 6-10% of people with AIDS will develop cryptococcosis; it is the initial AIDS-defining illness in 40-45% of those individuals. Infection usually develops among HIV-infected persons with fewer than 100 CD4 cells/mm3. The combination of cryptococcosis and other OI, especially PCP, is fairly common in people with AIDS, occurring in 15-35%. Treatment for cryptococcosis The main treatment objectives for people with AIDS and cryptococcosis are to control infection, decrease early mortality, prevent relapse and maintain quality of life. Amphotericin B is the standard initial treatment for cryptococcal meningitis. Combination amphotericin B and flucytosine, the regimen generally prescribed for treating HIV negative people, involves considerable toxicity. Amphotericin B, a broad-spectrum yet highly toxic antifungal, causes side effects ranging from nausea and vomiting to permanent kidney damage. Amphotericin B also causes toxicity to the bone marrow, and penetrates the cerebrospinal fluid slowly. Flucytosine is a limited-spectrum antibiotic that is effective against certain strains of Cryptococcus. It causes toxicity to the bone marrow, liver and gastrointestinal (GI) system. For people with HIV who are already taking medications such as AZT that cause bone marrow toxicity, or experiencing HIV-related GI disturbance, the toxicity incurred with the standard combination of amphotericin B and flucytosine may be problematic. Thus, other regimens and formulations (of amphotericin B) are under study for HIV-related treatment. Currently, William Powderly, MD, of the Washington University School of Medicine in St. Louis, MO, recommends giving patients initial amphotericin B (0.7 mg/kg) daily plus flucytosine for 2-3 weeks, followed by therapy with either fluconazole or itraconazole (400 mg daily) for an additional 8-10 weeks. He also recommends using strategies to relieve the intracranial pressure that often accompanies cryptococcal meningitis, including intracranial shunts, lumbar punctures or drains. Lisa Bardaro, MD, a physician in San Francisco, recommends using 0.3 mg/kg/day of amphotericin B without flucytosine in HIV positive people, because the toxicity involved in the standard combination causes diarrhea and leukopenia. Different formulations of amphotericin B (lipid complex, colloidal dispersion and liposomal forms) are under investigation for use as treatments, as are the use of higher doses of fluconazole and itraconazole, and combinations of fluconazole and/or itraconazole with flucytosine. Life-long maintenance therapy is required for AIDS-related cryptococcosis. Fluconazole is the maintenance treatment of choice. Currently underway is ACTG 202, a Phase II double-blind trial of amphotericin B plus flucytosine, plus fluconazole with or without IV dexamethasone, for the treatment of cryptococcal meningitis. Another ongoing cryptococcal meningitis trial is a Phase I double-blind dose-escalating trial of the safety and pharmacokinetics of an experimental drug called RMP-7, plus amphotericin B (all agents are given intravenously). Finally, a cryptococcal prophylaxis trial is ongoing; the Phase II trial evaluates the safety and efficacy of oral fluconazole plus oral flucytosine for primary prevention of cryptococcosis. Prophylaxis for cryptococcosis Fluconazole has been under consideration for use as a prophylactic agent to prevent initial episodes of cryptococcosis, but whether or not this use is appropriate is not yet clear. There are anecdotal reports of fluconazole prophylaxis failures. There is also insufficient data on important questions about optimal dosing, contraindications and antifungal resistance. A recent study from Yale tentatively concluded that while fluconazole prophylaxis may reduce the risk of primary cryptococcal meningitis, the risks, costs and benefits of the strategy need to be evaluated within subgroups and geographic regions (Quagliarello and others). Studies have indicated that, for people with fewer than 50 CD4 cells/mm3, 200 mg/day of fluconazole decreases the incidence of both cryptococcosis and candidiasis. An abstract submitted by Dr. Powderly to the Fifth Focus on Fungal Infections conference in San Francisco in March states that "the incidence of cryptococcosis is relatively low, the attributable mortality ... is low and there is no survival benefit associated with fluconazole use; furthermore, there is a risk of selecting fluconazole-resistant Candida." He suggests the use of selective criteria rather than routine prophylaxis for all people with HIV. For example, candidates might be persons with positive cryptococcal antigen tests of the blood or cerebrospinal fluid. Histoplasmosis The agent that commonly causes histoplasmosis, Histoplasma capsulatum, is found worldwide but is endemic in the Americas. In the U.S., infection is found primarily in the Mississippi and Ohio river valleys, where the fungus grows in bird and bat excrement (in roosts, coops and caves). It also grows in soils mixed with manure (again, particularly bird and bat). The fungus produces spores that, when inhaled, convert to the yeast form in the lung. Infection can spread to the spleen, bone marrow and liver. In healthy individuals, the immune system mounts an intense defense and usually inhibits or kills the fungus; immune responses in people with intact immune systems usually limit infection to a mild respiratory illness. Histoplasmosis is a fairly common AIDS-related infection in areas where the organism is endemic. Infection in persons living outside endemic areas is mainly attributed to reactivation, whereas infection in persons living in endemic areas is usually due to new (primary) infection. Clinical features and diagnosis Infection may be mild and asymptomatic or severe, and appears to be related to the actual number of spores inhaled. Symptoms range from those of a cold to a severe flu, again in relation to the dose inhaled. AIDS-associated histoplasmosis usually presents as a disseminated infection characterized by fever and weight loss. Approximately half of people treated report respiratory symptoms. Swelling of the lymph nodes and liver, as well as lesions or ulcers of the mouth, skin and colon also have been reported; about 10% of people with disseminated histoplasmosis develop skin lesions. CNS involvement is rare. Individuals with histoplasmosis may also have anemia (low levels of red blood cells), neutropenia (low levels of a type of white blood cells called neutrophils) or thrombocytopenia (low levels of blood platelets, involved in clotting), and raised levels of liver enzymes. The CD4 cell count is usually below 100 cells/mm3. Treatment Amphotericin B (0.5-1.0 mg/kg/day) is associated with an overall response rate of 85-90% with disseminated histoplasmosis. Oral itraconazole at 400 mg/day was preliminarily shown in one study of patients with non-life-threatening histoplasmosis to have an efficacy rate of about 85%. Comparative data are not yet available for complicated cases, thus, amphotericin B is still the drug of choice. Itraconazole at 400 mg/day is now regarded as the maintenance treatment of choice, after an ACTG study showed that it was highly effective when used after primary therapy with amphotericin B. At standard doses, fluconazole appears to be less effective than itraconazole. An ongoing histoplasmosis prophylaxis trial is randomizing participants to receive either 200 mg daily itraconazole or placebo. Coccidioidomycosis Coccidioides immitis, the organism that causes coccidioidomycosis, lives in the soil in certain regions of the Americas. Generally, Coccidioides immitis is considered endemic to the southwestern U.S., and infections are increasingly common in residents of and visitors to Arizona, New Mexico, southern California and western Texas. An estimated 100,000 cases occur annually in the U.S. Coccidioidomycosis ranges from asymptomatic to severe and disseminated. Disseminated infection is most common in immunocompromised people. Pregnant women and non-Caucasians, particularly Filipinos and those of Filipino descent, appear at increased risk relative to nonpregnant women and Caucasians. As with many other fungi, infection results after spores are inhaled. The spores grow in the lungs, forming large structures called spherules and causing inflammation. Pregnancy levels of female sex hormones stimulate the growth of the organism, and are thought to render pregnant, nonimmunocompromised women extremely susceptible to infection. Pregnant women with HIV are at additional risk for infection. Many people with relatively intact immune systems show no signs of infection or have symptoms of an upper respiratory illness. As immune function declines, symptoms are more likely to occur. Fever, weight loss, cough and shortness of breath, the most common symptoms, tend to develop within 1-3 weeks after exposure. Swollen lymph glands, skin ulcers and peritonitis (inflammation of tissue lining the abdominal cavity) also may occur. Sites of infection in disseminated disease are the meninges, bones and joints, skin and soft tissues, e.g., the eye. Subacute or chronic meningitis occurs in about 10-12% of patients. A small number of people have lung disease only. HIV positive people may develop a very serious form of coccidioidomycosis. HIV-related disease appears to occur both by primary infection as well as through reactivation of previously acquired infection. For exposed HIV positive residents of endemic areas, risk of active illness is estimated at greater than 10%. People with fewer than 250 CD4 cells/mm3 are considered at increased risk. Treatment for coccidioidomycosis Amphotericin B is the current treatment of choice. Cerebrospinal fluid leukocyte counts and antibody titers may help monitor treatment response. Prolonged maintenance therapy is warranted, for which the azoles are usually used. Preliminary data suggest a high rate of relapse with the azole drugs after therapy is stopped (about 75%), but the ease of using oral drugs may make life-long suppression with azoles preferable to the toxicities and difficulties associated with use of amphotericin B, especially for people with HIV. Breakthroughs have occurred with ketoconazole, an oral azole that is approved for treatment. Other azole antifungals currently not FDA-approved for treatment of this fungal infection (fluconazole, itraconazole) are being evaluated as primary treatments. The National Institute of Allergy and Infectious Diseases (NIAID) Mycosis Study Group (MSG) recently published results of a trial of fluconazole for chronic pulmonary or nonmeningeal coccidioidomycosis. Participants included 78 adolescents and adults with coccidioidomycosis, 7 of whom were HIV-infected. (Investigators note that the number of HIV-infected people was too small to detect significant differences from the group overall.) Doses ranged from 200-400 mg/day. Overall, the drug was well tolerated and effective for these indications, but the relapse rate after treatment (37%, or 15 of 41 people prospectively followed) was high, suggesting that higher treatment doses be tried. Currently, a trial is ongoing to comparatively evaluate fluconazole with itraconazole as initial treatment for nonmeningeal coccidioidomycosis. A phase II trial that randomizes participants to receive fluconazole or placebo for coccidioidomycosis prophylaxis is also ongoing. Aspergillosis Fortunately, aspergillosis is rare in AIDS, usually occurring in people with advanced HIV disease and other specific risk factors such as neutropenia, steroid use and/or alcoholism. As with many fungal diseases, infection follows inhalation of spores. Most people with AIDS and aspergillosis begin with lung disease which disseminates to many sites throughout the body. Infection of the brain and sinuses is possible, and cutaneous manifestations may also appear. Aspergillus grows in soil and decaying vegetation. It also has been found growing on moldy marijuana and on Kombucha mushrooms. The organism may be inhaled while smoking marijuana, which some people with HIV do to increase appetite and/or decrease nausea. A letter in the Annals of Internal Medicine suggests baking marijuana at 300 degrees F. in an oven for at least 15 minutes in order to kill the fungi without losing the benefits of the marijuana. Kombucha mushrooms have been promoted as a natural anti-HIV treatment in some alternative circles, and anecdotally, a considerable number of persons with HIV have experimented with them. Aspergillosis should be added to the list of concerns about the mushrooms' use by people with HIV. Gastrointestinal disturbances and mushroom-associated yeast infections also have been reported. Treatment for aspergillosis The standard therapy for invasive infection is amphotericin B at 1.0 mg/kg/day, but the prognosis is poor. Amphotericin-B lipid complex, a formulation made by the Liposome Company, has been approved for the treatment of invasive aspergillosis. Oral itraconazole is being evaluated as an alternative treatment for people intolerant of amphotericin B, and as a suppressive treatment. A multicenter study of itraconazole vs amphotericin B for invasive infection in both HIV negative and HIV positive people is underway through the Mycosis Study Group (MSG 21). Blastomycosis Blastomycosis is caused by the fungus Blastomyces dermatitidis. Even in endemic areas such as the midwestern U.S., infection is rare. Studies suggest that male sex hormones may increase susceptibility to this infection. In studies in mice, the severity of infection depended upon several factors including the virulence of the strain, which varies greatly. In addition, the age and host immune factors of the mouse play roles. Infection in humans is incompletely understood, but people with disseminated infection often display generalized anergy, an abnormal lack of reactivity to proteins injected within the skin. Anergy is fairly common in people with weakened immune systems. The organism causes a primary lung infection that may disseminate to other sites. People with the infection usually present with lesions of the lung as well as the skin, and fever. While widespread disseminated infection has a poor prognosis, people with less advanced HIV disease and lung or skin disease may respond to antifungal therapy. Treatment for blastomycosis Amphotericin B is the treatment of choice for disseminated blastomycosis. Itraconazole at 200-400 mg/day may be used for less severe disseminated infection and for maintenance treatment. Other Fungal Infections There have been rare reports of sporotrichosis (caused by Sporothrix schenckii) in people with AIDS, characterized by diffuse cutaneous disease and polyarthritis. Amphotericin B is the treatment of choice. In southeast Asia, increasingly frequent reports of disseminated infection with the mold Penicillium marneffei in people with AIDS indicates the emergence of an important HIV-related OI in that part of the world. The disease paracoccidioidomycosis is endemic to South and Central America. The majority of infected individuals do not develop disease. Adults who develop chronic or progressive disease usually have immune deficiencies. Several fungi of the Mucor group can cause infection. Invasive mucormycosis occurs rarely, usually in people with severely compromised immune systems or in intravenous drug users. Brain or sinus involvement is typical, with a poor prognosis. At the Fifth Focus on Fungal Infections conference (San Francisco, March 1995), presenters discussed the increasing appearance of new fungal pathogens, in association with growing numbers of immunocompromised persons. For example, transplant patients recently have been developing cutaneous phaeohyphomycosis, a group of fungal infections caused by Drechslera spicifera, and hyalohyphomycosis, a fungal infection related to immune deficiencies. Molds of the Trichosporon and Fusarium species, along with Aspergillus, are increasingly common risks to people with neutropenia. Healthcare providers at the conference were reminded that severely immunocompromised people may have multiple, simultaneous fungal infections, that non-albicans species of Candida are increasingly responsible for yeast infections and that the widespread use of azoles in people with chronic immunosuppression will likely increase the frequency of azole-resistant fungi. Allergy Many fungi can cause allergies. The allergic reaction is caused by spores that travel through the air, sometimes in great numbers, and are therefore difficult to avoid. Fungal spores are small and can penetrate deep into the airways of the lungs. The fungus Alternaria alternata is the best known allergen, but species of Penicillium, Aspergillus, mushrooms and other fungi may also cause asthma, rhinitis (inflammation of the nasal membranes) or hives. Some fungi cause food allergies. Non-Candida Mucocutaneous Fungal Infections Tinea infections are fungal infections of the skin, nails or hair. Overgrowth of a fungus commonly found on healthy skin, Malassezia furfur (Pityrosporum orbiculare), causes a disorder called tinea (or pityriasis) versicolor. Tinea versicolor is characterized by patches of discolored skin. However, numbers of M. furfur are not increased in AIDS. Seborrheic dermatitis, a condition common in AIDS, is related to immunologic abnormalities as well as to fungi. The primary cause is Pityrosporum ovale. Seborrheic dermatitis is characterized by redness and flaking of the skin of the scalp, face and occasionally chest and scrotum, and sometimes itchiness. While the condition is not disabling, the extreme redness and flaking may impact an individual's quality of life. Shampoos containing tar may alleviate the scalp condition, and antifungal agents such as ketoconazole 2% cream (Nizoral) may be used on the skin. Hydrocortisone creams are also used to treat seborrheic dermatitis, especially to reduce itching. One percent (1%) creams are available over-the-counter, and 2.5% creams are available by prescription. While these treatment strategies are usually effective, the condition may intermittently flare up and resolve. Dermatophytes are fungal organisms which use the protein keratin, present in hair, skin and nails, and cause infection characterized by inflammation and lesions. Chronic dermatophytic infection (dermatophytosis) is associated with immunosuppression. Dermatophytid tinea infections are common in people with HIV. Tinea pedis, or athlete's foot, is most common and may be accompanied by onychomycosis (fungal infection of the toenails, characterized by discolored and thickened nails). Tinea cruris, or jock itch, is also common. In those with severe immunosuppression, the presentation may be slightly unusual, i.e., the lesions may not be typically erythematous (red) and will lack a typical area of central clearing. Tinea corporis or ringworm usually first appears as scaly annular plaque-like lesions with central clearing. However, in the severely immunosuppressed, ringworm also may have an atypical appearance, with nonelevated borders and no areas of central clearing. Topical agents can be tried for tinea (naftifine 1% twice daily); for tinea corporis, a systemic antifungal (50 mg daily oral fluconazole) may also be needed for one month. The Antifungal Resistance and Prophylaxis Debate The increasing prevalence of fluconazole resistance in people with HIV provokes concern. Most people with fluconazole resistance have received previous antifungal treatment, and cross-resistance to other antifungal drugs has been seen (although the extent to which it actually occurs is unclear). Growing numbers of clinical failures on fluconazole in people with HIV and mucosal candidiasis are reflections of one adverse impact of resistance on patients' health. Also increasingly common are cases of candidiasis caused by non-albicans species, which are naturally more resistant to azole therapy and are therefore "selected" in people on antifungal azole therapy. Fluconazole-resistant candidiasis may also reflect incomplete therapy (e.g., compliance issues) or less than optimal dosing regimens (with respect to metabolism and drug absorption). As a fungal treatment option for people with HIV, fluconazole was considered a major breakthrough. The effective oral drug provided a welcome alternative to the more toxic, more difficult-to-use amphotericin B. Therefore, resistance to fluconazole has serious implications. The rise of fungal infections resistant to treatment with azole drugs, particularly fluconazole, has been noted with increasing frequency and concern over the past 2 years. As a result, whether or not to offer primary prophylaxis against systemic fungal infections to people with AIDS is currently a matter of great controversy. People at the greatest risk for developing systemic fungal infections are those with fewer than 50 CD4 cells/mm3. Yet only 8-10% of all people with AIDS will develop cryptococcosis, the most significant, life-threatening fungal infection. Proponents of primary prophylaxis feel that persons with fewer than 50 CD4 cells/mm3 (with respect to concern about cryptococcosis) and those living in endemic areas of histoplasmosis and coccidioidomycosis are the best candidates for chronic fluconazole prophylaxis. Opponents emphasize the dubious cost-effectiveness of such a policy, and the contribution to the rising numbers of resistant fungal organisms made by routine (and widespread) use of antifungal agents. ACTG 981 was designed to evaluate some of these issues. The study enrolled over 400 people with fewer than 100 CD4 cells/mm3, all of whom were involved in a primary study of PCP prophylaxis (ACTG 181). The nested antifungal study randomized participants to receive either fluconazole 200 mg/day or clotrimazole troches 5 times/day. The median follow-up period was 35 months. Systemic fungal infections occurred at a much higher rate in the clotrimazole group (cryptococcal meningitis and esophageal candidiasis in particular). Participants, in particular those with fewer than 50 CD4 cells/mm3, benefitted from the reduction of superficial, serious and invasive fungal infections caused by fluconazole prophylaxis. Fluconazole was well tolerated by all participants. However, breakthrough candidiasis occurred in 10.6% of fluconazole recipients. Moreover, there was no survival difference between the 2 groups. Since prophylactic use of fluconazole decreased the incidence of infections but had no impact on survival, as well as involving significant cost, the study arguably raises more important questions than it answers. Michael Saag, MD, commented that the cost-benefit analyses currently underway are needed "to assess the overall advantage of preventing systemic fungal infections with no resultant survival advantage vs the monetary and potential toxicity costs (including drug interactions and potential development of resistant organisms) Until then, routine prophylaxis with fluconazole or itraconazole is not recommended." Toward a standard of care In San Francisco, Mark Illeman, RN, FNP, of Dr. Marcus Conant's Medical Group, noted that their policy is not universal; they manage their patients on an individualized basis. While cryptococcal meningitis is not commonly seen in their practice, its extremely debilitating, painful and life-threatening nature led them to develop ad hoc prophylactic guidelines. First, cryptococcal meningitis and antifungal prophylaxis do not become real concerns until CD4 cell levels fall below 50 CD4 cells/mm3. Next, whether or not to offer antifungal prophylaxis depends on the health status of the individual. For example, candidates for prophylaxis would include people with fewer than 50 CD4 cells/mm3 and a number of OI who are weak and debilitated, with a host of chronic and nonspecific symptoms like headache, fever and fatigue, which might mask the emergence of cryptococcal meningitis. Other candidates would be people who live outside metropolitan centers, who are less likely to have immediate access to healthcare should they begin to develop cryptococcal meningitis, the onset of which may be sudden. The cryptococcal antigen blood test can be positive before the cerebrospinal fluid becomes positive. Thus, in the profiles described, a positive blood test would be followed with a lumbar puncture. Those with positive lumbar punctures would be treated. Those with a negative lumbar puncture would be offered prophylaxis. Currently, they are giving 100 mg/day three times a week (on Mondays, Wednesdays and Fridays); this schedule was designed with respect to the short half-life of fluconazole. Itraconazole and amphotericin B are available for back-up if resistance becomes an issue. On the other hand, a patient with 0 CD4 cells/mm3 who is functional and feeling well, in whom the onset of cryptococcal meningitis could be more readily identified, might not be offered antifungal prophylaxis. This prophylactic regimen primarily seeks to prevent the occurrence of disseminated cryptococcosis, or cryptococcal meningitis. Ideally, it also protects against a wide range of other, less common fungal infections such as histoplasmosis, to which people from or visitors to the Midwest may have been exposed, and aspergillosis. Breakthrough cryptococcal meningitis (infection that occurs in spite of prophylaxis) remains a concern but has not been a serious problem. It is not known whether or not breakthrough histoplasmosis is less likely to occur than breakthrough cryptococcal meningitis. A few cases of florid oral candidiasis resistant to fluconazole have been seen. Prophylaxis with low-dose fluconazole is a probable factor in the emergence of the strains of Candida detected in those cases. Because cryptococcal meningitis is much more painful, debilitating and life-threatening than other fungal infections, it is the main fungal concern of the Conant group, and guides their practice. Donald Abrams, MD, of the University of California/San Francisco's (UCSF) San Francisco General Hospital, has a different perspective than that of the Conant Group. In 1990, Dr. Abrams and colleague Don Northfelt, MD, also from UCSF, considered conducting a fluconazole prophylaxis study but ultimately decided that the cost-risk/benefit ratio was too high. Most fungal infections are readily treatable, Dr. Abrams told BETA, and the serious fungal infections cryptococcosis, coccidioidomycosis have available treatments and are low-incidence events in people with AIDS. About 5% of people present with cryptococcal meningitis as their AIDS-defining event; overall, 7-10% of people with AIDS develop cryptococcal meningitis at some point. Therefore, 90% of people with AIDS will never develop the infection even without prophylaxis. That leaves a very large margin of people who, through prophylaxis, would be unnecessarily exposed to fluconazole and who might well develop resistance. Given a theoretical 50% reduction in incidence rate, only 5 of 100 people treated will receive any benefit, a cost-risk/benefit ratio that does not warrant prophylaxis, Dr. Abrams feels. Fluconazole is relatively nontoxic but it does interfere with other medications; it recently was implicated in causing uveitis (an inflammation of tissues in the eye), when taken in combination with rifabutin. And, at $9/day, it is second only to AZT as a major expense on the formulary at the University of California at San Francisco. Conclusion Dr. Powderly states that important fungal prophylaxis-related research questions include those pertaining to: the incidence of azole failures, the morbidity involved with refractory mucosal candidiasis, the risk and consequences of azole-resistant candidiasis and the wisdom of routine chronic or intermittent antifungal treatment with fluconazole. In an article on resistant candidiasis, he summarizes the fundamental issues: "the long-term implications of using chronic antifungal treatment to prevent relatively rare diseases such as cryptococcal meningitis or to reduce the morbidity of intermittent candidiasis must be balanced with issues of emergence of antifungal resistance to common pathogens such as Candida that may not generally cause mortality but are associated with significant morbidity." Resources Barchesi F and other. DNA subtypes and fluconazole susceptibilities of C. albicans isolates from the oral cavities of patients with AIDS. Clinical Infectious Diseases 20: 634-640. March 1995. Fan H and others. The Biology of AIDS, 3rd edition. Jones and Bartlett Publishers, Boston. 1994. Catanzaro A and others. Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. The American Journal of Medicine 98: 249-256. March 1995. Clinical Aspects of Immunology, 5th edition. Lachman P and others, editors. Blackwell Scientific Publishers, Boston. 1993. Ennis DM and Saag MS. Cryptococcal meningitis in AIDS. Hospital Practice 99-109. October 15, 1993. HIV, Manual for Health Care Professionals. Muma R and others, editors. Appleton & Lange, Norwalk, CT. 1994. Powderly WG and others. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. The New England Journal of Medicine 332(11): 700-705. March 16, 1995. Powderly WG. Cryptococcal meningitis and AIDS. Clinical Infectious Diseases 17: 837-842. November 1993. Powderly WG. Fungi. In Textbook of AIDS Medicines. Broder S, Merigan TC and Bolognesi D, editors. Williams & Wilkins, Baltimore. 1994. Powderly WG. Resistant candidiasis. AIDS Research and Human Retroviruses 10(8): 925-929. 1994. Quagliarello and others. Primary prevention of cryptococcal meningitis by fluconazole in HIV-infected patients. The Lancet 345: 548-552. March 4, 1995. Saag M. Cryptococcosis and other fungal infections (histoplasmosis, coccidioidomycosis). From The Medical Management of AIDS, 4th edition (chapter 23). Sande MA and Volberding PA, editors. WB Saunders Company, Philadelphia. 1995. Stevens DA. Coccidioidomycosis. The New England Journal of Medicine 332(16): 1077-1082. April 20, 1995. ------------------------------------------------------------------ The CD8 Cell Antiviral Factor: An Interview with Immunologist Jay Levy, MD Mark Mascolini Mark Mascolini is a freelance writer who specializes in HIV infection. Jay A. Levy, MD, of the Cancer Research Institute at the University of California at San Francisco (UCSF), was the first scientist to isolate the AIDS virus from an American infected with HIV. He worked with a budget so slender that for many months he could not even afford some of the most rudimentary equipment. From his laboratory at UCSF, Levy continues to contribute compelling data and insightful essays on several research fronts. Perhaps his most intriguing finding is that a factor produced by CD8 cells stops the replication of HIV-1 in CD4 cells. Although Levy has not been able to isolate this factor (partly because of modest funding), he remains confident that he will soon pinpoint what he calls CD8-cell antiviral factor, or CAF. Levy believes that CAF is critical in helping people infected with HIV to maintain a cellular immune response against the virus. Cellular immunity, which controls infected cells or clears them from the body, is directed by intercellular messengers called cytokines that are principally produced by CD4 T-helper type 1 cells, or TH1 cells. Many investigators are convinced that a robust TH1 immunity is the best anti-HIV "medicine" available, and that high priority should be given to strategies that keep TH1 cells pumping out the appropriate cytokines. Scientists think that when the body resorts to a TH2 immunity, which relies primarily on antibodies to thwart HIV, the onset of AIDS-defining symptoms is not far behind. The importance of the so-called TH1-TH2 shift remains a hotly contested issue in HIV research. In his recently published book HIV and the Pathogenesis of AIDS (Washington, DC: ASM Press), Levy examines the evidence cited in this debate while tying together many other strands of research into a coherent view of HIV infection, disease progression and treatment. BETA invited Levy to discuss what his recent work means for people with HIV infection, to analyze related questions about how HIV subverts the immune system and how the virus might be stopped. HIV: Where It Came From and Where It's Going BETA: There's a lot of debate about whether HIV-1 and HIV-2 are relatively new viruses or whether they've been infecting humans for thousands of years. Do you think it's important to know how old these viruses are, and if so, why? LEVY: Eventually we learn a lot from studying how new agents emerge in the population, so information about the origin of HIV would be helpful not for the people who are infected or for the development of a vaccine, but mostly to help prevent the emergence of new infectious diseases. An example is the new measleslike virus that caused a fatal respiratory infection both in horses and in a man in Australia (Murray and others, 1995). The investigators are now trying to find out where it came from, in the hope that they can prevent it from reemerging. But right now, with HIV, we don't need to know where the virus came from as much as we need to know where it's going. BETA: The question of where HIV is going was raised by Harvard retrovirologist Max Essex in the last few weeks, when he brought up the possibility that a more virulent subtype of HIV-1 (a subtype more likely to be transmitted heterosexually) may have gotten a foothold in this country. Do you think there are any good reasons to begin looking closely for subtypes different from the B subtype of HIV-1 that has been dominant in the United States until now? LEVY: The basic point to remember is that heterosexual spread is no different from homosexual spread because what matters is the ability of this virus to be passed through body fluids. Probably the reason there is such a high sexual transmission rate [among heterosexuals] in some developing countries is the concomitantly high rate of venereal [sexually transmitted] diseases that allow accumulation of lots of virus-infected cells and disease-causing pathogens in the body. I suppose one ought to be alerted to the possibility of an agent that has adapted itself to be spread more easily by the sexual route. But just because we're seeing HIV spread heterosexually in one part of the world does not mean there is a specific heterosexually spread type of virus. More important are the cofactors that allow it to be spread more easily by that sexual route. Opportunistic Infections and Neoplasms BETA: At the cytokines conference in Reims [March 15-17, 1995], Thomas Folks from the CDC talked about how so-called cofactor infections, as well as immunizations and other events that stimulate immune system cells, can contribute to increased production of HIV in infected people. Studies are showing that various drugs can prevent some of the most common opportunistic infections, but resistance to some of these therapies is likely, and no one patient can get prophylaxis for everything. How aggressive do you think clinicians should be in starting prophylactic regimens for other infectious agents? LEVY: First, remember that the major concern about these opportunistic infections is the challenge they pose to an immune system that can't respond well. The secondary concern is whether they can induce a change in cytokines, the proteins that immune system cells use to communicate with one another. Cytokines can induce proliferation of HIV, inhibit HIV replication or prevent the immune system from responding to the virus. Tom Folks was talking more about the cytokine influence on the immune system, saying that there may be some opportunistic infections, such as kala-azar or leishmaniasis, that cause a type 2 [TH2] cytokine response. Some of us believe that the type 2-mediated [TH2] immune response is detrimental to a normal type 1-mediated [TH1] cellular immune response to HIV. Folks also was concerned about activation of the immune system by other infections. That's a reasonable concern, but there is no evidence yet that activation actually speeds up the course of HIV infection. For example, we found that if we inoculated a primate cytomegalovirus into HIV-infected chimpanzees, HIV would be detectable in their blood, whereas previously it wasn't. However, the animals showed no clinical symptoms. This study and similar research suggest that other infections can increase the level of HIV by activating resting immune cells that were infected with HIV but weren't releasing the virus. But, again, there's no clear evidence that any of these "activating events" are detrimental to a person's clinical status. The major conclusion, clinically, is that we should certainly prevent opportunistic infections whenever possible and take care of them as they arise. In general, prophylaxis against these opportunistic infections should begin at a time when an individual is most susceptible. By and large, that means when CD4 cell counts drop below 100 cells/mm3, or even below 50 cells/mm3, for some of these infections. Why wait that long? Because when you give a prophylactic drug for too long, there's a greater risk that the pathogen you're trying to inhibit will mutate in such a way that it becomes resistant to the prophylactic drug. Then, if active infection does occur, the drug will be useless. A more logical strategy than long-term drug prophylaxis would be vaccines against opportunistic infections, and I know some groups are looking at this possibility. They are considering whether a vaccine could be developed to prevent infection with Cryptococcus, Pneumocystis, Toxoplasma or the mycobacteria, so that we won't need to use drugs to prevent or later to treat the diseases they cause. A problem with developing these vaccines is similar to a key problem in developing a vaccine against HIV the heterogeneity of the infecting organism. But vaccination would be the best answer to these diseases for people infected with HIV. BETA: In your book you wrote that when Paul Volberding asked you to consult on a patient with Kaposi's sarcoma (KS) in 1981, one question was whether that unusual presentation might lead to [the discovery of] a viral cause for a cancer. Now it appears that a herpesvirus [Kaposi's sarcoma-associated herpes virus or KSHV] may cause KS (Chang and others, 1994). But if KS is caused by a sexually transmitted virus, why is the prevalence of KS so much lower in women than in men? LEVY: This is a difficult question to answer now because we aren't completely certain how this herpes-like virus that's associated with KS actually causes the cancer. Our laboratory, for instance, has not found evidence of this virus in laboratory cell lines derived from people with KS (Ambroziak et al, 1995). Thus, the effect the virus has in causing KS may be indirect. One thing that needs to be considered is whether having anogenital contact permits easier infection with this agent. The other possibility is that there are factors [present] in women such as estrogens that may prevent the formation of KS, or factors [present] in men such as testosterone that may encourage its formation. Most importantly, until we have a good blood test for the herpes-like virus, we won't be able to know how widespread it is in the general population. I would imagine it's pretty common. With this information, we can begin to ask those questions about whether or not women are infected as easily as men. Perhaps they are resistant to development of this tumor. If they aren't infected, then we're back to asking why transmission is different for men and women. It may be that anogenital contact is the easiest way for the infectious agent to be transmitted, although let me remind you that KS has been found in Africa in a nearly normal gender distribution. And KS does occur in children, particularly in Africa. So it appears likely that there are other factors that are playing a role in the induction of this cancer. BETA: Do you think that there is enough evidence now that this herpes-like virus [KSHV] is associated with KS to start studying antiherpes drugs, such as foscarnet, as possible therapies? LEVY: Yes, I do. Is CAF the Best Defense Against HIV Progression? BETA: Let me ask you a few questions about the CD8 cell antiviral factor CAF. First of all, can you explain how you know it exists and why it's so difficult to isolate? LEVY: We know it exists because of experimental work that we have conducted in the laboratory. We found that fluid from CD8 T-cells of HIV-infected individuals who are asymptomatic or are long-term survivors when added to CD4 cells in which HIV is replicating contains something that suppresses that replication. When the CD8 cell culture fluid is removed, replication of HIV starts again. Before trying to say what this factor is, we first had to determine what it isn't. So we looked at all the other known cytokines that have been described the interleukins (IL-1 up to IL-13), TNF-alpha and TNF-beta, and growth factors such as TGF-alpha and TGF-beta. We found that none of them, alone or in combination, gives this same type of HIV-suppressing activity. In fact, some of the cytokines I mentioned actually increase replication of HIV. So we're left with the conclusion that there's something else in that CD8 cell fluid that is suppressing replication of the virus. We then treated CD8 cell fluid with enzymes to see if we could break up a protein in the fluid. And, in fact, we can eliminate the HIV-suppressing activity with an enzyme that destroys proteins. That's good evidence that some protein in the CD8 cell fluid inhibits HIV. On the basis of these experiments, we decided to call this novel cellular protein the CD8 cell antiviral factor or CAF (Mackewicz and Levy, 1992). We have had a problem purifying CAF because it is produced in very low amounts by the CD8 cells. It's not meant to be a protein that circulates throughout the body; it is produced by CD8 cells when they are interacting with an infected CD4 cell. Protein chemists estimate that we would need up to 100 liters [about 26 gallons] of CD8 cell fluid to be able to see this protein. Most cellular factors are produced in much larger amounts, so their identification was easier and less costly. We don't have the finances to conduct all the experiments needed to identify CAF. While we try to get more funding, we are also discovering other features of the protein, even if we can't see it. These features will help us in the final purification and identification procedures. BETA: Do you feel confident that finding CAF is just a technical problem that if you get the support you need you will be able to pinpoint it? LEVY: There's no question in my mind that if we had the funding and the technical help from protein chemists we would find this factor. Within a year we would have CAF. BETA: Is one of your goals in isolating CAF to see if it can be synthesized and tested as a therapeutic intervention? LEVY: Once CAF is isolated, we would synthesize it and, of course, begin to think about possible clinical trials. My concern is that most cytokines, when given at the doses needed to have a clinical effect in people with HIV, have so many side effects that therapy with them becomes impractical. A better strategy may be to make antibodies to CAF and set up a procedure by which we could measure its production by CD8 cells. Using these antibodies, we might even be able to measure the expression of CAF protein on CD8 cells. We could then use a technique called flow cytometry, or "FACS analysis," to follow the number of CAF-producing cells. That information could be helpful in predicting the course of HIV infection in individuals. With the ability to measure CAF production using the anti-CAF antibodies, we could also ask what treatments will induce CD8 cells to produce more of this factor. We would have the answer very quickly, just by looking for the factor, using an immunologic technique. I think the real breakthrough will be to find ways to induce production of CAF so that the CD8 cells from each person infected with HIV can be made to produce more of his or her own CAF. BETA: A study you published last year showed that AZT may for a short time increase CD8 cell anti-HIV activity (Mackewicz and others, 1994). Is it possible that other antiretrovirals or other agents may stimulate this effect more? LEVY: We stated in that article that AZT does not harm the CD8 antiviral response. In fact, if you look at the people we studied individually, AZT increased their CD8 antiviral activity. However, because of differences in how they took AZT (some people stopped therapy, then started again) it was difficult to come to an overall conclusion about AZT's effect on CD8 cells. My view of the data is that these antiretroviral drugs may actually be increasing the cellular immune response. That possibility may explain why AZT has no effect in some people, even though the strain of the virus in those people is still sensitive to AZT. The same is true for other antiretroviral drugs. Their effect may be more a reflection of these drugs' impact on the cellular immune response directed by CD8 cells rather than the anti-HIV activity of the drug. BETA: Your book also mentions the work of Nancy Klimas of the University of Miami on CD8 cell-based therapy. What has she found? LEVY: What Nancy Klimas's group has done, working with Applied Immune Sciences, is to take CD8 cells from people with HIV, expand their number outside the body, and then give them back to the donors (Klimas and others, 1994). She found in these initial studies that Kaposi's sarcoma lesions of 2 people with AIDS cleared when the expanded CD8 cells were given back. There's now a larger trial looking at whether that result is reproducible and whether just giving CD8 cells in large amounts can have an effect on a clinical state. The answers aren't in, but one has to hope that the CD8 cells that are being given are producing a lot of CAF. Rationale for "Locking in" Cellular Immunity BETA: In your book you note that the TH1-TH2 paradigm is not as clear-cut in humans as it is in mice, yet much of the evidence you review suggests that it may make sense to maintain cellular immune function through immune-modulating therapies. Are you convinced that the shift from TH1 immunity to TH2 immunity is critical to disease progression and should be prevented? LEVY: Even if the TH1-TH2 distinction isn't as clear-cut in humans as in mice, it offers a direction that seems to be giving us answers. The cytokines produced by TH1 T-cells are increasing the CD8 cell response, at least in laboratory studies, and TH2 cytokines are suppressing it (figures 1 and 2). So we are very much in favor of studies that try to modulate the immune system to preserve the TH1 response. Recent work at the National Institutes of Health showing that IL-2 stabilizes CD4 cell counts (Kovacs and others, 1995) was very encouraging. It may be that a short pulse of IL-2 allows the cellular immune response to control the virus enough that the immune system can regain the upper hand. The virus is being kept in control by CD8 cells. More work in this area should be done. Drugs should be directed at enhancing the immune response, not just at inhibiting HIV infection of new cells. The immune response can suppress the virus so replication cannot take place. BETA: Many clinical investigators are looking very closely at attacking the virus as the primary way to control HIV infection. Your book mentions some of the possibly deleterious effects of antiretroviral therapy during acute HIV infection. But David Ho and others are now saying that antiretroviral drugs may make sense even early in the course of infection. Where is your thinking on this question? LEVY: It's very obvious that if we could stop the virus early we would have an optimal approach. But we don't have the drugs yet to do that. My concern is that if we start using these antiretrovirals too early, before the immune system has recognized the virus and started to respond to it, we may do harm. I just mentioned that these antiretrovirals may actually increase the cellular immune response in people. But if that's true, it happens after the anti-HIV immune activity has been established. There are a few cases in which infected people got worse taking an antiretroviral, particularly AZT, soon after infection. That makes me concerned that using antiretroviral drugs in acute infection may be detrimental. BETA: One of the possibilities that you outline in your book when discussing the progression of HIV infection is that there are 2 phases of infection: an initial persistent but slow replication of virus, followed by much higher viral replication and the onset of AIDS. How do you respond, then, to the conclusion of the groups headed by David Ho (Ho and others, 1995) and George Shaw (Wei and others, 1995) that HIV replicates at a tremendously fast pace throughout the course of infection? LEVY: The Ho and Shaw papers looked at individuals who were not asymptomatic. They were people who needed to be taking antiretroviral therapy and whose CD4 counts were below the normal range. So these studies dealt with people whose immune systems were not functioning against the virus as well as in people who are asymptomatic. In symptomatic patients they showed that virus is released constantly and is constantly infecting new cells. But the question is whether suppressing the virus 100-fold (as some drugs can do transiently) is going to have a clinical benefit, since HIV is still being produced by cells in the body. That question is not answered in their papers. Another important question to be answered besides whether there is any clinical benefit to these antiretroviral therapies is whether the observed increase in CD4 cells is a direct effect of suppression of HIV by antiretroviral therapy, or whether the enhanced number of CD4 cells reflects an immune response to the antiviral therapy. For example, what would happen if these antiretroviral drugs were given to uninfected people? Would there still be a rise in CD4 cells? Also, in the studies by Ho and Shaw, the rise in CD4 cells was very transient. The authors say it was transient because viruses resistant to the antiretrovirals emerge, but there's no evidence that these resistant viruses are responsible for this fall in CD4 cells. That fall may merely reflect a transient response to the administration of the drug. Of course there are always a lot of questions when you publish papers that try to establish a certain paradigm about this disease. Such questions have to be asked to determine the validity of findings that can affect approaches to therapy. I think over the next few years we'll see a lot of answers to those questions. Future Directions for HIV Therapy BETA: As you just suggested, the ultimate goal of these debates about pathogenesis is to get a better understanding of the disease process to help clinicians make therapeutic decisions. How do you think therapy for HIV infection will evolve over the next 4 or 5 years? LEVY: What strategies will be used depends on who makes the decisions. If the decision is made by a virologist, you'll be seeing antiviral drugs used very early. I must say, though, that if the decision is made by people who understand HIV pathogenesis, the present drugs will not be used until the immune system starts to falter, when the CD4 cell count is reduced consistently below 400 cells/mm3. And then the therapy will probably be a cocktail of 1 or 2 reverse transcriptase inhibitors, a protease inhibitor drug and maybe an anti-integrase agent, if one is developed. That's the approach we could see in the immediate future. But what I'm hoping is that we're also going to have immune modulation strategies implemented. The goal then would not be to attack the virus directly with antiviral drugs, but to let the immune system do it. It does a much better job. It's the major reason that there are long-term survivors of HIV infection. Their CD8 cells are controlling the virus for a very long time. And even though there are episodic releases of virus detected in the blood during this suppression, this virus production may function to keep the immune system activated against HIV. Immune therapy would be the best approach when we have the appropriate drugs. BETA: What do you see as the best potential immune-modulating therapies? LEVY: I think IL-2 pulsing could be helpful (Kovacs and others, 1995). With this investigational strategy, large doses of IL-2 are given intravenously over 5 days every 8 weeks. IL-12 may also foster TH1 cell-mediated immune responses. Another intriguing possibility is immune modulation using gene therapy in which the IL-2 gene is placed into CD8 cells. If that works, the CD8 cells would be able to make their own IL-2, which would enhance their ability to attack the virus. What we are trying to do with immune modulation is to tip the balance in favor of the immune system and away from the virus. If you appreciate that this battle is between HIV and the immune system, then if the virus gets the upper hand, the immune system collapses. That collapse is the second phase you mentioned earlier, in which the virus replicates so much that the immune system can no longer control it. What we're trying to do is identify the time when the immune system looks like it's faltering, then give it the strength to regain control and maintain that control, with monthly injections or pills that help the anti-HIV immune response. In this way, the immune system can be maintained in full control for long periods. BETA: Let me ask you about a few specific therapeutic approaches that you cover in your book. Are you continuing to look at mycophenolic acid (MPA)? What's its mechanism of action? LEVY: MPA is a reverse transcriptase (RT) inhibitor that acts totally differently from current nucleoside analog RT inhibitors (AZT, ddI, ddC, d4T and 3TC). MPA functions by blocking nucleotide incorporation into the HIV proviral DNA. Let me explain that in simpler terms. In order for HIV to make a DNA copy of its own genomic RNA inside the cells it infects, it needs nucleic acids that form the building blocks of that DNA. MPA prevents the formation of those building blocks in infected cells. Thus HIV does not replicate. A potential problem is that those same building blocks are also needed to repair damaged DNA. For this reason, side effects need to be assessed in clinical trials before we can say that MPA's anti-HIV effect outweighs other possible unwanted effects. We would like to see some animal studies or pilot clinical trials of MPA for HIV infection. We have been unable to pursue these studies ourselves because of limits on research efforts in our laboratory. BETA: Another potential therapy you mention is the use of Nef proteins, products of the HIV-1 nef gene, as antiviral drugs (Cheng-Meyer and others, 1989). How would that work? LEVY: We have found that Nef proteins from some strains of HIV-1 are associated with suppression of viral replication. Nef proteins from other HIV-1 strains can either show no effect or enhance replication. A Nef protein that one might select for therapy would be one that could affect the infection cycle of HIV to prevent replication. This strategy is based on some of our early work in which we showed that, if you eliminate the nef gene from some strains of HIV-1, the virus replicates much more rapidly. This result suggests that Nef proteins suppress, or at least modulate, production of the virus. There is a controversy over Nef now because some investigators believe Nef is more important in enhancing replication than in suppressing it. I believe, though, that these differences reflect the particular nef gene studied. Once we know specifically how Nef works inside the cell, it might be manipulated for use as an antiviral strategy. BETA: Were you surprised by Ruth Ruprecht's finding that a vaccine based on a nef-deleted simian immunodeficiency virus (SIV) caused high levels of circulating virus, lower CD4 cell levels and symptoms of immunodeficiency in neonate (newborn) macaque monkeys (Baba and others, 1995)? As you know, her study appears to challenge the conclusions of Ron Desrosiers' group, which previously found that a vaccine using nef-deleted SIV protected adult monkeys from disease or challenge with pathogenic viruses (Kestler and others, 1991; Daniel and others, 1992). Because of Desrosiers' results, some people believed that a nef-deleted HIV might work as a live, attenuated vaccine to prevent AIDS in humans. LEVY: Biology always has its surprises. Here is a situation where, in cell cultures in the laboratory, the elimination of nef can at times lead to high replication of HIV. With SIV, the opposite is seen Nef is needed for high-level SIV replication. The lack of virus production after giving a nef-deleted SIV to an animal was encouraging, particularly because that animal became resistant to infection with a standard SIV strain and did not develop disease. The interpretation of those findings, however, was too optimistic, given what we have learned about HIV and the surprises that it holds in its relative abilities to infect different cell types and even different hosts. I must say that Ruth Ruprecht's observations were such a surprise; they reminded us that we need to be very careful and must consider all possible variables before we advocate a certain approach. BETA: The final chapter of your book raises again the possibility of inactivating another HIV protein, Tat. Given Tat's key role in viral replication, do you think it should be a higher priority than it is now? LEVY: I think the attack on Tat is being given a high priority. A lot of antisense Tat and anti-Tat antibody work has been done. It is interesting, though, that an effective anti-Tat drug has yet to be developed. I do believe that since the primary effect of the HIV tat gene seems to be increasing virus replication, this particular regulatory gene would be an appropriate one to attack, just as some investigators are trying to attack the Rev protein. BETA: The anti-HIV therapies that are available now and many that are being considered are expensive. What's going to happen in Africa and Asia and even in this country with the growing number of HIV-infected people who have no health insurance and can't afford these therapies? Will we just have to depend on education until a decent vaccine is found? LEVY: Right now, education is our vaccine. People who work in the field of behavioral change and education say that we haven't really learned yet how to present the subject of risk behavior in a way that people will believe. But we have to recognize that there has never been a completely effective treatment for, or prevention of, a sexually transmitted disease. So a vaccine is the best and only approach that's going to stop the spread of this virus. When you look at the millions of people infected in Africa, India and other parts of the world, drugs if they work will have to be provided by the governments. There will be pressure by the international community to make them available at a reasonable rate, and, if needed, these countries will have to get help through the World Health Organization or other organizations to make effective drugs available. I think most of us aren't as concerned about having the drugs available worldwide once effective ones are found. There will be a way to do it. But some drug companies may be reluctant to get into HIV research because of the demand that drug costs be controlled. People have to recognize that it takes millions of dollars to do a good clinical trial. The average cost is $50 million to $100 million. And recouping that kind of money, after you've had several failures along the way, has to be considered in the cost of the drug. Yet of course we all want the price to be affordable for patients and to make sure that patients who cannot pay have financial assistance. BETA: What is your sense of the prospects for an HIV vaccine now? Do you see any plausible candidates on the horizon? LEVY: Personally, I've not seen any data that make me believe that there are any immediate prospects for a vaccine to prevent HIV infection or to prevent disease once people are infected. With that said, I would add that there have been some very encouraging observations. For example, I am impressed by the evidence showing that when you infect an animal with one virus strain and then try to infect it again with another, there is either complete protection against the second infection the "superinfection" or absolutely no disease after the second infection. The virus is controlled. We've recently confirmed these findings when we tried to infect HIV-2-infected baboons with another strain of HIV-2 (Barnett and others, 1994). These results indicate that the infected animal, if presented with enough pieces of information reflecting the actual infecting virus, will be able to ward off the disease and prevent new viruses from coming in and causing the disease. I find that optimistic. And, getting back to the theme we discussed earlier, we believe that it's the cellular immune response that is the mechanism by which these animals are warding off the disease and the superinfection. Resistance to Infection and Long-Term Survivors BETA: Let me close with 2 issues that your lab has addressed and that have attracted a lot of attention recently: resistance to HIV infection and long-term survival. In the past year or so there have been several reports about people who have almost certainly been exposed to HIV, yet are now negative according to the most sensitive assays. You've found several seronegative sexual partners and children of seropositive people. Is there a common mechanism in all these cases, or many possible mechanisms? LEVY: I think there is one common mechanism and, again, I think it's the cellular immune response to the virus. While many of these people may have been exposed only to dead virus or viral protein, it seems much too optimistic to believe that none of these individuals got any infectious virus. What we have probably seen is that some people actually can eliminate the infectious virus, even after it has entered the body. BETA: Do you think these reported examples of exposed but still seronegative people are rare, or could there be lots more unreported examples of that type of clearing of the virus? LEVY: I'm sure that many people have been able to clear the virus, particularly in geographic areas where there is a high rate of transmission of HIV. If you look at the prostitutes Frank Plummer has been studying in Nairobi (Plummer and others, 1993) and the women Sarah Rowland-Jones is studying in Gambia (Rowland-Jones and others, 1995), there is something about their immune systems, I would presume, that allows them to defend against the virus. That's not to say that if they got an overwhelming amount of virus their immune system would still be able to prevent infection. This resistance to infection is probably a combination of factors. One is transmission of a low amount of virus, and another is a host immune system that can respond against the virus. BETA: Your book lists 5 characteristics of long-term survivors: low viral load, a relatively nonvirulent infecting strain, antibodies that don't enhance infection, TH1 cytokine production and a strong CD8 cell antiviral response. How many of those factors do you believe can be sustained by some therapeutic intervention? LEVY: If one maintains just CD8 cell production of CAF, all the rest will follow. CAF will stop the virus from replicating and cause a switch from TH1 to TH2 immunity (figures 1 and 2). There will be a low viral load. Moreover, the virus will not change or mutate to be sensitive to enhancing antibodies. Cytopathic [cell-killing] viruses will not result because such viruses won't be able to adapt to the cells in the host without adequate replication and mutation. One could essentially control HIV and the consequences of HIV infection with a strong cellular immune response and CAF production. References Ambroziak JA and others. Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma patients. Science 268: 582-583. 1995. Baba TW and others. Pathogenicity of live, attenuated SIV after mucosal infection in neonatal macaques. Science 267: 1820-1825. 1995. Barnett SW and others. An AIDS-like condition induced in baboons by HIV-2. Science 266: 642-646. 1994. Chang Y and others. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865-1869. 1994. Cheng-Mayer C and others. Differential effects of nef on HIV replication: implications for viral pathogenesis in the host. Science 246: 1629-1632. 1989. Daniel MD and others. Protective effects of a live attenuated SIV vaccine with a deletion of the nef gene. Science. 258:1938-1941. 1992. Comment in Science. 258:1880-1881. 1992. Ho DD and others. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373: 123-126. 1995. Kestler HW and others. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65: 651-662. 1991. Klimas NG and others. Clinical and immunological changes in AIDS patients following adoptive therapy with activated autologous CD8 T-cells and interleukin-2 infusion. AIDS 8: 1073-1081. 1994. Kovacs JA and others. Increases in CD4 T-lymphocytes with intermittent courses of interleukin 2 in patients with human immunodeficiency virus infection. The New England Journal of Medicine 332: 567-575. 1995. Mackewicz CE and others. Effect of zidovudine therapy on CD8+ T cell anti-HIV activity. Clinical Immunology and Immunopathology 73: 80-87. 1994. Mackewicz C and Levy JA. CD8 cell anti-HIV activity: nonlytic suppression of virus replication. AIDS Research and Human Retroviruses 8: 1039-1050. 1992. Murray K and others. A morbillivirus that caused fatal disease in horses and humans. Science 268: 94-97. 1995. Plummer FA and others. Evidence of resistance to HIV among continuously exposed prostitutes in Nairobi, Kenya. IX International Conference on AIDS. Berlin. June 6-11, 1993. Abstract WE-A07-3. Rowland-Jones S and others. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nature Medicine 1: 59-64. 1995. Wei X and others. Viral dynamics of human immunodeficiency virus type 1 infection. Nature 373: 117-122. 1995. ------------------------------------------------------------------ A Positive View of Safe Sex Mark Bowers Mark Bowers is the Treatment Hotline Manager at Project Inform and a frequent contributor to BETA. Sexuality is an important and satisfying expression of human nature. This is as true for HIV positive people today as it has been for all people for millions of years of human evolution. In fact, many psychoneuroimmunologists and other health care professionals agree that a healthy interest in and expression of sexuality can be immune enhancing. Taking a positive view of sex is difficult for many HIV positive individuals. In many cases, it was sex that got them infected in the first place, and they are not prepared to be responsible for the further spread of HIV. But sex is as important to seropositives as it is to seronegatives, and healthy expression of sexuality is an integral part of general health. Some considerations change with a change in serostatus, though not all. Many books and articles have been written on how to prevent the transmission of HIV from seropositive to seronegative individuals. The healthy expression of sexuality will allow sexual contact between 2 seropositive individuals, a seropositive and a seronegative, and 2 seronegatives. This article intends to go further in one direction than the published guidelines, and to explain the reasons and techniques that can help seropositives protect themselves from sexually transmitted diseases and from some opportunistic infections. A reanalysis of what constitutes sexual risk behaviors is due now because of recent evidence that HIV transmissibility is highest during the period immediately following initial infection, and when viremia (the number of virus particles in the body) is highest during advanced disease. Also informing the discussion is the recently published evidence that HIV is never latent, but rather is produced in up to a billion copies daily, while the host mounts an aggressive immune response, churning out up to a billion new T-cells daily. Together, these 2 pieces of evidence point to an infection by a rapidly propagating, highly infectious virus. Parallel research is being conducted in the field of psychoneuroimmunology on the many possible cofactors that contribute to long term survival with HIV. At this point, it is clear that complete human relationships, including sexual expression, make a powerful contribution to the psychological well-being of HIV positive individuals, and positive psychological states may lead to an increase in natural immunity. Healthy expression of sexuality can help strengthen the immune response. HIV Reinfection A common belief, and one that is erroneously supported by some less well-informed physicians, is that once a person is HIV positive, there is no longer any need to practice safer sex . The reality is quite different. Research has proven that seropositive individuals can be and often are reinfected by other strains of HIV than the one that originally resulted in their positive HIV tests. The same protective measures apply to a seropositive individual as to a seronegative one: the consistent use of condoms and/or barrier protection during penetrative sexual acts of any sort is the best protection. Authorities on the transmission of HIV are unanimous on one point: unprotected insertive or receptive sex is a very high risk behavior. There is more than one strain of HIV, and some strains clearly cause more rapid progression to AIDS than do others. There have been documented cases of transmission of AZT-resistant virus and of syncytia-forming virus. There are also reports of people who are infected with HIV-1 and HIV-2. Whatever strain of HIV infects an individual, there will be problems to one degree or another. It is crucial not to import other people's strains of HIV, and with them new problems. Reinfection with HIV must be carefully avoided. An HIV positive individual already has evidence that he or she is infectible: it is incumbent on each seropositive individual to reexamine sexual behavior and eliminate the practices that brought about initial infection. Just as is the case for initial infection, the data supporting transmission by oral routes is eclipsed by comparison with the obvious association of HIV transmission during penetrative sex acts, but the risks are still real. The number of individuals who have been proven to have been infected with HIV by anal-oral or oral-genital sexual contact is less than the number of individuals who have been infected through unprotected penetrative sex, but there are other reasons to be careful about sucking and rimming. A discussion of other diseases that can be contracted by oral routes follows. An understanding of the risks involved should help seropositives to make an informed decision about the practice of oral sex without protection. Sexually Transmitted Diseases Sexually transmitted diseases (STD) such as gonorrhea, syphilis, chancroid, condylomata, herpes and chlamydia have long been known to be cofactors in HIV transmission and progression. For the HIV-infected individual, these STD continue to be especially important. For HIV-infected women, pelvic inflammatory disease and vaginitis are sexually transmitted diseases that can complicate the course of HIV disease. Gay men (and all indiviuals who have anal sex) are more at risk for sexually transmitted ano-rectal diseases, including gonorrhea, chlamidia trachomatis, meningococci, cryptosporidiosis and herpetic proctitis. Gonorrhea that is resistant to penicillin, tetracycline and ampicillin, the usual agents used to treat the disease, is becoming more common in the United States. Gonorrhea infection is pandemic. It can be spread by both asymptomatic men and women, because the incubation period before symptoms appear is from 3 to 14 days. Gonorrhea may be asymptomatic, or may have characteristic symptoms. The first symptom in men is a discharge of pus from the urethra and difficulty urinating. Antibiotic-resistant gonorrhea can cause infections of the epididymis, the prostate gland and other adjacent structures. There is an increased risk of involvement of the pharynx (the throat) and the anal canal when gonorrhea is spread by oral-genital sex or oral-anal contact, among men or women regardless of the gender of their partners. Sore throat and sore anal tissues, both with a production of pus, are characteristic of gonorrhea in these sites. Women are likely to experience inflammation of the urethra or urinary bladder, vaginal discharge, frequent urgent urination, lower abdominal discomfort and unusual uterine bleeding. Continued infection with gonorrhea can result in acute pelvic inflammatory disease. Disseminated gonorrhea spreads through the bloodstream. Skin lesions and joint pain can often be followed by arthritis. This is the most common cause of infectious arthritis. Untreated or resistant gonorrhea can lead to endocarditis (inflammation of tissues around the heart) and meningitis (inflammation of the tissues surrounding the brain). The more disseminated the disease, the more complicated the treatment, the more toxic the side effects from treatment drugs, and the longer it takes to cure. There are several drug regimens that can be used if the organism is resistant or if the host is allergic, but doses must be increased and the course of treatment (up to several weeks) can be greatly lengthened. Retesting for infection is necessary to see if the course of treatment was successful. Safer sex can eliminate the transmission of gonorrhea altogether. Use of dental dams during oral-anal contact and condoms during oral-genital sex can completely prevent pharyngeal gonorrhea. Evidence continues to indicate that syphilis is a cofactor for the transmission of HIV disease. Papers are published on an average of once a month providing evidence of new or newly recognized relationships between syphilis and HIV disease. Although syphilis is not universally regarded as a cofactor for HIV progression, it is widely recognized that the course of each disease is often more serious in the presence of the other. Anyone treated for gonorrhea or chlamydia should also be tested for syphilis, since these infections so frequently travel together. In an HIV-infected individual, it will be more difficult to recognize syphilis, since the standard tests often are falsely negative because of immunocompromise. Tissue biopsies are often needed, at great discomfort and increased cost to the patient, before therapy can begin. Furthermore, treatment with antimicrobial agents can often fail. Neurosyphilis can follow quickly by comparison with the normal course of syphilitic disease in immunocompetent individuals. It has been suggested, and some clinicians have attempted, continuous maintenance therapy with penicillin for life in efforts to stave off the ravages of neurosyphilis. Chancroid, a ragged ulceration of the genitals, is also recognized as a cofactor for HIV transmission. The actual organism, hard to culture, incubates for 2 to 5 days before forming a papule that grows and finally bursts. Infected men usually have these lesions on the penis, while women may develop them on the labia, clitoris or vestibule. Both men and women may develop chancroid on the tissues of the anus following unprotected anal sex or oral anal contact. In HIV- infected individuals, it is not uncommon for the site of the chancre to be infected with a second organism, which may lead to mutilating tissue loss. Treatment is usually with ceftriaxone, azithromycin or erythromycin; HIV positive individuals are more likely to have chancres that are resistant to trimethoprim sulfamethoxazole (Bactrim or Septra) and are more likely to fail treatment. The use of condoms can prevent the transmission of chancroid disease. Chancroid can also be transmitted by oral sex. Protected oral-anal and oral-genital sex eliminates this risk. Urethritis not due to gonorrhea is often caused by Chlamydia trachomatis, Ureoplasme ureolyticus or Trichomonas. The methods for distinguishing among the various sources are well-known to health care professionals. Swab tests are used, in which a cotton swab is inserted 2 to 4 cm into the urethra. Chlamydia trachomatis has become the most frequently transmitted sexual disease in both men and women. In women, it is a frequent cause of pelvic inflammatory disease. Activists have long argued that chronic pelvic inflammatory disease should be an AIDS-defining infection in women. Chlamydia is frequently spread by asymptomatic individuals who are unaware that they are infected. The consequences of contracting chlamydia through unprotected sex, particularly to HIV positive women, can be severe. Pelvic inflammatory disease (PID) arises when infectious agents find their way from the vagina and endocervix to the endometrium and fallopian tubes. Damage to the internal genitalia, infertility and abdominal pain can result from PID. Proper condom and diaphragm use and the use of vaginal spermicides clearly reduce the incidence of PID. The role of oral contraceptives is unclear they may increase chlamydial infection at the same time that they reduce the incidence of PID. Use of intrauterine devices (IUDs) increases the risk of PID during the first 4 months after insertion, but decreases risk thereafter. Treatment in any event is bound to fail if the woman's sexual partner(s) remain untreated or fail to fastidiously practice safer sexual practices. HIV positive women have a higher incidence than the general population of vaginal candidal infections, tubo-ovarian abscesses as a result of PID, and higher rates of cervical cancer. Vaginitis is characterized by itching, irritation and discharge and infection with Candida, trachomatis vaginalis, bacterial vaginosis, or occasionally gonorrhea. Symptoms often are pronounced just after menstruation finishes. Although asymptomatic infections are possible, many women experience a change in vaginal discharge from odorless or mild to strong-smelling and from clear to whitish or yellow-green in color; the usual texture may change from viscous to thickened, the appearance of which has been likened to cottage cheese. Candidal vaginitis is treated with topical nystatin or an azole drug. It is particularly refractory in HIV positive women. Bacterial vaginosis is treated with Flagyl (metronidazole) or clindamycin orally or topically, although treatment failures and relapses are common among HIV positive women. Treatment with oral drugs is more common for HIV positive women, since physicians consider these infections to be more serious. Anal Sex Because of oral-anal (rimming) and oral-genital (sucking) sexual behaviors, gay men are at increased risk for pharyngeal and anorectal infection with STD. Gonorrhea is the most common sexually transmitted cause of anal itching, pain on defecation, pus discharge and constipation in gay men. Herpes is the second most common rectal infection in gay men. Symptoms are similar to gonorrhea, but also include painful sphincter spasms with a strong need to defecate, but very little passage. Men who are infected with gonorrhea in the rectum are more likely also to be infected with chlamydia. Ulcerative proctitis that resembles Crohn's disease can be caused by anal chlamydial infection. Such an infection can contribute significantly to intestinal disorders and wasting in HIV positive individuals. Finally, gay men are at increased risk of infection with Giardia, Shigella, salmonella, Campylobacter, and amebas when they engage in unprotected oral-anal contact. These parasites are less easily controlled in HIV positive individuals, and may result in weight loss, discomfort and impaired gastric secretion that may associate with altered metabolism of food, particularly in advanced HIV disease. Evidence continues to mount that infection with these parasites contributes to wasting. Amebiasis is associated with faster progression to AIDS and strongly associated with progression to Kaposi's sarcoma. Avoiding Opportunistic Infections The sexually transmitted diseases that can be avoided by diligent practice of safer sex among HIV positive individuals are detailed above, and would be compelling arguments even in the absence of other considerations. The opportunities to indefinitely avoid sexually transmitted opportunistic infections are increased immeasurably by the practice of protected sex. The relationship between unprotected oral-anal sexual contact and the transmission of Hepatitis A and B and cytomegalovirus is clear. Cytomegalovirus infection of the intestinal tract may be associated with a specific route of transmission of the disease. Repeated inoculation with this pathogen through unprotected sex likely increases the incidence of CMV enteritis, and can lead to the spread of CMV to the eye, where it can cause loss of vision. The oral-fecal route of transmission of hepatitis A is well-established. HIV positive individuals who are infected with hepatitis are at greater risk of progression to chronic liver disease. Although sexual contact is not the only route of infection with these opportunistic pathogens, there is an opportunity to significantly lower the odds of contracting them by simply observing the practice of protected sexual contact. An HIV positive individual is more at risk of contracting most infections from an HIV negative sexual partner than the reverse, with the exception of HIV infection itself. Both considerations should be compelling reasons for protecting yourself and your partner. Kaposi's Sarcoma For many years, researchers have noticed the relationship between the sexual route of acquisition of HIV infection and the increased incidence of KS. The etiologic agent of KS has yet to be definitively identified, but increasing evidence points to a newly identified herpesvirus. To balance recently published evidence of genetic sequences that match herpesvirus sequences in KS tissue, a report from the Lancet in 1992 provided evidence of human papillomavirus sequences in tissue derived from KS lesions. In either event, the sexual transmission of both herpes and papilloma viruses is well-established. It remains to be elucidated which virus is the needed cofactor for the development, and which sexual practices are closely associated with transmission. Some conclusions can be inferred from the higher incidence of KS in gay men, and oral-anal sexual practices among gay men, but this association is still speculative. Cryptosporidiosis Cryptosporidiosis is a parasitic infection that is spread by oral- anal contact as well as by drinking contaminated water (see article in December 1994 BETA by Leslie Hanna). It causes diarrhea, often severe, and may be a contributing factor to AIDS wasting. Treatment is unsatisfactory, particularly in advanced HIV disease. Some newer experimental treatments, including bovine immunoglobulin, show some promise in controlling the profuse diarrhea that is characteristic of cryptosporidiosis at very low T-cell counts, but it is best to reduce the risk of acquiring cryptosporidiosis by avoiding unprotected rimming. Also helpful is avoiding oral contact with a penis, sex toy or finger that has had direct contact with the rectum. If You Can't (Or Won't) Be Safe, Be Smart The wisest course of action is always to use condoms during anal sex or penetrative vaginal sex, dental dams during oral-anal contact with men or women or oral-vaginal contact with women, and latex gloves during manual stimulation of any orifice. There is ample evidence to suggest that HIV positive individuals are not assiduously following this advice. What other kinds of precautions might help to slow the transmission of HIV and other pathogens to an HIV-positive individual? Although they are not enough, the following list of suggestions is an attempt to negotiate some extra measure of safety during the second wave of the epidemic in the gay community, and the long-feared arrival of rapid HIV spread among heterosexuals.  Oil-based lubricants can cause latex condoms to break. Use water-based lubricants instead.  Strongly consider stopping sex play if cuts or scratches occur.  Do not floss or brush your teeth immediately before engaging in oral sex. Small tears in the mucosal lining of the mouth can allow microorganisms to gain a foothold. Treat gum disease promptly.  Maintain healthy gums with visits to the dentist every 6 months. If you have a cancer sore, herpes sore, or other ulcer in the mouth, wait until they're healed before having oral sex.  Do not have unprotected oral-anal contact (rimming).  Check your sex partner for sores. A condom won't protect you from sores that it doesn't cover.  Do not douche before or after sex. To do so washes away naturally protective body secretions.  If you do not wear latex gloves during rough sex play, make sure your nails are trimmed and clean.  Use nonoxynol-9 to reduce the spread of viral infections. HIV can be killed by nonoxynol, and some evidence suggests effectiveness against hepatitis viruses as well.  Use condoms before their expiration date. Don't carry them for long periods of time in your wallet or leave them to overheat in the glove compartment.  If you engage in receptive anal or vaginal sex, or have a history of genital or anal warts, have a regular pap smear. Identify potential problems early, and seek medical attention to them. The Bottom Line Sex is not a luxury that you can easily do without. There is no reasonable substitute that is as pleasurable. You can choose to practice lifelong celibacy, but to do so is like never crossing a city street for fear that you will be hit by a car. Using condoms and common sense are as practical and potentially lifesaving as looking both ways at a busy intersection. The chances of disaster striking increase in either case if you tightly close your eyes and just forge ahead. Think ahead, plan ahead, weigh the risks, and enjoy sex for what it is: the most intimate form of human contact. References The author gratefully acknowledges the assistance of Harvey Bartnof, MD, who provided most of these references. Archibald CP and others. Evidence for a sexually transmitted cofactor for AIDS-related Kaposi's sarcoma in a cohort of homosexual men. Epidemiology. 3:203-209. 1992. Brown M and others. Detection of HIV-1 in Entamoeba histolytica without evidence of transmission to human cells. AIDS. 5:93-96. 1991. Gill SK and others. Transmission of HIV-1 infection by oroanal intercourse. Genitourinary Medicine, 68:254-257. 1992. Karchmer AW. Sexually Transmitted Diseases, in Scientific American Medicine, Rubenstein E, MD, Editor. Scientific American, Inc. New York, 1995. Keet IPM and others. Orogenital sex and the transmission of HIV among homosexual men. AIDS. 6:223-226. 1992. Krieger JN and others. Recovery of Human Immunodeficiency Virus type 1 from semen: minimal impact of stage of infection and current antiviral chemotherapy. Journal of Infectious Diseases 163 (2):386-8. February 1991. Malamud D and Friedman HM. HIV in the oral cavity: virus, viral inhibitory activity and antiviral antibodies: a review. Critical Reviews in Oral Biology and Medicine. 4(3-4):461-6. 1993. McKenna JG and others. Cold sores and safer sex. The Lancet. 338:632. September 7, 1991. Murray AB and others. Coincident acquisition of Neisseria gonorrhoeae from fellatio. The Lancet. 338:830. September 28, 1991. Puro V and others. Male-to-female transmission of HIV by oro-genital sex. European Journal of Clinical Microbiology and Infectious Diseases. 10:147. January 1991. Romeyn M. Nutrition and HIV: A New Model for Treatment. Jossey-Bass, San Francisco In-press. 1995. Sanford JP and others. The Sanford Guide to HIV/AIDS Therapy 1994 Antimicrobial Press, Dallas. 1994. Sanford JP and others. The Sanford Guide to Antimicrobial Therapy 1994. Antimicrobial Press, Dallas. 1994. ------------------------------------------------------------------ Long-Term Non-Progressors, Survivors and HIV Positives Harvey S. Bartnof, MD Harvey Bartnof is a clinical faculty member at the University of California at San Francisco (UCSF) School of Medicine where he has been course director of "AIDS-HIV: Overview and Update" since 1985. He has been a member of the San Francisco AIDS Foundation Scientific Advisory Committee since 1987. Significant research on HIV-infected long-term non-progressors continues to accumulate, with the hope that it may provide insights into potential therapies and vaccines that may prevent primary HIV infection and enable HIV positive people to become or remain long-term non-progressors. The X International Conference on AIDS (see "Treatment Updates from the X International Conference on AIDS in Yokohama, Japan" in the September 1994 issue of BETA) and recent medical literature have provided new information on this topic. The definition of long-term non-progressors varies somewhat among different research groups. Except where otherwise noted, long-term non-progressors of HIV infection include people with documented HIV infection for over 10 years who remain asymptomatic; who have normal and stable immunologic profiles, e.g., non-declining CD4 counts; and who have not received any anti-HIV treatments. Some research groups use the alternative terms "long-term survivors" or "healthy HIV positives." In cohort studies of HIV infection, approximately 5% of participants are long-term non-progressors/survivors. David Ho, MD, Yunzhen Cao, MD, and colleagues from the Aaron Diamond AIDS Research Center at New York University School of Medicine reported their observations of 10 long-term survivors of HIV infection in the January 26, 1995 issue of The New England Journal of Medicine. All 10 subjects have remained asymptomatic, with normal and stable CD4 counts, despite 12 to 15 years of HIV-1 infection. The subjects, 9 men and 1 woman, are from the New York metropolitan area and range in age from 38 to 47 years. Seven had a transmission risk of male-male sex, 2 men were infected through injection drug use, and the woman was infected through heterosexual contact. The CD4 counts for all 10 were consistently in the normal range and did not decline. The highest CD4 count was 1200 cells/mm3 (2 people); 3 had a low of 500 cells/mm3; 1 had a one-time low of 400 cells/mm3. Four had received short courses of anti-HIV therapies: 2 had received short courses of AZT (zidovudine, Retrovir), 1 of ddI (didanosine, Videx) and 1 of recombinant gp160. At the time of the evaluations, no subject was receiving anti-HIV therapies. When the researchers evaluated for genetic markers (human leukocyte antigens, HLA), they observed no specific patterns. This differs from the Buchbinder findings in San Francisco described below. The Ho group performed several measurements of viral load and virulence (strength); the levels of HIV viral infectivity generally were very low to undetectable. This was revealed when the researchers tried to culture HIV from participants' blood plasma (liquid portion) or blood mononuclear cells (lymphocytes and monocytes); plasma cultures were negative for infectious virus. Plasma viral burden of RNA measured by the branch DNA (bDNA) test was very low; in 5 participants, the HIV RNA was below the limits of detection. Polymerase chain reaction (PCR) testing of blood mononuclear cells revealed very low levels of DNA, significantly lower than in those with progressive HIV disease. The culture, bDNA and PCR tests of the 10 long-term survivors indicated to the researchers that HIV-1 replication is well controlled in vivo. Dr. Ho and his group then attempted to determine whether in vivo control of HIV replication was somehow related to the virus or to the immune systems of the participants. The researchers removed some lymphocytes and monocytes from the subjects to determine whether those cells could resist infection from an entirely different HIV-1 strain in vitro. They found that a different HIV-1 strain would not grow very well in cultures of the participants' mononuclear cells, even though the same strain would grow in mononuclear cell cultures from HIV negative controls. However, when they removed the CD8 lymphocytes from the same cultures, the new HIV-1 strain grew easily. This is similar to the CD8 cell anti-HIV findings of Jay A. Levy, MD, of the University of California at San Francisco (UCSF) School of Medicine, and co-workers (see below). Dr. Ho's group concluded that "the CD4 lymphocytes from long-term survivors had no gross intrinsic resistance to HIV-1 infection in vitro. Instead, there is strong evidence to suggest that CD8 lymphocytes from the survivors had substantial HIV-1 inhibitory activity." In addition, the researchers found that CD8 cell anti-HIV activity in the participants was much stronger than in controls with progressive HIV disease. Specifically, non-progressors needed fewer CD8 cells to cause an anti-HIV effect than did progressors. In addition to a strong cellular immune response, Dr. Ho's group also determined that the humoral component of the subjects' immune systems contributed to the strong anti-HIV effect. "The plasma samples from our long-term survivors had broad neutralizing activity in general, especially when compared with the lack of neutralizing activity of plasma samples from subjects with progressive disease." These findings suggest that the "long-term survivors had vigorous functional antibody responses directed against HIV-1." In 2 subjects, viral growth indicated the presence of an attenuated (weakened) strain. The Ho group, however, did not find a defect in the nef gene of HIV among their long-term survivors. This differs from the report by Dr. Kirchhoff and colleagues, of Harvard Medical School, where the absence of the nef gene of HIV was associated with long-term non-progression (see below). Dr. Ho believes that their findings are consistent with numerous other reports in the medical literature which indicate that "HIV-1 disease progression is driven by an increasing viral burden." The group also believe that the high levels of neutralizing antibodies and the strong CD8 cell response indicate that "the immune system of the long-term survivors must have been continually exposed to (HIV) viral antigens." Giuseppe Pantaleo, MD, Susan Buchbinder, MD, Anthony Fauci, MD, and colleagues published their findings in the same January 26, 1995 issue of The New England Journal of Medicine. Drs. Pantaleo and Fauci are from the National Institute of Allergy and Infectious Diseases (NIAID); Dr. Buchbinder is from the San Francisco Department of Public Health AIDS Office. The Pantaleo group compared lymph node observations in 15 long-term non-progressors to HIV positive progressor controls. They defined long-term non-progressors as having: documented HIV infection for more than 7 years, stable CD4 counts above 600 cells/mm3, no HIV-related symptoms and no antiretroviral therapy. Thirteen of the 15 had been HIV positive for more than 10 years. The 15 participants included 7 from the Multicenter AIDS Cohort Studies (MACS) from 4 U.S. cities, 4 from the San Francisco City Clinic Cohort and 4 from a lymph node study at NIAID. The age range of the participants was 32 to 46 years. All 14 men acquired HIV infection through male-male sex, while the woman acquired HIV through heterosexual contact. The mean CD4 count was 865 cells/mm3, with a low of 674 cells/mm3 and a high of 1,287 cells/mm3. The mean CD4 lymphocyte percentage was 33%, with a low of 20% and a high of 44%. The CD8 counts were all high, ranging from 527 cells/mm3 to 2,483 cells/mm3. The lymph nodes in the majority of HIV positive persons are known to undergo predictable changes over time. Early changes include an expansion of the germinal center, where B lymphocytes increase in number. In late-stage AIDS, the lymph glands involute, i.e., shrink and lose their normal shape and internal structures. This latter stage is associated with the period of CD4 cell depletion. In 9 of 14 lymph nodes from 14 long-term non-progressors, Pantaleo found very few of the abnormal changes in lymph node architecture that were seen in the control patients with progressive HIV disease. When the researchers compared the long-term non-progressors to the control progressor group, they observed the following 4 statistically significant results: 1. viral burden of HIV DNA in mononuclear cells, measured by PCR, decreased more than 5-fold in both the lymph nodes and blood of the non-progressors; 2. viral replication in mononuclear cells, measured by HIV RNA, was reduced 4- to 10-fold in both the lymph nodes and the blood of the non-progressors; 3. plasma viremia, measured by HIV RNA outside of mononuclear cells in plasma, was substantially reduced (up to 20-fold) in the non-progressors and; 4. neutralizing antibodies were significantly higher in the non-progressors. Standard cultures revealed no in vitro HIV growth whatsoever when plasma from the non-progressors was added, whereas cultures with plasma from progressors readily grew HIV. Cultures with mononuclear cells from either non-progressors or progressors revealed viral growth. The Pantaleo group reached conclusions similar to those of the Ho group: "The presence of high titers of neutralizing antibodies, together with the consistent detection of HIV-specific cytotoxicity, indicates that both humoral and cell-mediated immune responses are preserved in the subjects with long-term non-progressive [HIV] infection and strongly suggests that these persons are constantly exposed to HIV antigens. Subjects with long-term non-progressive HIV infection have preserved lymphoid tissue despite a low but persistent level of viral replication In persons who remain free of disease for many years despite HIV infection the viral load is low, but viral replication persists. Lymph node architecture and immune function appear to remain intact." In the past, infection by a defective strain of HIV in long-term non-progressors was a hypothetical situation. A third report in the January 26, 1995 issue of The New England Journal of Medicine reveals that one research group has found such a strain. Frank Kirchhoff, PhD, and co-workers from Harvard Medical School found 7 long-term survivors with non-progressive HIV infection from a cohort group of patients with hemophilia. Kirchhoff defined non-progressive HIV infection as: known HIV infection since 1983 or earlier, asymptomatic state, no history of anti-retroviral therapy, a CD4 count above 400 cells/mm3 and more than 30% of total T-cells, or a CD4 count above 600 cells/mm3, regardless of CD4 lymphocyte percentage. Researchers focused on the nef gene of HIV. The nef gene function has not been clearly determined; considered an auxiliary gene, it is not required for HIV replication in vitro. However, in a rhesus monkey AIDS model, nef is required for the development of AIDS after infection with simian immunodeficiency virus (SIV). When rhesus monkeys are infected with nef-deficient SIV, they do not manifest AIDS. Rather, they show characteristics of a long-term non-progressor. Specifically, those monkeys are SIV-antibody positive, have normal CD4 counts, have low SIV-viral burden and show no signs of disease progression. In examining the nef gene of HIV from 5 of the 7 non-progressor hemophiliacs, Dr Kirchhoff's group found a 44-year-old man who had only defective forms of nef over a 10-year period. This man's HIV DNA viral burden in mononuclear cells was 10- to 3,500-fold lower than controls with progressive HIV disease. In multiple attempts to grow HIV in vitro from the man's plasma or mononuclear cells, cultures have remained negative. Normal nef was found in the other 4 non-progressors examined. The researchers believe that their results indicate that infection with attenuated HIV-1 may be a factor in the non-progression of their patients and perhaps in a minority of other non-progressors. The research group stated that the clinical and virologic characteristics of the man with defective nef were similar to those of rhesus monkeys infected with nef-deficient SIV. Interestingly, rhesus monkeys infected with nef-deleted SIV are protected against subsequent infection by normal AIDS-inducing SIV (with normal nef). In an accompanying editorial in the same New England Journal of Medicine issue, David Baltimore, PhD, amplifies the implications: "an interesting corollary of non-progressive [HIV] infection is that if viral mutations are responsible in some cases, those hosts [may] be immune to a second infection ... for example, the person harboring the strain with nef deletions has hemophilia and probably had multiple exposures to HIV [through blood protein factor VIII infusions]." Dr. Kirchhoff and colleagues have suggested that HIV-1 strains with multiple gene deletions should be considered for trials as an experimental live attenuated vaccine. They concluded, "the finding of only HIV-1 variants with nef deletions in a healthy man with long-term non-progressive HIV-1 infection provides additional impetus for consideration of this vaccine approach." Drs. F. Huang, David Ho and colleagues also examined the HIV nef sequence in their 10 long-term survivors and reported the findings in the January 1995 Journal of Virology. PCR and DNA sequencing were performed on their subjects' mononuclear cells, and no gross deletions within nef were found. The researchers did find other genetic defects in 2 of the 10 patients. Specifically, those defects were found in the "NF-kappa-B and Sp1 sites within the viral long-terminal repeats." Australian researchers have epidemiologic evidence of a likely HIV-1 mutant strain being associated with non-progression. In a 1992 issue of Lancet, Dr. Jennifer Learmont and colleagues reported on a cluster of 6 long-term HIV-infected non-progressors who received blood transfusions 7 to 10 years earlier from a blood donor who is also a long-term non-progressors. Five of the 6 transfusion recipients and the blood donor had normal CD4 counts and no HIV symptoms. HIV could be cultured from only 1 of the 5, and that 1 isolate showed weakened growth in vitro. One of the 6 recipients developed Pneumocystis carinii pneumonia (PCP) after receiving immunosuppressive therapy for autoimmune lupus disease, and died 4 years after the HIV-related transfusion. Susan Buchbinder, MD, and colleagues from the San Francisco Department of Public Health AIDS Office published an update of their findings on 42 gay/bisexual men who are "healthy long-term HIV positives" in the August 1994 issue of AIDS. The men were part of the San Francisco City Clinic Cohort comprised of individuals initially recruited in 1978-1980 for hepatitis B vaccine trials. Dr. Buchbinder's definition of "healthy long-term HIV positive" required documented HIV infection for 10-15 years, no AIDS diagnosis and a CD4 count greater than 500 cells/mm3. Forty-two of 539 men (8%) with known HIV seroconversion before 1983 met this definition of healthy long-term HIV positive. Dr. Buchbinder's analysis included 2 comparison groups consisting of HIV progressors and male HIV negative controls. Thirty-eight percent (38%) of the healthy long-term HIV positive group had a history of prior antiretroviral use. The mean CD4 count of the healthy long-term HIV positive group was 692 cells/mm3 compared to a mean of 984 cells/mm3 in the HIV negative control group. Although the healthy long-term HIV positive group had lower CD4 counts than the HIV negative controls, the healthy long-term HIV positive counts were stable over time. When compared with HIV progressors who had a median CD4 lymphocyte loss of 85 cells/mm3 annually over 4 years, the healthy long-term HIV positives had only a median 6 cells/mm3 annual loss of CD4 cells. HIV negative controls lost a median of 7 cells/mm3 CD4 cells annually. When compared with progressors, the healthy long-term HIV positives had significantly higher CD8 counts, CD4/CD8 ratios, white blood cell counts, hemoglobin and platelet counts, and significantly lower beta 2-microglobulin levels. The healthy long-term HIV positives also had significantly higher CD8 counts than the HIV negative controls, contributing to the lower CD4/CD8 ratio. When compared with the HIV negative controls, the beta 2-microglobulin was higher in the healthy long-term HIV positives (none was detected in the controls), while the white blood cell count was significantly lower. Further comparisons of the HIV negative controls with the healthy long-term HIV positives revealed no differences in the hemoglobin or platelet counts. Since 12 out of 42 (29%) did have HIV-related symptoms or signs, it is possible that this healthy long-term HIV positive group comprised some individuals who are slow progressors and not "true" non-progressors. The authors suggest that "HIV-induced immunologic destruction may be slowed or arrested in healthy long-term HIV positives." The significance of the CD8 elevations were discussed in the description of the Ho study above and will be addressed under the report of the Levy study below. At the X International Conference on AIDS in Yokohama (see BETA September 1994), Dr. Buchbinder updated her percentages reported in AIDS. Her update encompassed 552 patients infected with HIV for 10-16 years; 6.9% are healthy long-term HIV positive. She also reported a statistically significant difference in the incidence of certain genetic markers (HLA, both class I and II) among the healthy long-term HIV positive group when compared with progressors. Ongoing studies of healthy long-term HIV positives from the City Clinic Cohort are analyzing viral burden, qualitative CD8 cell functioning and apoptosis (premature cell death) measurements. For more than 10 years, Jay A. Levy, MD, and colleagues from the University of California at San Francisco (UCSF) School of Medicine have been evaluating several aspects of long-term HIV survivors from San Francisco. His most recent reviews appear in the October 1994 issue of Hospital Practice and the July 1993 issue of AIDS. He also presented his findings at a plenary session with Drs. Robert Gallo and Luc Montagnier at the X International Conference on AIDS. Dr. Levy's research group identified 5 characteristics of long-term survivors (LTS) (three of the 5 features have been mentioned in one or more of the studies discussed above): 1. Low viral load: PCR and HIV cultures of lymph nodes and blood mononuclear cells of LTS reveal low HIV viral burdens, compared with those of progressors. 2. HIV strains with low cytopathogenicity (ability to cause disease in cells): HIV strains of LTS tend to be slow replicators in macrophages and do not thrive in most other cell types. Some LTS have been identified as being infected with weakened or mutated HIV strains. 3. Absence of enhancing antibodies: enhancing antibodies bind to viruses like HIV but, instead of inactivating them, actually facilitate viral entry into uninfected macrophages and CD4 cells. Enhancing antibodies, commonly found in HIV progressors, are not found in LTS. 4. Greater TH1 response than TH2 response: the TH1 subset of CD4 lymphocytes promotes a cell-mediated immune response, whereas the TH2 subset promotes the humoral or antibody-mediated immune response. Each of the 2 subsets is associated with a different cytokine-response profile. TH1 cells promote production of interleukin 2 (IL-2) and gamma interferon, whereas TH2 cells promote production of IL-4 and IL-10. While there have been somewhat conflicting reports in the literature, Dr. Levy has found that LTS have a predominant TH1 profile, while progressors tend to have a predominant TH2 profile. 5. Strong CD8 cell anti-HIV response: Drs. Levy, Chris Walker and colleagues at UCSF were the first researchers to report this phenomenon in 1986 in the journal, Science. Since that time their research group has published numerous research papers characterizing the CD8 response in LTS. Several aspects of their findings were recently duplicated in the LTS of the Ho group study. Dr. Levy's group has determined several characteristics of the CD8 cell anti-HIV factor (CAF). They include:  the CAF effect is strong in LTS and weak in progressors.  CAF inhibits HIV replication in CD4 cells and macrophages without killing the cells.  CAF blocks HIV replication after HIV is integrated into human genes by blocking production of HIV RNA.  CAF has no effect on CD4 cell activation or reproduction.  CAF is produced only by activated CD8 cells.  CAF is most evident in the CD28 subset of CD8 cells, a subset known to decrease in progressors.  CAF's effects are enhanced somewhat by AZT (see "Research Notes" in the March 1995 issue of BETA).  CAF's effects are enhanced by TH1 cells secreting IL-2 and blocked by TH2 cells secreting IL-10.  CAF is not any other known cytokine.  CAF is active against HIV-1, HIV-2 and SIV.  CAF is a small protein (smaller than 30 kilodaltons).  CAF is heat-stable and pH- (acid) stable. The CD8 cell anti-HIV factor was one of the reasons for instituting clinical trials of expanding the CD8 cell population in HIV positive patients. In those studies CD8 cells are removed from an HIV positive patient, grown and expanded in vitro and reinfused into the patient in an attempt to achieve an increased anti-HIV effect. The recently announced benefits of IL-2 infusions 5 days every 2 months for 1 year (see "News Briefs" in the March 1995 issue of BETA) may be related to the TH1 profile-associated CAF observed in LTS. The research was reported by H. Clifford Lane, MD, and colleagues from NIAID in the March 2, 1995 issue of the New England Journal of Medicine. Dr. Levy's group and other research groups are continuing their efforts related to CAF and other aspects of long-term survivors. References Altman LK. Long-term survivors may hold key clues to puzzle of AIDS. The New York Times B7. January 24, 1995. Baltimore D. Lessons from people with non-progressive HIV infection. New England Journal of Medicine 332(4): 259-260. January 26, 1995. Bartnof HS. Long-term non-progressors and long-term survivors. In "Treatment Updates from the X International Conference on AIDS in Yokohama, Japan." Bulletin of Experimental Treatment for AIDS: 10-17. September 1994. Buchbinder SP and others. Long-term HIV-1 infection without immunologic progression. AIDS 8(8): 1123-1128. August 1994. Cao Y and others. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. New England Journal of Medicine 332(4): 201-208. January 26, 1995. Greenough TC and others. Normal immune function and inability to isolate virus in culture in an individual with long-term human immunodeficiency virus type 1 infection. AIDS Research and Human Retroviruses 10(4): 395-403. April 1994. Huang Y and others. Characterization of nef sequences in long-term survivors of human immunodeficiency virus type 1 infection. Journal of Virology 69(1): 93-100. January 1995. Kirchhoff F and others. Brief report: absence of intact nef sequences in a long-term survivor with non-progressive HIV-1 infection. New England Journal of Medicine 332(4): 228-232. January 26, 1995. Learmont J and others. Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet 340(8824): 863-867. October 10, 1992. Levy JA. Long-term survivors of HIV infection. Hospital Practice 29(10): 41-44,47. October 15, 1994. Levy JA. HIV pathogenesis and long-term survival. AIDS 7(11): 1401-1410. November 1993. Pantaleo G and others. Studies in subjects with long-term non-progressive human immunodeficiency virus infection. New England Journal of Medicine 332(4): 209-216. January 26, 1995. Walker CM and others. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234(4783): 1563-1566. December 19, 1986. ------------------------------------------------------------------ Turning the Corner on Wasting? A Symposium on Wasting Disorders Jeff Getty Jeff Getty is an AIDS treatment activist with ACT UP/Golden Gate in San Francisco. On February 23, 1995, Serono Symposia/USA sponsored a major meeting of leading endocrine researchers in the field of wasting disorders. The purpose of the symposium was to gather together specialists from several medical fields to compare notes and to further the current state of knowledge about wasting. Exchanges between people in different medical specialties was highly encouraged. Before beginning an analysis of the various posters and presentations at the symposium, it might be helpful to review the current state of endocrine research as it pertains to AIDS-related wasting. Malabsorption and Metabolic Disturbances The causes of wasting can be divided into 2 main categories: malabsorption and metabolic disturbances. This article focuses on endocrine involvement in AIDS-related wasting, and will touch only briefly on malabsorption in AIDS. Malabsorption is often caused by intestinal disease that directly affect the intestinal surface area and its ability to absorb nutrients. Intestinal diseases and diarrhea are common in AIDS; there are limited ways to help solve these problems. Early and precise diagnosis of intestinal opportunistic infections (OI) can help alleviate some cases of malabsorption. However, not all AIDS-related wasting follows a typical pattern of starvation. Simple nutrition and infection control are not enough to solve the problems associated with malabsorption. Metabolic Disturbances and Endocrine Dysfunction Scientists are just now piecing together the highly complicated puzzle of endocrine-related wasting in HIV disease. Essentially, the human endocrine system is made up of the glands and pathways that the body uses to produce and secrete hormones. The main components of the endocrine system are the hypothalamus, the pituitary gland, the thyroid gland, the adrenal gland and the ovaries or testes. Each of these glands secretes specific hormones that directly affect the body's metabolism, immune system and reproductive system. The pituitary gland, for example, produces growth hormone (GH), luteinizing hormone (LH) and others. The endocrine system also contributes to the maintenance of weight and energy levels. What do we know so far about endocrine involvement in wasting? Furthermore, what impact do HIV, OI and certain drugs have on the endocrine system? At what point in HIV disease progression do metabolic disturbances take place? In an attempt to answer such questions, a summary of relevant finding from The Endocrinology of Metabolism of HIV Infection follows. Several glands of the endocrine system are thought to be involved in wasting. Though some glands are directly infected by HIV, cytomegalovirus (CMV), Toxoplasma gondii and herpes simplex virus (HSV), these organisms do not usually directly cause glandular destruction. However, HIV may affect metabolic function and output without direct organ infiltration. These hormonal disturbances can be attributed to stress and to the body's reaction to disease. Early signs of metabolic and endocrine involvement in HIV disease can be seen in the results of studies suggesting that basal aldosterone levels (a measurement of a potent electrolyte-regulating hormone that causes sodium retention by cells) were significantly lower even in asymptomatic HIV positive men. The same studies also showed higher than normal free serum testosterone levels; yet testosterone levels appear to be deficient in later disease progression. Cytokines may play an important role in wasting since interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) are known to disrupt normal hormone production. Also, TNF-alpha has a direct effect on testicular tissue by reducing both weight and testosterone levels. IL-1 inhibits testicular steroidogenesis in the test tube, which has led to calls for more study of the relationship between gonadal steroids and wasting. Some researchers believe that the thyroid gland either affects or is affected by AIDS-related wasting. The debate centers on whether thyroid T3 levels (a measurement of energy uptake and calorie burn) are higher than they should be when compared to other catabolic states, such as exist in late-stage cancer (catabolism is the breakdown of stored tissue for energy). It has also been noted that TNF-alpha may cause T3 levels to remain too high, implying that AIDS wasting patients are burning too much energy and causing depletion of nutrient stores. Some researchers say that T3 levels do, in fact, drop appropriately during acute infections and return to near normal during healthy phases. Indeed, this would imply that comparing the T3 levels in stable AIDS patients with wasting and in catabolic cancer patients with numerous tumors may yield misleading conclusions. Most researchers agree that the adrenal cortex is affected in patients with AIDS-related wasting, although mostly only at a subclinical level. Hypercortisolemia (higher than normal cortisol levels) is noted at most stages of HIV disease, particularly during a secondary infection. Since cortisol is a by-product of immune activation and is part of the anti-inflammatory process, there may be some long-term adrenal endocrine abnormality that is not yet known, but is directly linked to wasting. The base level metabolic rate is elevated in asymptomatic HIV positive individuals. The hypothalamic-pituitary-gonadal axis (HPG axis), is a favorite among many endocrinologists as a probable link to hypogonadism (inadequate gonadal function caused by deficiencies in the secretions of hormones), and is associated with elevated levels of LH and follicle-stimulating hormone (FSH), a hormone that promotes the creation of ovarian follicles and sperm. Hypogonadism is common among HIV-infected men and there is speculation that it could be a cause of testicular failure, although there is evidence of direct pathogen infiltration of the testes in as many as 25% of those who have died from AIDS. Elevated LH and FSH levels occur with low, free testosterone levels; this is a hormonal pattern associated with testicular failure. It has also been noted that direct CMV infection, and perhaps HIV infection of the glands of the HPG axis could be indirectly responsible for AIDS wasting. Recent findings about recombinant human growth hormone (rHGH) from an intensive 7-day baseline and 7-day treatment study at the University of California, San Francisco General Hospital, produced some carefully defined results regarding nitrogen retention, substrate oxidation and body weight. For the first time in AIDS-related wasting, this study documents the reversal of lean body wasting as demonstrated by decreased nitrogen in the urine and decreased protein oxidation. Substantial body weight increases after only 7 days of therapy have also been demonstrated. Interestingly, HIV negative control subjects produced a greater amount of insulin growth factor 1 (IGF-1), than did HIV positive subjects, leading researchers to conclude that AIDS wasting patients are probably resistant to their own GH. Other factors in AIDS wasting include: 1. inability to clear lipids from the body, causing futile lipid cycling which could deplete energy and nutrient stores (not well proven); 2. hyponatremia (low sodium levels), partially related to trimetrexate use; 3. hyperkalemia (high potassium levels), partially related to trimethoprim use; 4. calcium disorders; and 5. pancreatic abnormalities. Finally, certain drugs commonly used in HIV may contribute to wasting disorder. The table below summarizes the effects of these drugs. Symposium Highlights Poster presentations at the Serono Wasting Symposium were limited, with only a few directly related to AIDS wasting. "HIV Illness and Testosterone Replacement Therapy: Anabolic Effects" by Richard Rabkin, MD, of Columbia University, reported on a study of 72 men who completed a 12-week trial of biweekly testosterone replacement therapy. Mean weight increased significantly, (though researchers did not state actual figures), and body composition changes were noted. Symposium presentations of interest on the subject of AIDS-related wasting included the following: "The Role of Malabsorption in Nutritional Balance" by Donald P. Kotler, MD, symposium co-chair, outlined the importance of malabsorption in wasting and pointed out that certain intestinal disorders can destroy intestinal surface area as well as lead to motility disorders. Kotler also stated that malabsorption can have a negative effect on appetite, further exacerbating wasting. Kotler also spoke on "Nutritional Alteration in HIV Infection." He stressed the importance of nutritional support and effective treatment of underlying infections. He reviewed the various forms for repletion of body cell mass, such as total parenteral nutrition (TPN), tube feeding and appetite stimulation. Kotler also mentioned human growth hormone to promote fat-free mass repletion. "Nutritional Therapies in HIV Infection: Implications of Metabolic Abnormalities" by Mark Hellerstein, MD, showed that HIV-related wasting is not a starvation model, and that simply adding more nutrients will not improve wasting. Any therapy that increases lean body mass, such as anticytokines, androgens, growth factors and exercise should be considered, he said. Patients should be identified and stratified as to type of wasting before treatment begins. Probably the most important speaker on AIDS-related wasting was Morris Schambelan, MD, of San Francisco General Hospital, who presented "The Use of Anabolic Agents in HIV Infection." Schambelan reported on 2 double-blind studies of 178 HIV positive patients who received recombinant human growth hormone (Serostim) for wasting. He reiterated that there were both total body weight gain and lean body mass gain along with simultaneous decreases in fat levels. Of special interest was the metabolic information Schambelan presented indicating the reversal of AIDS wasting for the first time. Patients in his studies had documented nitrogen level changes and protein oxidation changes, thought to be hard evidence of lean mass building. Schambelan's use of a nitrogen-retention assay and a new body-scanning system may pave the way for future FDA approval of anabolic agents for the treatment of wasting. Schambelan also spoke about future wasting studies that he and his colleagues hope to pursue in the coming year. He suggested that anabolic steroids in combination with anti-cytokines, (e.g. thalidomide) are the newest therapies for AIDS-related wasting (see Research Notes, page 57). Steven B. Heymdsfield, MD, spoke about new methodology in understanding body composition. He covered the latest formula for quantifying body composition and pointed out that research is now yielding powerful and precise ways to gather these data. The implication is that the better one can measure wasting, the better one can prove that a given therapy is working. The lack of validated assays to measure body mass has long been a problem that has delayed the approval of AIDS-related wasting therapies. Carl Grunfeld, MD, symposium co-chair, helped rule out some of the previously theorized causes of wasting in his talk, "Changes in Lipid Metabolism as Part of Host Defense." Hypertriglyceridemia, thought to be a possible cause of wasting, may be no more than a sign of normal "host defense," the body's natural reaction to infection. Grunfeld noted that in AIDS, TNF-alpha increases triglycerides (high triglycerides are often seen in AIDS and wasting patients) by increasing liver lipogenesis (fat production) and mobilizing fatty acids from the triglycerides. He pointed out that hypertriglyceridemia can be seen in animals that receive cytokine therapy and yet do not waste. Grunfeld proposed that changes in lipid metabolism may have some beneficial effects, helping the body to deal with the effects of chronic infection. Finally, a more detailed research update on thalidomide bears mention. Researchers were quite interested in preliminary results from the thalidomide study of Gilla Kaplan, MD, which was recently concluded at Rockefeller University in New York City. In an article published in the May 1995 issue of Molecular Medicine, Kaplan reports that thalidomide helped patients with HIV and tuberculosis by reducing weight loss. In Kaplan's study of 30 male patients who had active TB and HIV, 20 in Thailand and 10 in the U.S., researchers gave thalidomide (300 mg daily) or placebo in 14-day cycles. Patients reported only minor side effects. No increase in neuropathy was seen. Thalidomide caused a decrease in serum TNF-alpha and a significant enhancement of weight gain. All patients who received thalidomide gained weight, with some patients gaining nearly 3 kg in 14 days. Researchers noted that some of the thalidomide-induced weight gain was retained for 4 weeks after thalidomide cessation, indicating that weight gain was not attributable to transient fluid retention. Lean and fat mass scans were not performed in this study, but will be reported later from ongoing work at Rockefeller University. The author wishes to thank Karen Eisenhauer, Dr. David Katz, Dr. Morris Schambelan, Dr. Carl Grunfeld and Kenneth Klueh for their help and guidance. References Coodley G and others. Endocrine function in the HIV wasting syndrome. Journal of Acquired Immune Deficiency Syndromes 7(1): 46-51. 1994. Croxon and others. Changes in hypothalamic-pituitary-gonadal axis in HIV infected homosexual men. Journal of Clinical Endocrinology and Metabolism 68(2): 317-321. 1994. Dobs A and others. Endocrine disorders in men infected with human immunodeficiency virus. The American Journal of Medicine 84: 611-616. March 1988. Grunfeld C and others. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. New England Journal of Medicine 327-337. July 1992. Hellerstein M. HIV-associated metabolic disturbances and body composition abnormalities: therapeutic implications. Clinical Notes SFGH 8(1). March 1994. Kuby J. Role of cytokines in the inflammatory response. Immunology, second edition 313-315. 1994. Merenich J and others. Evidence of endocrine involvement early in the course of HIV disease. Journal of Clinical Endocrinology and Metabolism 70: 566-571. 1994. Mosmann T. Cytokine patterns during the progression to AIDS. Science 265: l93-194. July 1994. Mulligan C and others. Anabolic effects of recombinant human growth hormone in patients with wasting associated with HIV. Journal of Clinical Endocrinology and Metabolism 77(4): 956-962. 1994. Norbiato G. The endocrinology and metabolism of HIV infection. Bailliere's Clinical Endocrinology and Metabolism 8(4): 735-882. October 1994. Schambelan M. and others. Endocrine abnormalities associated with HIV infection and AIDS. Textbook of AIDS Medicine. Broder S, Merrigan TC and Bolognesi D, editors. Williams & Wilkins, Baltimore. 1994. ------------------------------------------------------------------ State of the Art in Wasting: An Interview with Carl Grunfeld, MD, PhD Jeff Getty BETA interviewed Carl Grunfeld, MD, PhD, PharmD, Professor of Medicine at the University of California, San Francisco. Dr. Grunfeld has published numerous articles on growth hormone (GH) and AIDS-related wasting. BETA: What similarities are there between AIDS-related wasting and other types of wasting? Carl Grunfeld: Much of the early work on wasting was done on patients with sepsis (overwhelming infection) and cancer cachexia. Everyone presumed that they were very similar to people with AIDS-related wasting. We now know that there are interesting differences. We need to learn more about these differences and where they come into play. The first difference between AIDS and cancer cachexia is that patients with the latter are at an end stage with a lot of tumor growth that is not treatable and with an essentially very poor prognosis. In AIDS, the object is to prevent and/or treat secondary infections and complications. As we become more successful at that, prognoses have gotten better, and wasting itself then becomes an indicator of a bad prognosis. If cancer wasting were to be completely reversed, you would still be left with growing tumors. If you could totally reverse AIDS wasting, you would have a person with a chance of being somewhere between much more functional and very close to normal. BETA: What similarities are there between AIDS wasting and sepsis wasting? CG: In sepsis wasting there is a negative nitrogen balance and the wasting away of muscle tissue that is almost irreversible. It is certainly not reversible with nutritional supplements. In AIDS wasting it is not as extreme. If someone has an untreated severe secondary infection (such as unresponsive cytomegalovirus disease), providing nutritional supplements does not help build back muscle mass. With sepsis, nutritional supplementation sometimes does not prevent loss of muscle mass. In AIDS, supplementation doesn't build it back, and the studies have not been going on long enough to know whether it prevents the decline in total body nitrogen. Untreated or untreatable infection in AIDS is similar to sepsis. We need to understand the different causes behind wasting and begin to adapt therapies and approaches that match those situations. BETA: Early metabolic disturbances in HIV were documented some time ago. What are the endocrine connections here? CG: That's a pet project of mine. All of us working in the field noted the early metabolic disturbances in the late 1980s, and I presented data to the AIDS Program Advisory Committee in 1990. The virus is not latent, but it is contained. Metabolic disturbance is a reflection of the host response against the virus: cytokines, lymphocytes, macrophages. This disturbance may not represent viral burden per se as much as it represents the ability at that stage of the game for the host to respond by containing the virus. BETA: What metabolic disturbances have the greatest impact on the endocrine system? CG: It's not clear how the metabolic disturbances affect that system or how the endocrine system affects the metabolic disturbances. For instance, early in HIV disease there clearly is some dysregulation of the hypothalamus- pituitary-thyroid axis, in that thyroid-stimulating hormone (TSH) tends to be slightly elevated despite apparently normal thyroid function. The body is overworking to keep the thyroid functioning at normal levels. In AIDS, the active form of thyroid hormone, which is called T3, remains normal but drops during secondary infection. In any severe illness the conversion of T4 [a precursor form of T3] to T3 is decreased and there is less T3. That is thought to be a protective factor, so that you waste less nitrogen and you limit the increase in your resting energy expenditure. Piedmont tried to blame wasting on failure to lose T3, because most persons with AIDS have normal T3 values. That's because they were measured when the individuals were not ill. If you look at someone with AIDS who is acutely ill, their T3 appropriately decreases. So the mechanism is there. This represents a preservation strategy, and no one should attempt to replace T3 hormone when it is low. BETA: What still needs to be studied in order to understand AIDS-related wasting? CG: Clearly we need to study the loss of testosterone. Again, when anyone gets acutely ill they will lose elements of pituitary function. One of the earliest losses is gonadotropins and testosterone. Caloric restrictions will also make this happen, and nobody really knows why. I don't know why the system works to decrease testosterone when you're ill or not eating. One could speculate that in evolutionary times when food was lean, one didn't want unchecked reproduction because there wasn't enough food. So the gonadatropins in both men and women drop to low levels, women become infertile and men lose their testosterone. On the other hand, during a chronic illness a drop in testosterone could in the long run lead to a loss in muscle mass. What we don't know is if replacing the testosterone (a) will work, because there may be resistance to it, and (b) will be helpful. We know that if we replace the thyroid hormone when the thyroid hormone is low, it's bad for you. We presume that testosterone replacement will be helpful, but researchers have not shown that yet. There is some funding for research to make sure we are not doing something stupid or wrong. BETA: Do you think that AIDS patients become resistant to their own growth hormone? CG: I think that there are 2 possibilities: (1) there is an element of resistance, and (2) there is an element of decrease in growth hormone secretion. It has been difficult to document this. Other people have data that GH levels might be slightly high with a normal IGF-1 level; this would suggest a little bit of GH resistance. The data are unconvincing. I think that we have to presume that there is a small decrease in GH secretion in some patients and some GH resistance in others. We experimented with growth hormone therapy because we knew that it was anabolic (mass building) in severe wasting syndromes such as wasting related to sepsis or surgery. BETA: What looks hopeful to you right now, in terms of combining anti-cytokines and anabolic steroids? CG: I think that's an intriguing approach. The problem that I've always raised with anti-cytokine therapy is that you have to have the right amount or you get into trouble. For instance if you totally block TNF, you can't respond to certain bacterial infections. There is a mouse that doesn't make TNF in response to gram-negative bacteria. If you give a fragment of that bacteria to humans, rats and mice, they get very ill. In fact you can use that fragment as a toxin to kill a normal mouse. It will not kill the TNF knockout mouse because that mouse does not produce TNF in response to infection, but if you give that mouse a small amount of gram-negative bacteria which a normal mouse would easily neutralize, the TNF knockout mouse will die because TNF is part of the host defense system. BETA: You are describing a host defense system response that has run amok? CG: Right. In septic shock, the host defense system has totally run amok and you go into shock. But if you completely block TNF and IL-1 you may prevent someone from responding to a bacterial bronchitis, sinusitis or pneumonia. You may prevent the response to Pneumocystis carinii pneumonia (PCP). So anti-cytokine trials need to be done with extreme caution. The only trials that have been done and published with regard to AIDS have been done with pentoxifylline. They were unsuccessful. BETA: Why would Ketotifen (an anti-asthma drug currently being sold in buyer's clubs for wasting) stimulate appetite? CG: TNF is known to cause anorexia. During an infection that causes anorexia, we are fairly positive it's the cytokines that are responsible. Theoretically, if you block the cytokine action appropriately you get rid of the most toxic aspects, but you don't prevent the host response, and that is how you could stimulate appetite. The only data I've seen on Ketotifen is not encouraging. I think other studies need to be done. Thalidomide is high on the list of potential cytokine therapies, but this is the kind of thing that really needs a careful, placebo-controlled study. Grunfeld stressed that the best therapy for wasting is early OI intervention. Accepting that the patient is wasting, as if it were a normal AIDS condition, is not a correct solution. It may be appropriate to conclude that the most important defense against wasting is both a persistent patient and a well-informed and diligent doctor. Drug Hormonal/Metabolic Effect Abnormalities Didanosine Pancreatic inflammation Foscarnet Decreased ionized calcium Hypocalcemia Nephrogenic diabetes insipidus Ketaconazole Reduced adrenal and testicular steroidogenesis Hypoadrenalism Reduced 1,23-dihydroxyvitamin D formation Hypogonadism Megastrol acetate Diabetes mellitus Opiates Increased cortisol metabolism Phenytoin Increased cortisol metabolism Pentamidine Pancreatic islet cell destruction Hypoglycemia or Hyperglycemia Renal magnesium wasting Hypomagnesemia, Hypocalcemia Rifampin Increased cortisol metabolism Trimethoprim Interference with renal potassium secretion Hyperkalemia and pancreatic inflammation Source: Norbiato G. The endocrinology and metabolism of HIV infection. Baillere's Clinical Endocrinology and Metabolism 8 (4): 735-882. 1994. ------------------------------------------------------------------ Reform at FDA: Faster Access To Promising Drugs? Ronald Baker, PhD Ronald Baker is Editor-in-Chief of BETA and Director of Treatment Education and Advocacy at the San Francisco AIDS Foundation. The U.S. Food and Drug Administration (FDA) is the government agency responsible for ensuring that drugs, vaccines and medical devices are safe and effective. FDA also ensures that foods meet certain safety standards. In fulfilling these responsibilities, FDA has jurisdiction over more than $1 trillion worth of products, which represents about 25% of the total value of the U.S. economy. This fact alone makes FDA one of the most powerful and influential forces in American society. In its early history, FDA's mandate focused exclusively on protecting consumers from unsafe foods and drugs. In 1976, Congress gave the agency broad new regulatory powers over drug development and medical devices. During the past 2 decades, FDA has expanded its influence and oversight of these 2 areas. Today, many members of Congress, some patient advocacy groups and drug and medical product manufacturers feel that FDA's regulatory oversight has mushroomed into a bureaucratic quagmire. They argue that FDA's unbridled regulatory expansion slows drug and medical device development to the extent that the public health is threatened rather than protected by the agency. However, not everyone agrees with this assessment. Certain members of Congress, the Clinton administration and a faction of the AIDS community believe FDA basically is doing a good job and doesn't require legislative reform. In fact, they argue, any changes in FDA regulations should be made by the agency itself, not by congressional interference. Below is a review of key issues related to AIDS treatment in the ongoing debate on FDA reform proposals. The Clinton/Gore Proposal In April 1995 the Clinton Administration published a position paper on FDA reform entitled, "Reinventing Drug and Medical Device Regulations." The administration recommends reducing or eliminating certain FDA regulations "that won't result in lowering health and safety standards." The Clinton administration favors excluding drug and biologic manufacturers from requirements for most environmental assessments. In addition, the Clinton/Gore proposal recommends administrative reforms concerning marketing clearance for medical devices, and calls for a "harmonizing" of FDA's drug and device testing requirements with those of other countries. The administration proposal addresses AIDS drug development only indirectly, when the document calls on FDA "to issue a public statement clarifying how FDA determines the effectiveness of new drugs and devices and that a single, multi-center study may support approval of a drug." The Democratic Bill by Representative Ron Wyden Oregon Democratic Congressman Ron Wyden introduced FDA reform legislation in the House of Representatives on June 7, 1995. "This bill ensures that as the FDA prepares for the 21st century, the agency's health and safety mission is left intact, while the time and cost of getting life-saving products to the public is reduced," said Wyden. Wyden's bill, "The FDA Modernization Act of 1995," is the first legislative proposal on FDA reform introduced to the 104th Congress. Undoubtedly, it will not be the last. Both houses of Congress appear to be gearing up for a vigorous public debate on the appropriate role of the FDA. Wyden claims his FDA reform bill will lead to faster and less expensive drug and device approval systems and "a refocusing of limited federal resources on the most vital safety issues involving health care products." The first item in Wyden's bill addresses the development of drugs for AIDS and other life-threatening illnesses. Wyden's legislation would authorize FDA to use expert panels, independent testing organizations and institutional review boards (IRB) to help speed new drugs and devices through the FDA approval process. The bill also calls for a fast-track, conditional approval process for drugs and devices with breakthrough, life-saving potential. While FDA already has regulations governing fast-track, conditional approval, Wyden and others are seeking to reduce further the time required for drugs to receive accelerated (conditional) approval. The Wyden bill calls for the use of IRB for the approval (or denial) of applications for Phase I review of new drugs. IRB review of Phase I drug development would apply to all drugs, not just those for serious or life-threatening illnesses such as AIDS. In addition, the proposed legislation would "reform and reduce" FDA's restrictions on the sharing of scientifically valid information about "off-label" uses of drugs (e.g., acyclovir use to increase survival time, or thalidomide to treat aphthous ulcers). Other key aspects of the bill include limiting pre-market research requirements to 1 pivotal Phase III study and developing incentives for faster evaluation of new drugs. Republican Bills in the House and Senate At this time (early June), the Republicans have not yet settled on the provisions of their FDA reform bill. But the general expectation on Capitol Hill is that the Republicans soon will introduce a strong bill proposing significant changes in FDA regulations and structure. The Republican bill in the House and in the Senate likely will contain many of the provisions of the Wyden bill plus much more. Republican Senator Nancy Kassenbaum is writing a Senate version of FDA reform legislation, which she insists will be crafted with a bipartisan effort. The AIDS Community and FDA Reform Not surprisingly, the AIDS community does not speak with one voice on the subject of reform at FDA. One treatment advocacy organization working to influence the debate on FDA reform is the Treatment Action Group (TAG), whose members hold key positions at Gay Men's Health Crisis, National Minority AIDS Council, Human Rights Campaign Fund, AIDS Action Council and AmFAR. Essentially, TAG supports the status quo at FDA, and is lobbying AIDS organizations across the country to sign on to its "FDA Reform Principles," a 3-page document with 12 statements relating to the "mission" of FDA. Examples of these "reform principles" include: "FDA must be accountable"; "FDA must have sufficient resources to perform its duties"; and "FDA must ensure that data are gathered on all populations likely to use a drug." Other AIDS treatment activists, such as Jeff Getty of ACT UP Golden Gate and Jules Levin of ACT UP New York, have a different perspective on FDA reform. "People with AIDS desperately need new approaches to drug development at FDA," says Getty, who favors local IRB jurisdiction over Phase I research. Currently, FDA requires that all Phase I research be subject to FDA oversight. "Let research subjects and their doctors determine risks and benefits in early research. Do not suppress and punish potential life-saving experimentation by overprotecting the public," Getty told BETA. Jules Levin of ACT UP New York's Treatment and Data Committee sees the current congressional and public debate over FDA reform as a unique opportunity for people with AIDS: "With Congress and the public focused on the issue of reform at FDA, we have the rare opportunity to press for progressive ideas like faster approval of promising AIDS drugs and innovative new designs for AIDS clinical studies." Some AIDS activists have even stronger views concerning the necessity for reform at FDA. In a June 4, 1995 editorial published in the Los Angeles Times, gay Republican James Driscoll of Direct Action for Treatment Access writes, "FDA [continues to] churn out burdensome regulations that delay drug approval and actually harm patients To prevent a few mistaken [drug] approvals, FDA sacrifices countless patients to approval delay, slows the pace of medical progress and drives health-care costs through the roof and jobs out of the country. It's time for Congress to put patients above bureaucrats and to hold FDA strictly acountable for the human cost of regulatory delays." Whatever the outcome, a lively debate on Capitol Hill and in the AIDS community on FDA reform may animate an otherwise lackluster summer session of Congress. ------------------------------------------------------------------ AZT Use by Pregnant Women Stirs Policy Debate Leslie Hanna Leslie Hanna is Associate Editor of BETA. Published last November in The New England Journal of Medicine, the impressive results of ACTG 076 have precipitated considerable scientific and policy debate. The significant reduction in the rates of perinatal HIV transmission among pregnant women taking AZT, observed in ACTG 076, clearly entreats practical application (8.3% of women who took AZT compared to 25% of women who took placebo transmitted HIV to their infants). However, the study enrolled a representationally limited group of HIV-infected pregnant women and also provoked many questions, which remain to be answered. These outstanding questions caution against instituting healthcare changes before obtaining further, significant data. (For a complete review of ACTG 076 and the recommendations the U.S. Public Health Service issued subsequently on the use of AZT during pregnancy, see "Mother-to-Child HIV Transmission" in the September 1994 issue of BETA, p. 71.) A separate but highly significant issue is that the vast majority of HIV-infected women worldwide, particularly in developing countries, may never have the opportunity to benefit from any advancements related to ACTG 076. Because the cost of AZT is prohibitive in these countries, access to therapy is not an option for these women. Officials met last June to discuss the preliminary results of ACTG 076, to develop new recommendations on the use of AZT during pregnancy (published in Morbidity and Mortality Weekly Report [MMWR] in August 1994) and to discuss the implications of those recommendations for HIV treatment, counseling and testing. The draft U.S. Public Health Service Recommendations for HIV Counseling and Testing for Pregnant Women were released on February 23, 1995; the public comment period began the same day and ended on April 9. Currently, the comments are being reviewed and may be incorporated into the draft guidelines; the modified, finalized guidelines will be published in a future issue of MMWR. Because the debate has aroused widespread interest, the Centers for Disease Control and Prevention (CDC) probably will try to issue final recommendations as quickly as possible. Background The highly charged public debates related to HIV counseling and testing of pregnant women involve a multiplicity of complex issues concerning fundamental civil rights, confidentiality and privacy. Many HIV/AIDS advocates, like Paul DiDonato of the San Francisco AIDS Foundation, feel that real access to quality health care for both mother and child transcends other issues, which tend to become divisive (mother vs. child) and, ultimately, of less practical import (e.g., the identification of seropositive persons without consideration of access to treatment and health care). Since 1988, the CDC has anonymously tested newborns for HIV in 45 states, the District of Columbia, Puerto Rico and the Virgin Islands. Anonymity or blinding is one way to gather data from the widest possible cross-section of the population. Approximately 80% of newborns who test seropositive later test negative, and never develop HIV disease or AIDS; these tests at birth reveal antibodies acquired from the mother. (Newborns carry maternal antibodies for approximately 15-18 months after birth. When their own immune systems develop and become viable, maternal antibodies are shed.) Thus, the blinded survey was one way for CDC to measure the incidence of HIV infection in women of childbearing age. The data enabled CDC and others to determine the needs of HIV-infected women and to target funds and design appropriate healthcare services. Enter Policy Makers After the release of ACTG 076 results, the CDC's blinded seroincidence survey of newborns became a key feature of certain proposed legislation that would have substantially impacted the goals of the CDC survey. At least one proposal before Congress sought to unblind the results of the study, ostensibly to permit the identification of HIV positive candidates for improved medical treatment. Other proposed legislation also would effectively mandate HIV testing without informed consent. HR 1289, the "Newborn Infant HIV Notification Act" proposed by Congressman Gary Ackerman, a Democrat from New York, would require unblinding the CDC serosurvey in all states and reporting of the newborn's test results to the parent or legal guardian (state agency, foster or adoptive parents). The bill, which does not require a mother's consent or even knowledge of newborn HIV testing, can be considered tantamount to mandatory HIV testing of the mother, since the infant's antibody test results really only give accurate information about the mother's serostatus. In California, SB 889, proposed by Senator Tim Leslie, would add mandatory HIV testing to existing regulations that require newborns to be tested for certain hereditary diseases. HIV test results would be given to the mother, father or legal guardian, as well as to the mother's physicians and certain other parties (prospective adoptive parents, for example). On May 11, 1995, the U.S. House of Representatives held a hearing on the issue of HIV testing of pregnant women and children. At the hearing, Representative Ackerman urged other members of Congress to support his bill. Later in the same hearing, the CDC stunned many by announcing their decision to suspend the entire serosurvey, officially known as the "HIV Survey in Childbearing Women." CDC officials reportedly cited a need to re-evaluate the use of the $10 million for the serosurvey, to determine if the money would be better spent elsewhere. Current debate about mandatory testing issues extends beyond the scope of the present discussion. Suffice it to say that a study by Janet Mitchell, MD, in New York found that 90% of women voluntarily chose to have an HIV antibody test after receiving information on HIV. A majority returned for regular continued care after delivery. Other studies have found similar results. The National Association of People with AIDS (NAPWA) issued a press release on May 11 stating: "We do not believe that the Congress should ignore the wisdom of organizations such as the American Pediatrics Association, the American College of Obstetricians and Gynecologists, the Association of State and Territorial Health Officials and the March of Dimes who all oppose mandatory testing." CDC Recommendations and the Activist Response The CDC/U.S. Public Health Service recommendations call for noncoercive HIV counseling for all pregnant women. The goal of the counseling is to provide information on HIV infection, pregnancy and testing so that each woman can make an informed, personal decision about HIV testing. The CDC decision to suspend the newborn seroincidence survey appears to be closely related to their recommendation that all pregnant women receive accurate information about HIV infection. Although the CDC decision to discontinue the serosurvey seems reasonable, given their recommendation to offer HIV-related counseling to all pregnant women, the information gathered from that survey had been put to valuable use by advocates for people with HIV. Terry McGovern, an attorney with the HIV Law Project, an affiliate of the AIDS Service Center of Lower Manhattan, said that her group and others used the data to successfully lobby for expanding the AIDS definition as well as for targeting and influencing the appropriation of funds. The CDC survey provided valuable epidemiologic information on HIV in women and children to diverse researchers, including scientists, policy makers and advocates. With regard to the overall climate, McGovern seriously questions the stream of events that followed in the wake of 076. "Should one conclusion from one study be the centerpiece for federal policy?" she asks. She stresses that while perinatal HIV transmission was indeed reduced, the official response seems to regard the study results as tantamount to a new HIV prevention rather than a transmission- reduction strategy. McGovern also is angry that no one has asked questions about the 75% of children needlessly treated with AZT, children who would have been seronegative without any intervention. The situation is spiralling out of control, largely due to the fact that, as she puts it, both "the pharmaceutical industry and government needed wins, and now they've gone hog-wild." As an advocate for women with HIV on the National Task Force on AIDS Drug Development, McGovern has been working for years to force the FDA to ensure that clinical trials enroll adequate, representative numbers of women, and that trials look at such gender-relevant and important factors as hormonal variations and dosing levels. A response or semi-justification on the part of the trial administrators has been that the science needed to detect such features simply does not yet exist, says McGovern. She asks, "In the absence of science and technology to even detect answers to vital questions, how is it that everyone has suddenly become so completely comfortable playing around with dosing and administration schedules of AZT during pregnancy?" Motions underway to essentially mandate HIV testing are not only objectionable but also valueless for the persons who supposedly would benefit HIV positive women and their children. In other words, these proposals neglect the fundamental issues so real to HIV positive women and children, which involve socioeconomic class and race and largely revolve around access. What value is there in learning the serostatus of an infected child without ensuring that she or he will have access to health care and drugs? These are troubling questions. One sinister legacy of 076 has already developed, at least in New York, where McGovern says doctors are reporting HIV positive pregnant clients who choose not to take AZT to the state agency Child Welfare Administration. The directives (i.e., potential removal of custody) provided by such actions may be the most devastating of all to some HIV-infected women. McGovern recommends attending to the real issues for women and children by mandating peer-based counseling that begins as early as possible in the prenatal phase, and suggests extending such counseling to women of childbearing age. This more humane approach also may be more effective. On Related Notes The timing of transmission is another factor in perinatal HIV transmission that requires further study. A better understanding of when transmission occurs would enable better prevention strategies. In the April 1995 issue of AIDS, French researchers published the results of DNA testing of fetal tissue. Polymerase chain reaction (PCR) HIV testing of thymic tissue from 100 fetuses at known stages of development allowed researchers to estimate the rate of in utero transmission through the second trimester. Of 100 thymic tissue samples, 2 tested positive. In brief, researchers found that early in utero HIV transmission is relatively infrequent, which suggests that perinatal transmission occurs later in pregnancy and/or at delivery. Many aspects of perinatal transmission remain poorly understood. Consequently, current strategies aimed at interrupting transmission may be regarded as preliminary or inadequately informed. Further research as well as analysis of follow-up data from ACTG 076 is needed to illuminate the roles of factors that may increase the risk of perinatal HIV transmission, including: low maternal CD4 cell count, high maternal viral burden, maternal history of HIV-related illness and maternal nutritional status. Improved understandings of these and possibly other factors will enable the implementation of the most informed, appropriate strategies for preventing perinatal HIV transmission. Finally, a research update on pediatric AZT deserves mention here. Recently, the data safety and monitoring board (DSMB) of an ACTG study (ACTG 152) of antiviral therapy in children aged 3 months to 18 years stopped the treatment arm that provided AZT monotherapy. The children in that arm apparently were doing far worse in terms of clinical progression and side effects than those in the other 2 arms, which provided either ddI or combination ddI/AZT. The monitoring board halted the AZT arm, while allowing the other 2 to continue. The pediatric response to these standard antivirals seems to differ appreciably from the adult response; apparently, what works in adults with HIV cannot be extrapolated or directly applied to children. This event (halting the AZT arm) underscores the importance of carefully following children born to participants in ACTG 076, as well as avoiding the temptation to make swift but premature treatment recommendations (e.g., based solely on 076). References Brossard Y and others. Frequency of early in utero HIV-1 infection: a blind DNA polymerase chain reaction study on 100 fetal thymuses. AIDS 9(4): 359-366. April 1995. McGovern T. Personal Communication. May 17, 1995. Newborn AIDS tests being suspended. The San Francisco Chronicle p. A3. May 12, 1995. U.S. Public Health Service. Draft recommendations for HIV Counseling and Testing for Pregnant Women. February 23, 1995. (sidebar) A large coalition of AIDS service organizations, including the San Francisco AIDS Foundation, were co-signers to a letter written by the AIDS Legal Referral Panel and the Women's AIDS Network (both located in San Francisco) that comments on the CDC recommendations. Excerpts follow: The AIDS Legal Referral Panel and the Women's AIDS Network congratulate you on your Recommendations for HIV Counseling and Testing for Pregnant Women. Specifically, we applaud your recommendation against mandatory testing of pregnant women and your focus on counseling and voluntary testing.... The AIDS Legal Referral Panel and the Women's AIDS Network are concerned with efforts to develop broad-based HIV public policy on the shaky foundation of one narrow, interrupted and controversial study [076].... In every possible instance, women must be given the information they need to make informed, non-coerced decisions about their health care, the health care of their child(ren) and their private medical information. [Regarding voluntary testing] While the CDC took pains to focus on "routine counseling" and "voluntary testing," the public perception, as reflected in media reports on the release of the guidelines, is that the CDC simply called for testing of pregnant women.... Without an explicit emphasis on noncoercion, it is likely that these Recommendations will be politically interpreted as providing justification for mandatory testing, even though they explicitly do not endorse this strategy. [Regarding statements in the Recommendations such as "These services are optimally delivered through a readily available medical system with support services designed to retain patients in care."] There is a seriously problematic presumption in the Recommendation that all women are actively engaged with the medical care system in prenatal and perinatal care. The CDC should consider the question posed by the fact that positive women have relatively poor access to and often face discrimination within the medical system. [Regarding AZT] There are a number of unanswered questions relating to the implementation of the 076 ZDV [AZT] regimen. What will happen to women who refuse to take ZDV? Will women, especially incarcerated women, face discrimination or other punishment for this decision? Will the CDC offer guidance to providers regarding alternative methods of decreasing the risk of perinatal transmission? Where will the resources come from for the additional ZDV needed for pregnant women? And how will the administration of ZDV to children be handled, given that if a mother has an AIDS diagnosis but her HIV positive child does not, it is unclear whether or not Medicaid programs will cover ZDV for her child? These comments are reprinted to provide a broad sample of activist perspectives. ------------------------------------------------------------------ Research Notes Harvey S. Bartof, MD Harvey Bartnof is a clinical faculty member at the University of California at San Francisco School of Medicine where he has been Course Director of "AIDS-HIV: Overview and Update" since 1985. He has been a member of the San Francisco AIDS Foundation Scientific Advisory Committee since 1987. HIV Progression Loss of CD4 and CD8 "Naive" Subsets Correlate with HIV Disease Progression Researchers from Stanford University have published 2 papers that they believe represent significant inroads into the understanding of HIV disease progression. Using a new technology to measure certain subsets of CD4 and CD8 cells, they have discovered that a loss of the "naive" or uncommitted subsets of both CD4 and CD8 lymphocytes occurs in asymptomatic HIV positives. This loss is progressive, occurs with worsening HIV disease and occurs both in children and adults. The researchers believe that these subset losses may help to explain the abnormalities in immune functioning of those with HIV/AIDS. The lead authors from each of the 2 articles are Mario Roederer, MD, and Ronald L. Rabin, MD. The articles were published in the May 1995 issue of Journal of Clinical Investigation. The concept of "naive" and memory functions can be assigned to either CD4 or CD8 lymphocytes. The memory subsets are believed to be longer living and capable of mounting an immediate immune response to a certain antigen by producing large amounts and a wide variety of cytokines (intercellular hormones). The naive subsets do not have those memory properties and have limited capabilities to produce cytokines. Instead, the naive subsets are able to proliferate rapidly when exposed to a new antigen and they are able to generate a wide variety of responses to more generic antigenic stimuli. After exposure to a new antigen, a naive cell differentiates and expresses the marker of and becomes a memory cell. Naive T-cells are believed to have recently exited from the thymus gland, behind the breast bone. In the study of adults, the researchers enrolled 266 HIV positives from the San Francisco Bay Area. All participants had less than 500 CD4 cells/mm3, except for 28 who had counts greater than 500 cells/mm3. Participants were excluded if they had current opportunistic infections or were ingesting "large amounts" of antioxidants, minerals or vitamins ("large amounts" was not defined). The control population was 44 healthy HIV negative adults. In the pediatric study, 19 HIV positive children and 17 HIV negative control children were enrolled. Eight of the 19 HIV positive children had AIDS. The HIV positive children included those who acquired the infection from their mothers and some who acquired HIV from blood product transfusions. The HIV positive children had a median age of 5.7 years, ranging from 10 months to 13 years of age. The loss of the naive subset was shown to be most marked in the CD8 cells. In healthy HIV negatives, 50% of their CD8 cells are naive, whereas in most HIV positives, less than 15% of their CD8 cells are naive. Conversely, a greater proportion of HIV positives' CD8 cells are memory cells. As a rule, the CD8 naive cells decreased as the CD4 cell count decreased, the traditional hallmark of HIV disease. The decrease was noted even for HIV positives with a CD4 cell count greater than 500 cells/mm3, during the asymptomatic phase. Therefore, the authors believe that the loss of CD8 naive cells occurs as HIV disease progression occurs, and begins even when CD4 cell counts are relatively normal. Shortly after HIV infection, the total number of CD8 cells increases and remains high until the CD4 cell count decreases to less than 150 cells/mm3, at which time the total CD8 count also begins to decrease. Adding the researchers' findings, this means that the increase in CD8 cells is comprised mainly of memory cells and not naive cells. Also, since naive cells are precursors to memory cells, the progressive loss of naive CD8 cells may mean an eventual loss of CD8 memory cells and an inability to effect an appropriate immune response. The authors show that the loss of the naive subset also occurs in the CD4 cells. In healthy HIV negatives, greater than 50% of their CD4 cells are in the subset of naive cells, whereas in HIV positives with a CD4 cell count less than 200 cells/mm3, the naive subset comprised approximately 25% of the CD4 cells. Just as with the CD8 naive subset, the progressive loss of the CD4 subset correlated with HIV disease progression. The researchers believe that the progressive loss of the naive subsets of T-cells may explain part of the immune dysfunction of HIV disease: the inability to generate an adequate immune response to new antigens. Moreover, since HIV is constantly mutating, the immune system may eventually become depleted of naive cells so that there are not enough left to recognize the "new face" of a mutated HIV. In addition, if the naive subset of CD8 cells is the one that secretes the soluble CD8 anti-cellular factor (CAF; first described by the Jay A. Levy, MD, laboratory, see page 18 in this issue of BETA), that subset will not be present to suppress HIV replication. The researchers further describe some of the implications of their findings. The loss of the naive subsets of T-cells indicates that HIV positives with no naive cells will be unable to respond to any vaccination, including therapeutic HIV vaccinations. All future therapeutic HIV vaccine trials may need to measure and monitor the naive T-cell subsets of participants. Other implications described by the authors include the potential limitations of therapeutic trials that expand the CD8 subsets of patients ex vivo (outside the body) and then re-infuse them. Highly variable results of those studies may occur, depending upon the percentage of naive T-cell subsets among the participants. Furthermore, the authors believe that the results of many therapeutic trials in HIV/AIDS may need to be re-analyzed and be stratified for the percentage of naive T-cell subsets among participants. An anti-HIV drug that was concluded not to be of benefit may indeed have shown benefit if the variable of naive T-cell subsets was included in the analysis. (Frozen white cell specimens are unlikely to be remaining for many studies already completed and published.) The researchers continue with additional implications of their findings. They believe that many in vitro studies previously reported in the literature that compare lymphocyte cultures of HIV positives to HIV negatives may have had misleading results. Since memory subsets of T-cells produce interleukin 4 (IL-4), interleukin 10 (IL-10), and gamma-interferon, lymphocyte cultures of HIV positive individuals would have shown a preponderance of those cytokines due to a relative lack of naive cells and not necessarily due to a primary HIV effect. Naive subsets are known to produce mostly interleukin 2 (IL-2). The authors note that HIV disease is not the only condition where a decrease in naive subsets occurs. Chronic alcohol ingestion often causes a decrease in the naive T-cell subsets as well as the loss of T-cell function. Indeed, those with alcoholism do have more difficulty fending off infections than those without alcoholism. However, alcoholism does not result in a loss of naive subsets or a loss of CD4 cells. The researchers indicate that their findings do not explain all of the immune dysfunction in HIV/AIDS. Indeed, "the immunodeficiency in HIV disease could be mediated either by low CD4 cell counts, low naive CD8 cell counts, or most likely, a combination of both in conjunction with other factors." One can foresee the day when the relevant cocktail of HIV predictive markers will include CD4 cell counts, CD8 naive cell counts and RNA viral burden. Rabin RL and others. Altered representation of naive and memory CD8 T-cell subsets in HIV-infected children. Journal of Clinical Investigation. 95:2054-2060. May 1995. Roederer M and others. CD8 naive T-cell counts decrease progressively in HIV-infected adults. Journal of Clinical Investigation. 95:2061-2066. May 1995. Infant Clears HIV without Treatment A well-documented report from UCLA School of Medicine has shown that an infant boy infected with HIV at birth has effectively cleared the virus from his body without any HIV treatment. There have been a few reports in the past of similar cases, but they were always attributed to possible laboratory error or contamination. Yvonne J. Bryson, MD, and colleagues published the report in the March 30, 1995 New England Journal of Medicine. Their patient was born 4 weeks prematurely by normal vaginal delivery. The mother was 33 years old and was found to be HIV positive without symptoms during routine HIV screening in her fourth month of pregnancy. The mother indicated that she had sexual relations with a former injection drug user and denied any other HIV risk behavior. During the pregnancy, the mother's CD4 count was greater than 1,000 cells/mm3, and she had no HIV symptoms or diseases. She has remained HIV positive but without HIV symptoms for 4 years after this pregnancy. The infant boy was normal at birth, but required an 8 day hospitalization for respiratory problems related to premature birth. He did not receive any transfusions and was not breast fed. As of March 1995, he is 5 years old, healthy and attends kindergarten. His growth and development have been normal. The results of the boy's blood counts, including CD4 and CD8 counts, as well as immune globulins, all have been normal. Blood was obtained at birth and at 19, 33 and 51 days after birth for HIV specific tests. Blood mononuclear cells (lymphocytes and monocytes) were cultured for HIV. Those cultures were negative at birth, positive at 19 days after birth, negative at 33 days, and positive for HIV at 51 days after birth. The 2 positive cultures were at relatively low levels (titers). An HIV culture of the infant's plasma was also positive at 51 days of age. Tests for p24 antigen and IgA by dot blot assay (often abnormally elevated in HIV-infected infants) during these same time periods were all negative. HIV antibody tests by ELISA and Western Blot methods became negative at 12 months of age. They were positive before that time, but this was likely due to passive antibody from the mother that can remain in a child up to 15-18 months of age. HIV cultures performed at age 13 months were negative. Despite numerous subsequent attempts to culture HIV from his blood, all have been negative. Furthermore, many attempts at performing PCR (polymerase chain reaction) of HIV DNA from blood lymphocytes after age 12 months have all been negative. In an attempt to look for possible contamination, frozen samples of the child's lymphocytes from the 2 positive cultures were subsequently analyzed for HIV strain similarity. The DNA sequences of each positive isolate were closely related, although not 100% identical. Comparing the infant's HIV DNA to other control infants, there were significant differences. Although the researchers did not have a sample of the mother's lymphocytes from pregnancy, a subsequent sample indicated that the DNA sequence of her HIV isolate was similar to the DNA sequence of her child's isolates when his were positive within the first 2 months of life. The authors indicated that an "evolutionary relationship" between the mother's and infant's HIV isolates existed, and that "...it is highly likely that both viruses found in the infant originated from the mother." In a further attempt to rule out possible contamination, the researchers performed routine PCR genetic marker analysis of the HIV positive and HIV negative samples of the child's lymphocytes. PCR analysis of 6 different markers from the infant at age 19 days and age 2.5 years indicated that the samples were from the same person. The sample at age 19 days was HIV positive by PCR; the one from age 2.5 years was negative. Based on their statistical analysis, the authors indicated that the probability of an identical genetic profile in a randomly selected Caucasian population was less than 1 in 1,000. The authors believe that their case represents an example of an infant who acquired HIV infection associated with birth and who subsequently cleared the HIV infection without treatments. They cannot rule out the possibility that HIV DNA could be in some bodily location they have not tested. For example, the child may have HIV DNA in a lymph node or in the central nervous system, but they feel this is unlikely. The mother did have characteristics associated with a decreased probability of transmitted HIV to her infant: she was healthy with a normal CD4 cell count and presumably a low viral load. Her HIV strain was less likely to be virulent, i.e., associated with a non-syncitium-inducing phenotype. These factors may be associated with an increased chance of the infant's own immune system fighting off HIV. In an accompanying editorial from the same issue, Kenneth McIntosh, MD, and Sandra K. Burchett, MD, from Children's Hospital in Boston, indicate that there have been a number of cases in the literature of HIV-exposed infants who are HIV culture and PCR negative, but who have immune system evidence in vitro of HIV exposure. The in vitro studies show that lymphocytes from such infants respond to HIV gp160 (envelope) antigens by producing IL-2. Infants born to HIV negative mothers do not show this response. Similar responses have been seen in some HIV negative, PCR negative gay/bisexual men with sexual exposure to HIV and in health care workers with documented needlestick exposures to HIV who remain HIV negative. Lymphocytes from the child in this reported case did not show a proliferative response to HIV antigens in vitro. Further study of HIV-exposed but uninfected children and adults will likely provide insights into potential treatments and vaccines for HIV. Bryson YJ and others. Clearance of HIV infection in a perinatally infected infant. New England Journal of Medicine. 332(13):833-838. March 30, 1995. Longer Lifespan for Those with CD4 Cell Counts Less than 50 Cells/mm3 An analysis of 553 gay/bisexual men from the Multicenter AIDS Cohort Study (MACS) with CD4 cell counts less than 50 cells/mm3 indicates that they are living longer than previous studies had indicated. Past studies indicated a life span of approximately 12 months. The current study reveals a median survival of 1.3 years (16.4 months). For statistics mavens, the 95% confidence interval was 1.25-1.45 years. Survival was over 2 years for 25% of the total group. The MACS is made up of participants from 4 U.S. cities: Los Angeles, Pittsburgh, Chicago and Baltimore-Washington DC. In the final analysis, each of the following was statistically significant in terms of relative risks for death among the group: Acyclovir (Zovirax) use. . . . .50% lower risk AZT use after CD4 count less than 50 cells/mm354% lower risk Employed full time** . . . . . .31% lower risk Red cell hemoglobin greater than 12g/dl**35% lower risk African-American race**. . . . .48% lower risk CD4 cell count greater than 30 cells/mm3** . .20% lower risk Higher alcohol use (at least once per week consuming at least 3-4 drinks, borderline statistical significance) .20% lower risk Greater than a 4.5 kg weight loss in last 6 mths**30% higher risk Severe AIDS symptoms (vs. no AIDS illnesses)** . .98% higher risk ** For those HIV positives with 6 favorable factors (full-time employment, hemoglobin greater than 12g/dl, African-American race, CD4 count greater than 30/mm3, 6 month weight loss less than 4.5 kg and no AIDS illnesses), the following percentage of people have a corresponding estimated survival time of: 95% estimated to survive 6 months; 91% estimated to survive 1 year; 64% 2 years; 29% 3 years; and 16% 4 years. This information will be helpful for HIV positives as well as their physicians in terms of being able to make informed decisions regarding health care and their lives. The researchers note that the results may not apply to other HIV behavioral risk groups. The lead author is Dr. Elizabeth G. Apolonio. The article was published in the April issue of Journal of Infectious Diseases. Apolonio EG and others. Prognostic factors in human immunodeficiency virus-positive patients with a CD4 lymphocyte count less than 50 cell/mm3. Journal of Infectious Diseases. 171:829-836. April 1995. Viral Load after Becoming HIV Positive is the Best Predictor of AIDS Finding the best predictive marker for the development of AIDS will help in determining which HIV positives are the best candidates for HIV and immunomodulating therapies. In the past, the best predictive markers have been: CD4 cell count, CD4 cell percentage, elevated serum beta-2 microglobulin and neopterin levels, the lack of reactivity to skin tests, HIV-related symptoms, and the presence of syncitium-inducing HIV strains. For most studies, the CD4 cell count and percentage have been thought to be the best markers. Yet, the CD4 cell count and percentage are not perfect markers for predicting AIDS. Many articles and research papers have been published in the literature and presented at HIV/AIDS conferences in the last 1-2 years regarding the utility of viral load. (See BETA. September 1994. pages 13 and 15-16.) Viral load or viral burden is a measure of the quantity of HIV genetic material, either DNA or RNA. One method has been to measure HIV RNA by using the branched chain DNA (bDNA) test. A number of studies have indicated that an elevated viral load is a good predictor of a worsened prognosis, and that a decrease in viral load after anti-HIV therapies are taken is a good indicator of a favorable prognosis. Most of the evaluations of viral load have been retrospective rather than prospective. Prospective studies have more validity than retrospective ones. Researchers from the Pittsburgh portion of the MACS have published a paper regarding the predictive value of viral load for developing AIDS when the measurement is performed after the HIV antibody test turns positive. The 62 men in the study were those with a documented seroconversion to HIV positivity after having been in the MACS study with prior HIV negativity. They have compared viral load with other predictive markers. Blood samples were drawn every 6 months. The maximum follow-up time was 8.3 years. The lead author is John W. Mellors, MD. The article was published in the April 15, 1995 Annals of Internal Medicine. The researchers divided the 62 men into 2 groups: progressors to AIDS and non-progressors. The 1987 definition of AIDS was used (specifically, that excluded a definition of AIDS using a CD4 cell count less than 200 cells/mm3). The researchers found that 18 of the 62 men were progressors after a median of 3.8 years (maximum 6.5 years) following seroconversion to HIV, whereas 44 of the 62 men were non-progressors after a median follow-up of 5.4 years (maximum 8.3 years) following seroconversion to HIV. The researchers found that a low level of plasma HIV RNA (less than 10,000 genome equivalents per ml) in all or most samples was associated with a stable CD4 cell count and a lower risk for AIDS or a subsequent decline in the CD4 cell count (i.e., non-progressors) than those with an elevated plasma RNA (progressors). The opposite was also true. A level of plasma HIV RNA greater than 10,000 genome equivalents in all or most samples was strongly associated with AIDS and a subsequent decline in the CD4 cell count (progressors) compared with a stable CD4 cell count (non-progressors). These findings were statistically significant. The authors conclude that a plasma HIV RNA level (viral load) greater than 100,000 genome equivalents per ml after seroconversion to HIV was the most powerful predictor of AIDS, independent of the CD4 cell count. The CD4 cell count did not add to the predictive ability of the HIV RNA level. They authors believe their findings indicate that the "failure of host immune mechanisms to adequately suppress viremia during the earliest stages of infection appears to be a critical factor in rapid progression to AIDS." Another research paper had not reached identical conclusions. Dr. S. Jurriaans and colleagues found that HIV RNA levels 3 years after HIV seroconversion had predictive ability to define those with a higher risk of developing AIDS within 5 years. However, that research group did not find a statistically significant difference of HIV RNA levels after seroconversion when comparing progressors with non-progressors. The Jurriaans group used blood serum, however, and not blood plasma as used by the MACS group. The MACS study was a larger one with more patients and thereby potentially more able to reach statistical significance. The MACS findings add to the evidence that viral burden is an important marker for HIV progression, perhaps better than CD4 cell counts or percentages. It is likely that all 3 will have value, perhaps along with the CD4 and CD8 "naive" cell subsets (see first report in Research Notes). Mellors JW and others. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Annals of Internal Medicine. 122:573-579. April 15, 1995. Jurriaans S and others. The natural history of HIV-1 infection: virus load and virus phenotype, independent determinants of clinical course? Virology. 204:223-233, 1994. Immunomodulating Therapies Intermittent Interleukin 2 Increases CD4 Cell Counts Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have published a report on the success of increasing CD4 cell counts with sequential treatments of intravenous (IV) interleukin 2 (IL-2). The report appears in the March 2, 1995 issue of the New England Journal of Medicine. The infusions were given for 5 days every 8 weeks over a period of 7-25 months. In those patients with CD4 cell counts greater than 200 cells/mm3, 60% had at least a 50% increase that lasted for up to 8 months after the IL-2 was stopped. Even in the early 1980s before the term HIV was coined, abnormalities in IL-2 production were noted among immune cells from AIDS patients. Given that there have been only limited long-term increases in CD4 cell counts from antiretroviral (anti-HIV) therapies, interest in immunomodulating therapies has remained high. IL-2 is a glycoprotein (sugar and protein compound) which is known to have a central role in regulating both the humoral and cellular components of the immune system. IL-2 can activate and induce proliferation of each of the following cells: both T- and B-lymphocytes, cytotoxic T-lymphocytes (CTL), and lymphokine-activated killer (LAK) cells. In addition, IL-2 can improve natural killer (NK) cell activity. In vitro studies of immune cells from AIDS patients indicate that IL-2 production is low. Adding IL-2 to those cells in vitro leads to improved NK cell activity and toxicity against cytomegalovirus (CMV, the primary cause of blindness in AIDS). IL-2 has demonstrated benefits for HIV negative cancer patients with widespread disease, particularly kidney cancer and melanoma (skin cancer). IL-2 has been in used various clinical trials in persons with AIDS, with some improvements in immune responses but without demonstrated long-term benefits. Some of those studies used subcutaneous injections of IL-2 instead of the IV route used in the current study. IL-2 has a significant toxicity profile which limits dosing and patient tolerance. Joseph A. Kovacs, MD, and colleagues reported on a trial of 25 HIV positive patients who were given IV IL-2 by continuous infusion at doses of 6-18 million international units (IU) daily, 5 days every 8 weeks. The infusions were continued over a duration of 7-25 months. Follow-up was up to 40 months. All participants received 1 or more antiretroviral therapies for the entire treatment course. For almost all, that treatment was AZT (zidovudine, Retrovir). Patients could not have an opportunistic infection at the time of enrollment. For purposes of analysis, the 25 were divided into 2 groups: 10 with a CD4 cell count greater than 200 cells/mm3; and 15 with a CD4 cell count less than 200 cells/mm3. The 10 patients (8 women and 2 men) with baseline CD4 counts greater than 200 cells/mm3 received a total of 4-13 courses of IL-2. They were followed for 22-40 months. Six of the 10 had at least a 50% increase in the CD4 cell count 1 and 2 months after a course of IL-2. A few had increases that lasted 8 months after the last course of IL-2. Several had an increase to over 1,000 cells/mm3. Four of the 10 had a stable or slightly decreasing CD4 cell count. The CD8 cell count remained stable. Analysis revealed that there were increases in many T-cell clone types. Four of the 10 did have transient increases in HIV RNA, as measured by the bDNA test. The remaining 6 patients had no increase or a decrease in HIV RNA. All 4 of the 10 with the largest increase in CD4 cell counts had no detectable HIV RNA before or after IL-2 infusions. The starting dose was 18 million international units (IU) of IL-2 daily. Six of 10 required a dose reduction to 12 million IU daily, while another 2 required a dose reduction to 6 million IU daily. An increase in the CD25 cell marker after the first course of IL-2 predicted those who had a subsequent increase in the CD4 cell count. Two of the patients who had no increase in their CD4 cell counts were diagnosed with Pneumocystis carinii pneumonia (PCP) 8-9 months after the last IL-2 infusion. There were 15 patients enrolled with baseline CD4 cell counts less than 200 cells/mm3. Twelve of those 15 received 2-5 courses of IL-2. (The other 3 included 2 who withdrew before 2 full courses and 1 who died after 1 course of IL-2 and who was taking illicit trichosanthin, also called compound Q, without the researchers' knowledge.) None of 6 with baseline CD4 cell counts less than 100 cells/mm3 had increases in the CD4 cell count. Two of 6 with baseline CD4 cell counts between 100-200 cells/mm3 had a greater than 50% increase in their counts. HIV RNA levels increased in 10 of 12 patients in this group, with an increase from a mean of 97,000 copies/cc to a mean of 193,000 copies/cc. All 12 patients in this group required a dose reduction due to toxicities. Four patients required a dose reduction from 18 million IU daily to 12 million IU daily. The other 8 required a dose reduction to 6 million IU daily. Side effects and toxicities were significant in all patients. The known adverse effects meant hospitalization for all patients in the study. Those included the "capillary leak syndrome" (swelling, fluid retention and fluid in the lungs), severe flu-like symptoms (fevers, weakness, muscle and joint aches, headache), kidney and liver toxicities, bone marrow toxicities (low white cells and platelets), rash, nausea and diarrhea. These toxicities were the cause of the dose reductions discussed above. Toxicities were more severe in those with the lower baseline CD4 counts. The authors believe that IL-2 effects on the immune system led to a direct increased production of lymphocytes. They also believe that IL-2 may increase the survival of T-cells, perhaps by interfering with apoptosis, premature programmed cell death associated with HIV infection. Other possibilities include an improved cytokine profile associated with a trend towards increased T-helper type 1 (TH1) functioning and decreased T-helper type 2 (TH2) functioning. They conclude that intermittent IV IL-2 in moderate to high doses may have a role in increasing and maintaining the CD4 cell counts in HIV positives with a baseline count greater than 200 cells/mm3, in spite of the high toxicity profile. Concurrent therapy with antiretrovirals, i.e., more than 1, likely will be necessary to minimize the increase in viral load observed in some patients given IL-2. Additional research will be necessary to determine the effects of IL-2 on the lymph organs (spleen, lymph nodes) and whether IL-2 decreases viral production in lymph nodes. It is possible that the results of this study might be different if the analysis included the variable of naive and memory T-cell percentages (see first report in Research Notes). Kovacs JA and others. Increases in CD4 lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection, a preliminary study. New England Journal of Medicine. 332(9):567-575. March 2, 1995. Treatment for Opportunistic Infections Antibiotic Combinations to Prevent More than One Opportunistic Infection: Pneumocystis, Toxoplasma, and Mycobacterium avium Several research papers have appeared in the medical literature that have attempted to address the possibility of simultaneously preventing more than 1 opportunistic infection with 1 or more antibiotic regimens. Most of the studies include the use of pyrimethamine (Daraprim) and dapsone. The studies also tried to address what the optimal dose of the antibiotic regimen should be that would limit toxicity. The first study tried to determine whether simultaneous primary prophylaxis for Pneumocystis carinii pneumonia (PCP) and toxoplasmosis (TXP) was better with either trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, Septra and others) or with pyrimethamine (PYR) plus dapsone (DAP). The lead author is Daniel Podzamczer, MD, from the University of Barcelona. The article appears in the May 15, 1995 Annals of Internal Medicine. The trial was a nonblinded, randomized one that enrolled 230 HIV positive patients with CD4 cell counts less than 200 cells/mm3. Patients were excluded from participation if any of the following existed: there were a prior history of PCP or TXP; the patient were taking an antibiotic with known anti-PCP activity, including clindamycin (Cleocin) or clarithromycin (Biaxin); a history of allergy to sulfa or sulfone antibiotics; anemia; neutropenia; elevated liver enzymes; or elevated kidney function tests. There was no control group. The enrollees were given AZT (zidovudine, Retrovir) during the course of the trial. Intolerance to AZT or disease progression while taking it meant a switch to ddI (didanosine, Videx). Intolerance to both AZT and ddI meant a switch to zalcitabine (ddC, Hivid). Patients were randomly assigned to take either:  1 double-strength TMP-SMX tablet (160 mg of TMP and 800 mg of SMX) twice a day 3 times a week (on Mondays, Wednesdays and Fridays) orally; or  DAP 100 mg plus PYR 50 mg twice weekly (on Tuesdays and Fridays) orally. The results were analyzed after a median follow-up of 430 days. While no patient in the TMP-SMX group developed PCP, 6% of the DAP-PYR group did. The cumulative rates of PCP after 24 months were 0% in the TMP-SMX group and 11% in the DAP-PYR group. However, 5 of the 6 patients who developed PCP had stopped taking DAP-PYR at least 2 months before developing PCP. Approximately 65% of each group had a positive blood antibody test for Toxoplasma when entering the study, indicating prior infection and an increased risk of developing TXP disease. The analysis for the risk of preventing TXP includes only those who were antibody positive to Toxoplasma. Only 1 patient in the TMP-SMX group developed TXP, while 2 patients in the DAP-PYR group developed TXP. The cumulative rates of TXP after 24 months were 4% in the TMP-SMX group and 7% in the DAP-PYR group. In comparing the 2 treatment groups, there were no differences in each of the following: the rates of Mycobacterium avium infections (4% in the TMP-SMX group and 2% in the DAP-PYR group); death rates (14% in each group); or rates of bacterial infections including pneumonia (4 and 7 episodes, respectively), bacteria in the blood (12 and 17 episodes, respectively), and sinusitis (1 and 3 episodes, respectively). A greater number of patients were not compliant with taking DAP-PYR (15%) than TMP-SMX (5%), and this difference was statistically significant. Intolerance to the initially assigned preventive therapy, due to toxicity that led to a therapy change, was approximately 9% in each group. Most were switched to the other drug combination. Approximately 70% of those who were switched were able to tolerate the new antibiotic therapy. Adverse reactions causing a change in therapy were similar in each group, without statistically significant differences: fever or rash or both occurred in approximately 7% of each group, stomach intolerance was 1-3% in each group, and liver toxicity was 0-1% in each group. Examining all toxicities, including those that did not lead to a change of therapy, did reveal some differences in each of the following: fever was 3 times more common in the TMP-SMX group (13%) than in the DAP-PYR group (4%), stomach intolerance was twice as common in the TMP-SMX group (16%) than in the DAP-PYR group (8%), and anemia was 40% less in the TMP-SMX group (20%) than in the DAP-PYR group (33%). Other adverse reactions not leading to a change of therapy and that did not attain a statistically significant difference between the 2 treatment groups were: skin rash (9-10% each), liver toxicity (17% in the TMP-SMX group versus 25% in the DAP-PYR group), leukopenia (low white cells, 38% in each group), and low platelet count (11% in the TMP-SMX group versus 15% in the DAP-PYR group). Even though there was no control group in the current study, the 24 month rates of either PCP or TXP are much lower than historical controls with a CD4 cell count less than 200 cells/mm3. In those with a positive antibody test for TXP, the 24-month rate of TXP disease is approximately 25%. If the CD4 cell count is less than 100 cells/mm3, the 12-month risk is at least 25%. The authors conclude that 3-times-a-week TMP-SMX (1 tablet twice daily on those 3 days) is safe and effective in the simultaneous primary prevention of PCP and TXP. They also conclude that DAP-PYR twice weekly is a reasonable second alternative. There have been studies indicating that 1 double-strength tablet of TMP-SMX 3 times a week is effective for primary PCP prophylaxis, but that dose may not be effective for primary TXP prevention. Since the rates of seropositivity for Toxoplasma are much higher (over 50%) in central and southern Europe (including Spain) than in the United States (15-35%), one double strength TMP-SMX tablet 3 times a week for PCP prevention may be all that is necessary for those who are Toxoplasma antibody negative. The AIDS Clinical Trials Group (ACTG) 081 study (see below) found a much higher rate of intolerance to either oral TMP-SMX or oral DAP when either is taken daily as primary PCP prevention. That study compared twice daily TMP-SMX with either daily DAP 100 mg or monthly inhaled pentamidine 300 mg. Twice daily TMP-SMX leads to 79% of patients stopping that therapy due to toxicity. Daily DAP 100 mg (without PYR) leads to 75% of patients stopping that therapy due to toxicity. In the current study, Dr. Podzamczer indicates that only 9% in each group stopped therapy due to toxicity. A European study was designed to compare the efficacy of once-a-week DAP plus PYR to aerosolized pentamidine (AER PEN) for the simultaneous primary prophylaxis of PCP and TXP. In a separate analysis, the same authors found a trend toward a lower incidence (although not statistically significant) of mycobacterial disease (Mycobacterium tuberculosis and Mycobacterium avium) in the DAP-PYR treated group when compared with the aerosolized pentamidine group. The lead author of the 2 reports is Milos Opravil, MD, from the University Hospital of Zurich in Switzerland. The articles appeared in the February and March 1995 issues of Clinical Infectious Diseases. The study enrolled 533 HIV positives with AIDS or a CD4 cell count of less than 200 cells/mm3 from Switzerland, Italy or France. The trial was controlled and open-label. Women comprised 17% of the participants. Participants in the current study were excluded for similar reasons as in the Podzamczer study described above, except that the current study allowed those with a past history of PCP or prior PCP prevention with AER PEN to participate. The median CD4 cell count was 110 cells/mm3. Participants were allowed to take antiretroviral therapy during the trial. Over 90% had taken either AZT or ddI before. Participants were randomized to take either:  DAP 200 mg plus PYR 75 mg once weekly by mouth; or  AER PEN 300 mg once monthly by the Respirgard nebulizer. Note that compared with the Podzamczer study, the weekly dose of DAP is the same and the weekly dose of PYR is 25 mg less in the current study. The other difference is that in the Podzamczer study, the weekly DAP-PYR is divided into 2 doses; in the current study, all the weekly DAP-PYR is taken as 1 dose. The median follow-up was 483 days. Since AER PEN would not be expected to have prevention benefits for TXP, some of the results were not surprising. Based on the approximately 45% of patients who had positive antibody tests for Toxoplasma at baseline, there were 5 times as many patients who developed TXP in the AER PEN group than in the DAP-PYR group participants who did not interrupt their therapy. These results were statistically significant. The risk for developing TXP increased with decreasing CD4 cell counts. When comparing the development of PCP in the 2 groups, there was an equal number in both the AER PEN and DAP-PYR groups (13 and 12, respectively). Intolerance to therapy leading to discontinuation was different in the 2 groups. Whereas only 4% of the AER PEN group had to discontinue therapy, 30% of the DAP-PYR group had to discontinue and switch to AER PEN. (This compares to a 9% discontinuation rate in the DAP-PYR group in the Podzamczer study above.) The reasons for intolerance to DAP-PYR were nausea (51%), rash (40%), headache (37%), fever (34%), anemia (29%), loss of appetite (17%), low white cells (7%), all cell counts low (6%), vomiting (6%), diarrhea (3%) and abnormal liver enzymes (1%). Mortality rates were the same in both groups, approximately 75 in each. Mortality was not due to adverse reactions in either group. The authors conclude that either dapsone 200 mg plus pyrimethamine 75 mg once weekly by mouth or aerosolized pentamidine 300 mg monthly are safe and effective primary and secondary prophylaxis for PCP in spite of moderate intolerance from DAP-PYR. Also, the same dose of DAP-PYR is safe and effective for primary prevention of toxoplasmosis, considering moderate intolerance. Note that DAP 100 mg plus PYR 50 mg twice weekly (on Tuesdays and Fridays) in the Podzamczer study had a similar high prevention rate for TXP, but that the intolerance rate was much lower (9% versus 30% in the weekly study). In their discussion section, Dr. Opravil and co-authors state that for adequate prevention of both PCP and TXP, total weekly doses of 200-300 mg of dapsone and 50-75 mg of pyrimethamine seem to be necessary. Considering the intolerance rates and the half-lives (amount of time required for the drug to be metabolized and no longer present) of DAP and PYR, the twice weekly regimen of DAP 100 mg plus PYR 50 mg is probably the better choice. The half-life for dapsone is 24 hours; the half-life for pyrimethamine is approximately 90 hours. The once weekly dose of DAP-PYR will cause the blood level of DAP to be somewhat low on the 5th-7th days, whereas the once weekly dosing is able to maintain an adequate pyrimethamine level throughout the week. The authors also state that primary prophylaxis for TXP should be targeted to HIV positives with a positive antibody test for Toxoplasma and who have a CD4 cell count less than 100 cells/mm3. "A smaller yet not negligible risk also exists in association with a CD4 range of 100-200 cells/mm3." Dr. Opravil and his colleagues reported on a separate analysis of the same study to determine the benefit of DAP-PYR as a primary prevention for mycobacterial disease. For purposes of the analysis, participants who had prior mycobacterial diseases were excluded. The median duration of the study was 369 days for those who were not excluded. During that time, a total of 31 cases of mycobacterial (MYCO) disease were diagnosed. All patients with MYCO disease were symptomatic. MYCO infection was in the blood or bone marrow in 84%, i.e., was disseminated. Of the 6 cases of tuberculosis (TB), 1 was from the DAP-PYR group, while 5 were from the AER PEN group. Of the 22 cases of Mycobacterium avium complex (MAC) disease, 5 were from the DAP-PYR group versus 17 who were from the AER PENT group. Of the 3 cases of Mycobacterium genavense, all were in the AER PENT group. Therefore, 6 of 31 patients who developed MYCO disease were from the DAP-PYR group, compared with 25 of 31 patients who were from the AER PENT group. Even though this calculates out to a 50% decreased risk of developing MYCO disease with DAP-PYR, the results did not reach statistical significance and showed only a trend towards decreased incidence. If only patients with CD4 cell counts less than 100 cells/mm3 were considered, the relative risk for developing MYCO disease while taking DAP-PYR is 70% less than for those taking AER PEN. This also did not reach statistical significance, although a clear trend was noted. The researchers believe that their results "support the hypothesis that DAP-PYR might have prophylactic efficacy against mycobacteria." However, they note that their analysis is a "retrospective subanalysis of a prospective trial originally designed to assess the prevention of PCP and toxoplasmosis rather than antimycobacterial efficacy." They also note that 30% of the DAP-PYR group was intolerant at the specified dose. DAP is known to have activity against Mycobacterium tuberculosis and Mycobacterium avium both in vitro and, in some studies, in vivo. The authors note that there is no information on the efficacy of PYR on mycobacteria. The researchers conclude that "Dapsone-pyrimethamine (has) already been shown to prevent toxoplasmosis (encephalitis) in addition to being efficacious prophylaxis (prevention) for PCP. Because a trend toward decreased incidence of mycobacterial diseases was observed in the present analysis, combined prophylaxis for multiple opportunistic diseases (PCP, TXP, MAC and TB) with dapsone-pyrimethamine seems feasible." Future studies will be necessary to determine the safety and efficacy of weekly DAP-PYR in the prevention of mycobacterial diseases including TB and MAC. The AIDS Clinical Trials Group (ACTG) 081 study of PCP primary prevention was published in the New England Journal of Medicine on March 16, 1995. The trial, sponsored by the NIAID, attempted to determine which of 3 antibiotic therapies were best in preventing the first episode of PCP in HIV positives with a CD4 cell count less than 200 cells/mm3. The authors also examined whether there was any difference in the incidence of toxoplasmosis. The lead author is Samuel A. Bozzette, MD, from University of California at San Diego (UCSD) School of Medicine. The trial was an open-label one that enrolled 843 HIV positives from multiple institutions in the U.S. Women comprised 7% of the group. The mean baseline CD4 cell count was approximately 150 cells/mm3. The median follow-up time was 39 months. No patients had a prior history of PCP or toxoplasmosis. The patients were randomly assigned to 1 of the following 3 prevention therapies:  1 double-strength tablet of TMP-SMX every 12 hours; or  1 dapsone (DAP) 50 mg tablet every 12 hours; or  aerosolized pentamidine (AER PEN) 300 mg by Respirgard II nebulizer once a month. All patients received AZT therapy throughout the study until toxicity may have caused a dose reduction or discontinuation. At the end of the 39 month trial, there were 137 reported cases of PCP among the participants. Each of the following treatment groups had a corresponding 36 month cumulative PCP risk of: TMP-SMX (18%), DAP (17%), AER PEN (21%). These results were not statistically different. Further analysis also indicated no differences in PCP rates among the 3 drugs for those with baseline CD4 cell counts greater than 100 cells/mm3. However, for those with a baseline count less than 100 cells/mm3, there were some statistical differences. For TMP-SMX, the risk of PCP was 19%, compared with a DAP rate of 22% and an AER PEN rate of 33%. The lowest failure rates occurred with TMP-SMX. A dose reduction to DAP 50 mg once daily was associated with a higher failure rate than the original twice a day dosage. The overall risk of first episode PCP during the 36 months was 25% for those with baseline CD4 cell counts less than 100 cells/mm3. The similar 3-year risk was 15% for those with a baseline CD4 cell count between 100-200 cells/mm3. Most of the difference between the 15% and 25% risk was due to an increased risk for PCP in the AER PEN group with a CD4 cell count less than 100 cells/mm3. Due to toxicity, only 21% of those originally assigned to the TMP-SMX group were still taking the drug at its originally assigned dosage at the conclusion of the study. Similarly, only 25% of the DAP group were still taking it at the original dose. However, 88% of those assigned to the AER PEN group were still taking the drug at full dose at the end of 39 months. Baseline seropositivity to toxoplasmosis was approximately 20% in each group. Overall, 24 reported cases of toxoplsmosis occurred among the 169 patients who were antibody positive to Toxoplasma. Five cases each occurred in the TMP-SMX and DAP groups, while 14 occurred in the AER PEN group. Side effects revealed no surprises among the 3 treatment groups. Both TMP-SMX and DAP have a significant toxicity profile that led to dose reductions or switching therapy in a significant number (75%-79%). The adverse effects in the TMP-SMX group included fever, rash, bone marrow and gastrointestinal toxicities. Rare anaphylactic "shock" occurred. The adverse effects in the DAP group included fever, bone marrow, liver and stomach-intestinal toxicities. The authors conclude that the 3 treatment groups had similar rates overall of preventing PCP, with the 2 oral therapies being better for TXP prevention than AER PEN. However, they state that for those with fewer than 100 CD4 cells/mm3, the PCP prevention strategy that starts with either TMP-SMX or DAP is superior than one that starts with AER PEN. The high toxicity rates of the 2 oral therapies are noteworthy, particularly in view of the other articles discussed above. Dr. Bozzette and colleagues acknowledge that 2 daily tablets of TMP-SMX offer little over 1 daily tablet, except increased toxicity. Moreover, they acknowledge that 3-7 double-strength TMP-SMX tablets weekly are better tolerated than the twice daily dose. In spite of toxicity, the authors state that 100 mg of DAP daily is more active than 50 mg daily. Bozzette SA and others. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. New England Journal of Medicine. 332:693-699. March 16, 1995. Clumeck N. Primary prophylaxis against opportunistic infections in patients with AIDS. New England Journal of Medicine. 332:739-740. March 16, 1995. Opravil M and others. Dapsone/pyrimethamine may prevent mycobacterial disease in immunosuppressed patients infected with the human immunodeficiency virus. Clinical Infectious Diseases. 20:244-249. February 1995. Opravil M and others. Once-weekly administration of dapsone-pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus-infected patients. Clinical Infectious Diseases. 20:531-541. March 1995. Podzamczer D and others. Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Annals of Internal Medicine. 122:755-761. May 19, 1995. Primary Antibiotic Prevention for Invasive Fungal Infections Researchers from the ACTG have published their report regarding primary prevention of invasive fungal infections in the March 16, 1995 New England Journal of Medicine. ACTG 981 attempted to answer the question as to whether fluconazole (Diflucan) 200 mg daily or clotrimazole (Mycelex) troches 10 mg 5 times daily is effective in preventing fungal infections that invade into the body. The invasive fungal infections include Cryptococcus, Histoplasma, Coccidioides and a few other rare fungi. The invasive fungal infections in AIDS are distinguished from those which generally do not invade; Candida infections in the mouth, throat, swallowing tube, skin or vagina (note: rarely Candida can also be invasive). The issue is an important one since invasive cryptococcal disease (usually meningitis) occurs in approximately 5-10% of AIDS patients. It has a significant mortality rate. The lead author is William G. Powderly, MD. The study was carried out in tandem with the participants of the ACTG 081 study assessing PCP antibiotic prevention, discussed above. The participants were from 29 different institutions in the U.S. A total of 428 enrollees took part in the study over 35 months. Women comprised 5% of the group. The mean CD4 count was approximately 130 cells/mm3. Those who had a current Candida infection were excluded until successfully treated. Those with a history of past invasive fungal infection or a positive cryptococcal antigen were excluded. The results indicated that 10.9% of those in the clotrimazole (CLO) group and 4.1% in the fluconazole (FLU) group developed an invasive fungal infection. Cryptococcal infections developed in 15 patients from the CLO group and 2 patients from the FLU group. These results were all statistically significant. For patients with a CD4 cell count less than 50 cells/mm3, the benefit of FLU was greater than for those with a higher count. Also, FLU was over 5 times more effective than CLO in preventing both esophageal and oropharyngeal candidiasis. There were not enough women in the study to determine the effect of FLU on vaginal candidiasis. There were no differences in survival between the 2 groups. Compliance with taking medication at least 6 days per week for 33 months was different between the 2 groups. Whereas only 50% of the CLO group were compliant with medications, 95% of the FLU group were compliant. Information on resistance to FLU was not reported. Due to the potential confounding effect of toxicity from anti-PCP prevention antibiotics, only those who were on monthly aerosolized pentamidine will be reported. When compared with the CLO group, the FLU group had a statistically significantly greater number of patients with nausea, abdominal pain and blood transfusions. There were no significant differences in the rates of abnormal liver function between the 2 groups. Interestingly, the authors estimated that 11,756 doses of fluconazole were taken to prevent each case of invasive fungal disease in the study. The researchers conclude that, "Fluconazole taken prophylactically reduces the frequency of cryptococcosis, esophageal candidiasis, and superficial fungal infections in HIV-infected patients, especially those with 50 or fewer CD4 cells/mm3, but the drug does not reduce overall mortality." In an accompanying editorial, Nathan Clumeck, MD, from the St. Pierre Hospital of the University Libre de Bruxelles in Brussels, Belgium, provides a somewhat different conclusion: "It is currently inadvisable to recommend generalized primary prophylaxis against fungal infections in patients with AIDS." Such an approach is unrealistic for mucosal candidiasis, and primary prophylaxis against the fungi should be evaluated in areas of endemic disease. For patients with low CD4 counts who come from or live in areas of endemic cryptococcosis, primary prophylaxis with fluconazole must be considered. Clumeck N. Primary prophylaxis against opportunistic infections in patients with AIDS. The New England Journal of Medicine. 332(11):739-740. March 16, 1995. Powderly WG and others. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. The New England Journal of Medicine. 332(11):700-705. March 16, 1995. Cytomegalovirus Cidofovir Eye Injections Are Effective for Treatment of Retinitis  Retinitis progression halted for 2 months  A dose of 20 micrograms is effective  Side effects include treatable iritis, low eye pressure, and possible drug-related retinal detachment From 20-45% of AIDS patients will develop cytomegalovirus (CMV) disease at some point, most of which will occur in the retina of the eye. This threatens the vision of those affected. The current treatments have included IV ganciclovir (Cytovene) or foscarnet (Foscavir), and require indwelling catheters in the skin. An oral form of ganciclovir is currently available on an expanded access basis for primary prevention. Delivering anti-CMV medications directly into the eye has been targeted as a more effective means to help prevent progression in that organ. Reports of eye injections with ganciclovir have appeared in the literature, indicating some degree of success. Success with the use of ganciclovir eye implants was reported in the last issue of BETA (March 1995. page 73). Two articles were recently published indicating success in treating CMV retinitis with eye injections of cidofovir (HPMPC, Vistide). Cidofovir (CID) is an experimental anti-viral antibiotic with known effects against CMV, herpes simplex virus and Epstein-Barr virus (EBV), all members of the herpes group of viruses. It is more attractive than ganciclovir or foscarnet because it's longer half-life in cells would indicate that dosing could be much less frequent. In addition, CID is 10 times as potent in vitro than ganciclovir. Recent published reports of intravenous CID studies are discussed below. Researchers at the AIDS Ocular Research Unit of the University of California at San Diego have reported on their initial experience with CID injections in the eye for CMV retinitis in the April 1995 issues of Ophthalmology and American Journal of Ophthalmology. The lead author is Leonard S. Kirsch, MD. The first study was a Phase I/II unmasked consecutive pilot trial to determine dosing, safety and efficacy. Group 1 of the first study enrolled 9 patients. A total of 10 eyes received 14 CID injections. The pilot results indicated that the highest dose that was safe was 20 micrograms. Higher doses were associated with inflammation within the eyeball fluid (vitreitis) and abnormally low tone (hypotonia). All participants took oral probenecid (Benemid), 2 grams 3 hours before CID, 1 gram 2 hours after, and 1 gram 8 hours after the CID injection. This was given to help minimize potential toxicity in the eye, just as probenecid decreases CID-induced kidney toxicity (see discussion in the next section). All but 1 of the Group 1 patients were also receiving intravenous (IV) ganciclovir during the trial. This means that the true benefits of the CID eye injections alone would be more difficult to determine. However, the median time to progression after the first 20 microgram injection was 78 days. The median follow-up time was 76 days. At that time, 87% of the opposite-side, untreated eyes showed progressive CMV, in spite of IV ganciclovir. Group 2 in the first study included 8 patients who received 11 eye injections with 20 micrograms of CID alone, without IV ganciclovir. This group of 8 was made up of 6 who were intolerant of or resistant to ganciclovir or foscarnet or both. Another 2 had refused any IV therapy. The mean duration of CMV retinitis before CID injections was 32 weeks. The median follow-up after injections was 55 days. One patient received 3 injections in the same eye due to progression, another 1 received 2 injections and the remaining 6 received 1 injection each. The median time to progression after the first 20 microgram dose was 64 days. In this group, there were no complications of retinal detachment, bleeding or infection. However, there was a statistically insignificant trend towards lower eye pressure as a result of CID. At the end of follow-up, 50% of the opposite-side, untreated eyes did show progressive CMV. The authors conclude from their first study that CID eye injections may be useful as an adjunct to IV therapy for CMV retinitis. They also state that CID eye injections appear to have more lasting results than ganciclovir eye injections. The same authors published a second study of CID eye injections for CMV retinitis in the journal Ophthalmology. They imply that the second study did not include any patients from the first study, although the dates of each study overlapped. Study 2 enrolled 17 patients, all of whom were men except for 1 woman. It was an unmasked, consecutive series study (non-blinded). There were 37 CID injections into 24 eyes of the 17 patients. On the day of the injections, each participant took probenecid 2 grams by mouth 3 hours before, 1 gram 2 hours after, and 1 gram 8 hours after the injection, unless there was a history of sulfa allergy or stomach intolerance of the medication. The probenecid was given to help offset anticipated kidney toxicity. CID injections into both eyes occurred in 41% of participants. Twenty percent (20%) of the eyes received 3 CID injections, 12% of the eyes received 2 injections and 33% of the eyes received only 1 injection. The median follow-up was 62 days, with a range of 38-186 days. The median time to progression of retinitis was 55 days (mean 61 days). The median time to progression after the 8 repeated injections was 63 days. Comparing the time to progression after the first versus the second injections revealed no statistical difference. The location of CMV disease on the retina did not alter response times. CMV disease in other organs occurred among 31 (8%) of the participants during the observation period, requiring IV antibiotics. Those organs included the lung (pneumonia), colon (colitis) and adrenal glands (adrenalitis). In this expanded study, side effects were observed. Five patients (21%) developed iritis approximately 2 weeks after the CID injections. Inflammation of the iris (colored part of the eye) has symptoms of mild pain, light sensitivity and mild blurring of vision. All 3 had either 1 CID injection in each eye or multiple injections in 1 eye. All 3 of the patients with iritis responded to the usual therapy of eye drops including a steroid (1% prednisolone) plus a pupil dilator (atropine). The iritis resolved in all 3. Also, 3 retinal detachments occurred among 24 treated eyes (37%), possibly associated with low eye pressures. Note that retinal detachments also occur in 17-34% of untreated CMV retinitis. Lastly, there was a statistically significant decrease in median eye pressures as a result of the CID injections. This did not result in any symptoms, other than a possible relationship with retinal detachments. CID absorption out of the eye into the bloodstream was not measured and was assumed to be low to none. While not otherwise measured, it was assumed that CID caused no other bodily changes or effects. The authors conclude that a single 20 microgram dose of CID injected into the eye safely prevented progression of CMV retinitis for 55 days, without IV therapy. They also state that CID effects can be sustained after a second injection. Side effects include iritis, decreased eye pressure and possible retinal detachment. The eye injection of CID does not prevent CMV disease in the opposite-side eye or in other organs. The authors state that "conclusive demonstration of the efficacy of intravitreal (injection within the eye) cidofovir for treating CMV retinitis awaits a prospective, randomized, controlled clinical study." The ethics of such a controlled trial are questionable. Comparing eye injections of CID with similar injections of ganciclovir or ganciclovir implants would be more reasonable. The prevention of CMV retinitis progression with 1 eye injection of CID can be compared with each of the following therapies and their respective progression times: (1) daily IV ganciclovir, approximately 8 weeks; (2) daily IV foscarnet, 7-8 weeks or longer; or (3) daily oral ganciclovir, about 6 to 7 weeks. While the data are limited, it appears that the CID eye injections can be repeated at least once for another 8 weeks of prevention. Even though both IV ganciclovir and foscarnet have significant side effect profiles and require a continuous IV access site, each does have preventive effects against CMV in other organs. Oral ganciclovir does not require an IV, but does provide protection against CMV in other organs. The advantage of the CID eye injection not requiring an IV line must be balanced against its disadvantage of having little or no effect on the prevention of CMV disease in other organs. The various times to progression for each of those therapies can be compared to the ganciclovir eye implant, which prevents CMV progression for a median of 226 days (7.5). Surgically placing the implant is somewhat more invasive than the eye injection. One cannot help wondering what the prevention of progression time for CMV retinitis will be when CID is used in an eye implant. Kirsch LS and others. Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology. 102(4):533-543. April 1995. Kirsch LS and others. Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Journal of Ophthalmology. 119:466-476. April 1995. Intravenous Cidofovir Decreases CMV Levels  Dosing needed only once weekly or less  Beneficial for CMV and acyclovir-resistant herpes simplex  May have toxic effects on the kidney Since 20-45% of AIDS patients will develop CMV disease, there is great interest in new potential therapies. Cidofovir (CID) is a new antiviral antibiotic effective against many herpes group viruses. It remains in tissues longer than either ganciclovir of foscarnet. Two reports on the Phase I/II Studies of IV CID have been recently published. The first study was published by NIAID. The lead author is Michael A. Polis, MD. The article appeared in the April 1995 issue of Antimicrobial Agents and Chemotheapy. A total of 21 HIV positive patients with CMV in the urine were recruited for this dose-escalation study to determine an effective dose and the drug's safety profile. The CD4 cell count ranged from 0-389 cells/mm3, with a median of 39 cells/mm3. The participants were given IV infusions of CID every half, 1, 2 or 3 weeks. Paticipants were also given oral probenecid (Benemid) 2-3 grams, to limit the expected kidney toxicity. The results indicate that IV CID at a dose of either 5 mg/kg weekly with oral probenecid or 7.5 mg/kg every 3 weeks with probenecid is feasible. The first dose is probably the maximum tolerated. Those doses cleared CMV from the urine in almost all patients. However, those doses did not clear CMV from the blood. Those results are limited by the fact that the blood cultures for CMV were taken immediately prior to the subsequent CID dose. Toxic effects on the kidney included protein and glucose in the urine and abnormal elevation of kidney function. Six of 8 patients taking AZT with probenecid developed a rash. The authors conclude that CID has prolonged activity that makes it potentially useful to administer on an intermittent schedule, thereby avoiding the need for a continuous indwelling catheter. Further efficacy studies are needed with larger numbers of participants. The second report on a Phase I/II Study of IV CID appeared in the April 1995 Journal of Infectious Diseases. The lead author is Jay P. Lalezari, MD, from University of California at San Francisco (UCSF) School of Medicine. The researchers recruited 31 men with AIDS who had CMV in the urine or semen, without symptoms of CMV disease. The researchers had similar results as the NIAID group regarding decreased CMV in the urine from IV CID. They also found a decrease in CMV in semen, which occurred before the decrease of CMV in urine. The effects of CID on CMV levels in the blood were not reported. None of the participants developed CMV disease during the study. The report indicated that 3 to 4 weekly doses of IV CID 5 mg/kg with oral probenecid had similar anti-CMV effects as 42 doses of IV ganciclovir. Kidney toxicity was similar to the NIAID study. Adequate IV hydration and oral probenecid were beneficial in helping to limit the kidney toxicity. The report indicates that there were several other side effects which were reversible: nausea (48%), fever (35%), hair loss (16%), muscle aches (16%), probenecid allergy (16%) and low white cell counts (29%). CID did not affect the CD4 cell count. HIV viral load measurements were not reported. The researchers were able to document the antiviral effects on herpes simplex virus (HSV) infection in addition to CMV. They reported on the beneficial effects of weekly CID 5 mg/kg on a man with a 6 month history of acyclovir-resistant rectal herpes simplex infection. After 4 doses (one month), the area was nearly healed. As a result of their findings, the researchers state that CID requires further study in the clinical setting to determine its benefits for treatment and prevention of CMV organ disease. Lalezari JP and others. (S)-1-[3-Hydroxy-2-(Phosphonylmethoxy)propyl]cytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analog. Journal of Infectious Diseases. 171:788-796. April 1995. Polis MA and others. Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria. Antimicrobial Agents and Chemotherapy. 39(4):882-886. April 1995. Progressive Multifocal Leukoencephalopathy (PML)  AZT treatment effective with increased lifespan  Diagnosis possible from CSF; brain biopsy may be unnecessary Several reports have appeared in the medical literature regarding progressive multifocal leukoencephalopathy (PML), a debilitating brain disease in AIDS. PML is known to be caused by JC virus. PML occurs in approximately 4% of those with AIDS, and a rapid downhill course usually is the case within months after diagnosis. Spontaneous recovery and prolonged life with PML is uncommon, particularly in those with immune dysfunction. Some clinicians have reported improvements in PML symptoms among some patients who have received cytosine arabinoside injected into the cerebrospinal fluid (CSF). Others have noted no improvements with that therapy. One report indicated improvement with cytosine arabinoside combined with interferon. Researchers have continued to search for other potential therapies. Two recent reports indicate that moderate to high dose AZT may be of significant help to some AIDS patients with PML. The first report was published in the December 1994 issue of Acta Neurologica Scandinavia. Elyse J. Singer, MD, and colleagues from the University of California at Los Angeles (UCLA) School of Medicine authored the report. An HIV positive man with a CD4 cell count of 162 cells/mm3 had a progressive neurologic decline over a period of weeks. At first, he had difficulty using the computer at work and problems dressing himself. Thereafter he was unable to control his urine or stool. He quickly became bedridden, mute, and unresponsive. Physical examination revealed some weakness on the left side of his body. Brain MRI (magnetic resonance imaging) scanning revealed changes suggestive of possible PML. A brain biopsy revealed a diagnosis of PML. All other infections and tumors were ruled out as the cause of his neurologic decline. After 5 weeks of hospitalization, AZT was started at a dose of 1,200 mg per day. Within 2 weeks of therapy, the patient began to communicate and respond to verbal directions. After 3 months of AZT therapy, he was discharged to a group home and able to care for himself. He was able to control his urine and stool, able to walk and able to shop with minimal help. While he did not return to normal neurologic function, his improvement from the bedridden state was quite impressive. One year after AZT was started, his CD4 cell count was 167 cells/mm3. The patient died 2 years after his initial diagnosis of PML due to another AIDS-related illness (not specified in the report). A second article noting the benefit of AZT for PML appeared in Clinical Infectious Diseases. The lead author is O. Lortholary, MD, from the Institut Pasteur in Paris, France. A 41 year old man with a CD4 cell count of 359 cells/mm3 was diagnosed with PML from a brain biopsy. CT (computerized tomography) and MRI scans were consistent with the diagnosis. On physical examination, he had some weakness on the left side of his body. He was started on AZT 1,200 mg per day that had to be stopped after 3 months due to bone marrow toxicity. After being off drug for 3 months, it was restarted at a lower dose of 600 mg per day. The patient's condition did not deteriorate any further, and he was still alive 5 years later. There is 1 other report in the literature of an AIDS patient with PML who responded to 1,200 mg of daily AZT, but the follow-up was only 10 months. The lead author is B. Conway and the article appeared in Review of Infectious Diseases in 1990. The standard dose of AZT for anti-HIV therapy is 500-600 mg daily. These reports suggest that a higher dose may be necessary to be effective in the treatment of PML. The toxicity and side effects of AZT may make this difficult for many patients. The mechanism of action likely relates to the decreased levels of HIV tat protein, which are known to stimulate the expression of JC virus late genes which code for the JC capsid protein. In the past, the diagnosis of PML was made by brain biopsy, a procedure with inherent risks and sometimes refused by patients. Brain imaging including CT and MRI scans were often suggestive of the diagnosis. However, other opportunistic infections and cancers can have a similar appearance. Therefore, there has been strong interest in being able to diagnose PML more easily. Research had turned towards specific examination of the cerebrospinal fluid (CSF) to find JC DNA or antigens. While occasional reports of polymerase chain reaction (PCR) tests for JC DNA in CSF have existed since 1991, the tests were imperfect. Specifically, they had difficulties with false positive and false negative results. Researchers at UCSF School of Medicine have recently published their research regarding a PCR test for JC DNA from the CSF with minimal false positive or false negative results. Dawn McGuire, MD, and colleagues have authored the paper that appears in the March 1995 issue of Annals of Neurology. The researchers examined the CSF of 26 HIV positive patients with PML, 114 HIV positive control patients without clinical PML, and 16 HIV negative control patients without PML or HIV risk behavior histories. The JC PCR test was able to correctly identify 24 out of 26 patients with PML. All 8 of those 26 with PML confirmed by brain biopsy had a positive PCR result from the CSF. Sixteen of the other 18 PML patients diagnosed by clinical exam and MRI findings had a positive PCR result from CSF. Ten of the 114 HIV positive controls had a positive PCR result from the CSF: 9 of the 10 had an AIDS diagnosis, while the 10th had symptomatic HIV disease. One HIV negative control patient had a positive CSF result. The authors believe that the 10 HIV positive controls without PML but with a positive PCR CSF result represent a group who is at risk for developing PML symptoms in the future. Their positive CSF JC PCR results may represent a marker for the future diagnosis of PML. Eight of the 10 had brain scans at the time of their lumbar punctures for CSF. Two of the 8 had abnormalities thought to be due to either HIV encephalitis (brain infection) or possible PML, even though they had no symptoms of PML. One of the 8 had a normal brain MRI at the time of the CSF test, but developed PML 3 years later. The others will be followed to determine whether they may develop PML. With treatment trials for PML underway (see below), such asymptomatic JC virus positive individuals may be considered for such trials in the future. The 1 HIV negative patient without HIV risk behavior had chronic leukemia, a known risk factor for PML among HIV negatives. He also had an abnormal neurologic examination and may have had true PML. The sensitivity and specificity of the CSF results are 92% for each. Sensitivity of a test represents the ability to correctly label as positive those who have a condition. Specificity of a test represents the ability to correctly label as negative those who do not have a condition. A test with a low sensitivity has too many false negatives. A test with a low specificity has too many false positives. The authors conclude that the PCR test for JC DNA in the CSF represents an improvement in the ability to diagnose PML. They state that this test may avoid the need for brain biopsy in certain patients with possible PML. Lortholary O and others. Prolonged survival of a patient with AIDS and progressive multifocal leukoencephalopathy. Clinical Infectious Diseases. 18:826-827. May 1994. McGuire D and others. JC virus DNA in cerebrospinal fluid of human immunodeficiency virus-infected patients: predictive value for progressive multifocal leukoencephalopathy. Annals of Neurology. 37:395-399. March 1995. Perrons CJ and others. Progressive multifocal leukoencephalopathy in patients with AIDS: detection of JC virus DNA in CSF and brain. Genitourinary Medicine. 71:35-40. February 1995. Singer EJ and others. AIDS presenting as progressive multifocal leukoencephalopathy with clinical response to zidovudine. Acta Neurologica Scandinavia. 90:443-447. December 1994. Weber T and others. Progressive multifocal leukoencephalopathy diagnoses by amplification of JC virus-specific DNA from cerebrospinal fluid. AIDS. 8:49-57. August 1994. Tuberculosis Antibiotic Resistance Associated with Malabsorption of Drug Resistance of the Mycobacterium tuberculosis organism to standard antibiotic therapies has become an increasing problem in the era of AIDS. This occurrence had been attributed to poor compliance, with some patients not taking their medications regularly. Intermittent or irregular exposure of the organism to antibiotics likely allows for the development of resistant strains. These resistant strains are much more difficult to treat. Programs that incorporate direct observation of patients taking their medications have been associated with a higher likelihood of curing tuberculosis (TB). A recent letter to the Editor in the New England Journal of Medicine by Kalpana B. Patel, PharmD, and colleagues from Hartford Hospital in Hartford, Connecticut suggests another possibility. They documented malabsorption of TB antibiotic drugs from the gastrointestinal tract of 2 AIDS patients as being a co-factor in the development of resistant TB strains. Two AIDS patients with active TB were receiving their antibiotics under direct observation. Therefore, the drugs were being swallowed regularly as prescribed. The first patient developed a new TB lesion 4 months after therapy with isoniazid, rifampin and pyrazinamide. Cultures of the new focus of TB revealed an organism resistant to rifampin. The second patient developed a new TB lesion 10 months after continuous therapy with isoniazid, rifampin, pyrazinamide and ethambutol. Cultures of the new TB lesion revealed resistance to isoniazid and rifampin. Neither of the 2 patients were re-exposed to patients with drug-resistant TB. The authors measured antibiotic drug levels in the blood after swallowing the antibiotics. Levels of 4 out of 5 TB antibiotics ingested were very low ("subtherapeutic"), sometimes with marked delay of absorption. The levels of rifampin were zero up to 1.5 hours after ingestion. The second patient was known to have diarrhea and an abnormal D-xylose test, consistent with malabsorption, thought to be due to HIV. The first patient was not known to have malabsorption. A number of the intestinal opportunistic infections are associated with malabsorption of drugs and food. Some of those infections may be associated with symptoms of diarrhea and weight loss, while others may be asymptomatic. The authors propose that all HIV positive patients with TB should be routinely screened for blood levels of their TB antibiotics. They emphasize the importance of such measurements for those with advanced HIV disease. They point out that direct observation of ingesting TB medications may not be the only factor in the development of antibiotic resistant strains. The concept of malabsorption of antibiotic drugs in HIV/AIDS could easily apply to many different types of antibiotics, including those for other opportunistic infections. Patel KB and others. Drug malabsorption and resistant tuberculosis in HIV-Infected Patients. New England Journal of Medicine. 332(5):336-337. February 2, 1995. Thalidomide Accelerates Weight Gain during Tuberculosis Treatment Disease caused by Mycobacterium tuberculosis (TB) often causes significant weight loss for both HIV positive and HIV negative individuals. Adequate antibiotic therapy will slowly reverse the weight loss for most, but the weight gain takes weeks to months. The weight loss in TB and AIDS wasting syndrome is induced partly by increased levels of tumor necrosis factor (TNF) secreted by monocytes and macrophages. TNF is necessary for the immune system to control and clear the TB infection, but it was not known whether blocking the TNF-induced weight loss would still allow for normal healing of TB disease. Thalidomide (THAL) is a mild sedative with anti-nausea properties that also has beneficial immune system benefits when used to treat transplant patients and those with lupus and leprosy. Thalidomide has been shown to decrease the production of TNF. Researchers at Rockefeller University in New York attempted to determine whether oral thalidomide could increase weight gain in TB patients with weight loss. Thalidomide or placebo was given along with the TB antibiotics. The study included both HIV positive and HIV negative individuals. The lead author is Jane M. Tramontana, MD. The article was published in the May 1995 Molecular Medicine. The study was a placebo-controlled pilot. A total of 30 men with active TB were recruited. Due to severe congenital malformations that occur among the newborns of women taking THAL, women were not included in the study. While 20 of the patients were from Thailand, 10 were from New York City. The Thailand participants included 6 of 20 who were HIV positive, while the New York participants included 7 of 10 who were HIV positive. Patients with peripheral neuropathy were excluded since peripheral neuropathy is a known side effect of THAL. Four TB antibiotics were taken by 93% of the patients; the other 2 (7%) were Thai patients taking 3-drug therapy. In addition, all 7 HIV positive patients from New York took antiretroviral therapy. THAL 300 mg or placebo was taken at bedtime for 7 or 14 day periods. The New York group had several cycles of 7 days on medication followed by 7 days off. The results showed that THAL increased the weight gain more than placebo. The control group gained 2% of their starting weight after 14 days, while the THAL group gained 6% of their starting weight in the same time period. Moreover, the weight gain during THAL weeks was greater than the weight gain in the off-THAL weeks, which was the same as control weeks. The weight gain occurred among both HIV positive and HIV negative individuals. For patients who took THAL during week 1 and 3, but not week 2, the weight gained during week 1 was maintained during week 2 and did not return to the pre-week 1 baseline weight. They merely slowed their weight gain during week 2. THAL did not increase appetite, since caloric intake was the same during the THAL treatment weeks and off-THAL treatment weeks for all groups. The researchers did not measure whether the weight gained was muscle, fat or water, but they do not believe that it was due to water retention. The only side effects were morning drowsiness, dry mouth and constipation. (One patient had a rash due to his TB medication, isoniazid.) The THAL did not prevent the improved course of TB disease in HIV positive or negative patients, as measured by symptoms or chest x-ray films. THAL did not significantly change the white cell counts, including lymphocytes and subsets. The 1 exception was that THAL did increase the CD8 cell counts in the HIV positives, but did not in the HIV negatives. The before and after absolute CD4 cell count numbers were not stated. The authors were able to document that THAL did decrease TNF-alpha among both HIV positive and negative individuals who took the medication, when compared with controls. However, THAL did not eliminate TNF-alpha. The mechanism of action was correlated with a decrease in TNF-alpha RNA production. Conversely, gamma interferon was increased among those taking THAL, regardless of HIV status, when compared with controls. The researchers also measured the effect of THAL on purified protein derivative (PPD) and control skin tests, a simple measurement of immune function. A person with a positive PPD skin test indicates both past exposure to tuberculin protein and an immune system that is intact enough to make an immune response. That response is measured as the width of a skin lump 48 hours after the "bubble" injection. When the immune system is too damaged to make a response even when past exposure to tuberculin protein has occurred, "anergy" is present. Anergy is indicated by no lump or a lump with a width less than 2 mm on the skin. Of the 6 patients who were anergic at baseline, THAL caused a positive PPD in 5 when tested a second time. After the THAL cycle was finished, 3 out of 4 who were PPD-tested a third time returned to an anergic state. Note that 4 of the 6 who were anergic were also HIV positive. The authors conclude that THAL is well tolerated in TB patients, both HIV positive and negative, who are taking TB antibiotics, and THAL is associated with a decrease in TNF-alpha and an accelerated weight gain while on drug. They also suggest that the immune response in TB disease may be an overproduction of TNF-alpha, which is associated with fever and weight loss of muscle and fat. Since THAL has also been successful in the treatment of 2 AIDS patients with Mycobacterium avium complex (MAC) in terms of weight gain and decreased fever, it is possible that THAL may also have an independent role in the treatment of AIDS wasting syndrome and MAC disease. It is unfortunate that women of childbearing age would be ineligible to take THAL on ethical grounds, given the problems of malformations in newborns. Limitations of the study include: pre- and post-treatment CD4 cell counts were not given, viral load measurements were not done, long-term follow-up of the participants was not stated and tissue biopsies of healed TB lesions were not done, although this is difficult to do for TB in the lungs. Tramontana LM and others. Thalidomide treatment reduces tumor necrosis factor-alpha production and enhances weight gain in patients with tuberculosis. Molecular Medicine. 1(4): 384-397. Thalidomide Treatment Success for Aphthous Ulcers Aphthous ulcers are painful sores in the mouth, esophagus (swallowing tube) and rectum. They are common in HIV/AIDS. While they are not known to be caused by any known infection, it is likely that an infectious cause will be determined at some time in the future, probably viral, and possibly HIV itself. (Up to 35% or more of patients have ulcerations of mucous membranes during primary HIV infection.) Topical steroids and numbing agents (lidocaine gel) are used as treatments, with some success. However, those therapies are not always successful. The esophagus and rectum can be particularly painful and difficult areas to treat, and sometimes require narcotics for pain relief. Aphthous ulcers in the mouth, throat or esophagus can lead to painful, difficult swallowing, that can in turn lead to weight loss. Approximately 25 single case reports in the medical literature have documented success with treating HIV-related aphthous ulcers with thalidomide (THAL), after typical therapies were not effective. Researchers at the Royal Brisbane Hospital in Queensland, Australia have published a retrospective analysis of 20 HIV positive patients with aphthous ulcers, most of whom were successfully treated with ingested THAL after all other therapies failed. The lead author is David L. Paterson, MD. The paper was published in the February 1995 Clinical Infectious Diseases. The 20 patients had received 28 courses of THAL in an open label study over 3 years. Other causes of ulcerations were ruled out: fungi, spirochetes (e.g., syphilis) and known viruses. This was done by culturing for fungi, bacteria, mycobacteria, herpes simplex and cytomegalovirus (CMV). Biopsies ruled out lymphoma and Kaposi's sarcoma. Blood antibody tests for syphilis were also done. Eighty percent had baseline CD4 cell counts less than 200 cells/mm3. Fifty-five percent of the treatments were for mouth ulcers, 1/3 for throat or esophagus ulcers and 10% were for rectal ulcers. All had prior unsuccessful treatments with: topical and oral steroids; trials of antiviral therapies with acyclovir and/or ganciclovir; antacids; and histamine type 2 blockers (cimetidine, Tagamet and others). The dose of THAL was 200 mg per day at bedtime for 14 days. That dose led to healing of ulcers in 15 of 28 (53%) treatment courses. Symptoms decreased in another 2 patients. Another 3 patients stopped therapy early due to side effects; however, 2 of those 3 had complete healing after 10 days of THAL. In another 5 patients, treatment was extended beyond 14 days, with benefits. Those with rectal ulcerations all required prolonged therapy. Four patients had relapse after therapy was completed. Altogether, improvement of symptoms or healing occurred in 95%. Side effects occurred in 35% of the participants: rash (5 patients), peripheral neuropathy (1 patient) and extreme fatigue (1 patient). Side effects led to stopping THAL in 5 patients. There were no statistically significant differences in the levels of CD4 cell counts comparing pre- and post-therapy numbers. HIV viral load measurements were not reported. The authors conclude that HIV positive individuals with aphthous ulcers unresponsive to traditional therapies will often have symptom relief and healing of ulcers with 200 mg of thalidomide taken orally at bedtime for 14 days. Due to the risk of malformations at birth, THAL is not an ethical option for women of child-bearing age. Currently, THAL is available in the U.S. with a physician's prescription from San Francisco or New York AIDS treatment buyers' clubs (see BETA News Briefs, p. 8). THAL also is available through certain treatment protocols (call 1-800-TRIALS-A). Paterson DL and others. Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection. Clinical Infectious Diseases. 20:250-254. February 1995. Malignancies Foscarnet Effective for Kaposi's Sarcoma Two reports in the medical literature indicate that Kaposi's sarcoma (KS), the most common malignancy in AIDS, responds to therapy with foscarnet (Foscavir). Foscarnet is an antiviral drug used to treat cytomegalovirus (CMV) disease as well as herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections which are resistant to acyclovir. Foscarnet has known antiviral activity against HIV and each of the following herpes-group viruses: CMV; HSV types 1 and 2; VZV (the cause of shingles); and human herpes virus type 6 (HHV-6). The finding of new herpes-group virus DNA among KS lesions from those with AIDS, HIV negative gay men with KS, and classic KS, is consistent with the response to foscarnet. The first report appeared in the Scandinavian Journal of Infectious Diseases. Linda Morfeldt, MD, and Jan Torssander, MD, were the authors of the paper. They had accidentally noticed the regression of KS in 2 patients being treated for CMV disease with foscarnet. As a result, they instituted a small trial. Five patients with AIDS-associated KS were treated with foscarnet 60 mg/kg intravenously (IV) every 8 hours for 5 days, followed by 90 mg/kg IV every 12 hours for 5 days. The mean CD4 cell count was 66 cells/mm3 (range 6-270 cells/mm3). The 1 patient with a CD4 cell count of 6 cells/mm3 did not have a response to his KS from foscarnet therapy. The second patient had foscarnet therapy interrupted on day 6 due to side effects of nausea and headache. The third patient had a near total regression of his KS lesions 12 months after the 10-day treatment, with a gradual decrease in size starting at 1 month after therapy. However, 17 months after treatment, new lesions began appearing. His initial CD4 cell count was 24 cells/mm3. The fourth patient had a partial regression 6 weeks after foscarnet treatment, and a complete regression thereafter except for ear KS that was treated with radiation. His KS was in remission 20 months after treatment. His initial CD4 cell count was 26 cells/mm3. The fifth patient had no response 5 months after foscarnet; a second 10-day course was given at month 8. He had a complete regression of his KS 5 months thereafter. He was still in remission 2 months after that. The 3 patients who responded to foscarnet also received AZT therapy during the period of observation. Even though the 3 of 5 who did respond to foscarnet did not exhibit a stellar immediate response, the treatment duration was only for 10 days (except for the patient treated twice), much shorter than that for CMV retinitis. It is possible that a longer treatment duration may lead to a faster response of the KS lesions. Further studies will be necessary to determine the optimal dosage and treatment schedules. Since AIDS-related KS rarely resolves spontaneously, it is likely that further studies of foscarnet therapy for KS, with or without other agents, will occur in the future. A second study on the beneficial effects of foscarnet for AIDS-related KS has been reported in the February 24, 1995 issue of Science. Researchers from the Centers for Disease Control and Prevention (CDC) in Atlanta did a retrospective analysis of 20,228 patients with HIV/AIDS from 100 medical facilities in 10 metropolitan areas in the U.S. from January, 1990. They excluded those who already had a prior diagnosis of KS. Those who developed KS within the 14 months thereafter numbered 1,033 or approximately 5% of the total. In the total 20,228 patient group, if foscarnet had been given for any reason, those individuals had a 70% less chance of being diagnosed with KS than those who had not received that therapy. The results were statistically significant, even when controlled for CD4 cell count, age, race, sex, HIV exposure risk, AIDS opportunistic infections and antiretroviral treatment. There was no decrease in the rate of KS for those who were given ganciclovir for any reason. Interestingly, those who were given acyclovir at any time had a 40% increase in the incidence of KS. The authors note that foscarnet works by a different mechanism of action than either acyclovir or ganciclovir. They believe it is possible that the new herpes-group virus that may be causing KS is resistant to or develops resistance to acyclovir, given the low doses used for maintenance therapy of recurrent HSV infections. Foscarnet has a mechanism of action that interacts with the pyrophosphate attachment sites on DNA polymerase. In contrast, both acyclovir and ganciclovir have a mechanism of action by competitive inhibition of deoxyguanosine triphosphate incorporation into DNA after phosphorylation. Morfeldt L and Torssander J. Long-term remission of Kaposi's sarcoma following foscarnet treatment in HIV-infected patients. Scandinavian Journal of Infectious Diseases. 26: 749-752, 1994. Jones JL and others. AIDS-associated Kaposi's sarcoma. Science. 267:1088-1089. February 24, 1995. Skin Conditions Eosinophilic Folliculitis Some eosinophilic folliculitis is caused by:  Demodex mites, and  Pityrosporum yeast Some eosinophilic folliculitis responds to therapy with:  Topical permethrin cream, or  Oral itraconazole Two interesting reports about the causes and treatments of some cases of AIDS-associated eosinophilic folliculitis (EF) appeared in the March 1995 issue of Archives of Dermatology. While EF is not a life-threatening condition like many of the AIDS opportunistic infections, the itching associated with this skin condition makes it extremely uncomfortable for those who have it. Past treatments were fair-to-good in improving the itching, but the cause was not known. Prior to these reports, microscopic analysis of skin biopsies only showed eosinophils associated with the hair follicles. Eosinophils are white blood cells commonly involved in allergic reactions and parasitic infections. Past treatments for EF included topical steroids to block the immune response, oral antihistamines to relieve itching, and sometimes the use of ultraviolet light phototherapy. Rarely, oral steroids or PUVA therapy was used (oral psoralen with ultraviolet A phototherapy). Researchers at the Dermatology Branch of the National Cancer Institute have reported that some cases of EF are due to Demodex mites around the hair follicle, sometimes associated with Pityrosporum yeast. Both of these organisms are normal inhabitants of the skin in HIV positive and negative individuals. Andrew Blauvelt, MD, and colleagues reported on 6 AIDS patients with EF that did not respond to the usual treatments. All 6 had prior therapies which included: oral antihistamines; topical steroids; oral and topical antifungal and antibacterial antibiotics. The 6 had EF for 2-24 months. The CD4 cell count ranged from 10-60 cells/mm3. Four of the 6 had elevated immune globulin type E (IgE) antibody levels in the blood (IgE is elevated in certain allergic conditions). EF occurred on the face, chest, back and arms of the 6, and was more generalized in 1 of the 6. Skin scrapings from EF lesions from all 6 revealed numerous Demodex mites under the microscope. Biposies of the EF lesions revealed numerous Demodex mites at the center of the hair follicles under the microscope. Also seen were numerous eosinophils. They noted that 1 of the 6 patients not taking fluconazole (Diflucan) had Pityrosporum yeast infection along with the Demodex mites. (The authors imply that the other 5 were taking fluconazole and did not have Pityrosporum found on biopsy.) Stains for other yeast and for bacteria were all negative. In an open study, all 6 patients were prescribed topical 5% permethrin cream (Elimite) once daily to the rash area until the EF bumps flattened and the itching decreased. All 6 patients responded with flattening of the lesions and decreased itching. The treatment period was implied to be over several weeks. Since all 6 had recurrence after the permethrin was stopped, maintenance therapy was successful with 1-2 treatments weekly. Skin scrapings during permethrin treatment revealed fewer Demodex mites. The authors indicate that a double-blind vehicle-controlled study would be needed to further document their findings and to establish the exact dosing. Blood levels would also need to be measured to determine absorption from the skin and potential toxicities. Topical permethrin is a standard treatment for skin infestation with scabies, due to Sarcoptes scabiei. When used to treat HIV negative individuals with scabies, topical permethrin is associated with mild and temporary burning and stinging in 10% of patients. In this same group, itching due to permethrin occurs in 7%, while redness, numbness and rash occurred in less than 2%. Lower concentrations of permethrin are available without a prescription as Rid and Nix. The efficacy of the lower concentrations for EF are not known. The authors of the report hypothesize that the permethrin-induced decrease in the numbers of Demodex on the skin would decrease the antigenic production of IgE antibodies to the organism. Without treatment, the IgE antibodies could bind to Langerhans and mast cells in the skin, possibly leading to the release of chemical messengers associated with an itchy inflammatory response. In a related article in the same March 1995 issue of Archives of Dermatology, researchers at UCSF School of Medicine have published their findings regarding the successful treatment of EF with oral itraconazole (Sporanox), an antifungal used to treat histoplasmosis and certain other life-threatening fungal infections in AIDS. Timothy G. Berger, MD, Marcus A. Conant, MD, and colleagues were co-authors of the report. They reported on an open trial of 28 patients with EF. The mean CD4 cell count was 63 cells/mm3, with a range of 2-420 cells/mm3. Two-thirds had a CD4 cell count less than 50 cells/mm3. Most patients had been receiving prior topical steroids and oral antihistamines before the study. These medications were discontinued, and oral itraconazole was started. The dose was 200-400 mg per day. Those who had no or partial response to the 200 mg dose were increased to 300 or 400 mg daily. The study revealed a 61% control rate and a 14% partial control rate. If patients did improve, it occurred within 2 weeks. After 3 months, 35% no longer needed itraconazole due to resolution of EF, or were using topical steroids only. Another 60% were still taking oral itraconazole and showing benefits. The researchers noted that 1 patient who benefitted from itraconazole was switched to fluconazole due to the development of cryptococcal disease, and the EF returned. Adverse reactions to itraconazole occurred in 4 of the 28 patients (14%), although 3 of those reactions occurred at the 400 mg dose. Three of the reactions occurred in the skin, and 1 had elevated liver enzymes of hepatitis. The authors indicated that the response of EF to itraconazole suggests that a fungus or yeast is responsible for EF, a partial finding of the authors from the first report. They also state the possibility that itraconazole may be acting as an anti-inflammatory rather than as an antibiotic. They suggest that after EF is confirmed by biopsy, the starting dose of itraconazole should be 200 mg daily. If there is no response after 2 weeks, the dose could be increased to 300 mg or 400 mg. These 2 reports provide new information regarding the cause(s) and new potential treatments for some cases of AIDS-related EF. While the benefits of these therapies would need to be documented in additional studies, the findings of these reports will undoubtedly help some patients with EF. The much higher cost and potential systemic side effects of itraconazole would indicate that a trial of topical permethrin may be the better initial choice, assuming that Demodex mites are seen under the microcope from skin scrapings of EF. Blauvelt A and others. Eosinophilic folliculitis associated with the Acquired immunodeficiency syndrome responds well to permethrin. Archives of Dermatology. 131:360-361. March 1995. Berger TG and others. Itraconazole therapy for human immunodeficiency virus-associated eosinophilic folliculitis. Archives of Dermatology. 131:358-360. March 1995. Convulsions from Common Scabies Treatment Researchers recommend against using lindane (Kwell) for all HIV positives. The standard treatment for scabies among HIV positives and negatives is topical lindane 1% (Kwell) cream or lotion, applied to the skin overnight and showered off after 8-12 hours. In the past, there have been rare reports of seizures occurring in HIV negative individuals as a result of lindane application. However, most of these were in infants, children, the elderly, or when the medication was not used properly (including eating). Absorption of lindane through the skin does occur and can cause brain effects ranging from drowsiness to even convulsions (seizures). A small amount of lindane can be found in the blood after normal application to the skin. Small amounts of lindane can be found in breast milk after normal application to nursing mothers. Seizures (convulsions) occur over 5 times as often among HIV positive gay/bisexual men than their HIV negative counterparts. Some of these men had a prior history of seizures that was controlled by medication, only to have a recurrence after becoming HIV positive, even with adequate blood levels of anti-seizure medication. HIV encephalopathy (brain disease) has been identified as the cause of new-onset seizures in 24% of HIV positive men. It is likely that HIV lowers the "seizure threshold" in some way that causes HIV positives to be more susceptible. Depending on the duration of the seizure and the patient's location at the time of a seizure, serious adverse effects can result, including brain damage, stroke, physical trauma from a motor vehicle, or even death. If the patient is driving at the time of a seizure, the lives of others may be threatened. Barry A. Solomon, MD, and colleagues reported on the case of a 38-year-old HIV positive man who developed seizures after 1 application of lindane to the skin for scabies. The authors are from the State University of New York-Health Science Center at Brooklyn, and their report is published in the March 1995 issue of The Journal of Family Practice. Neither the patient nor his family had a prior history of seizures. The patient was taking chlorpromazine (Thorazine) 100 mg every 12 hours for psychosis. This medication was a likely co-factor in the patient's seizure. In addition to scabies, the patient had seborrheic dermatitis, another common skin condition among HIV positives. He also had tinea cruris ("jock itch") infection of the groin. The researchers believe that the extent of the 3 different rashes may have contributed to increased skin absorption of lindane. He also had a sponge bath 45 minutes before the lindane was applied. Skin moisture is associated with increased absorption of medications applied to the skin. The patient's seizure lasted 30 minutes and he suffered neurologic damage. All other causes of seizures were ruled out with appropriate brain scans and blood and cerebrospinal fluid tests. Blood levels of lindane 18 hours after his seizure were twice the toxic level. The toxicology report indicated no amphetamines or cocaine. His CD4 cell count was 200 cells/mm3. Nine days after the seizure, topical permethrin 5% cream (Elimite) was applied to his skin, and the scabies rash resolved within days. Some HIV positives with scabies have high numbers of the organisms in the skin that may require more than 1 treatment. The authors conclude with a recommendation against prescribing lindane for all HIV positive individuals. They note that reports of seizures from lindane among HIV positive individuals have come from San Francisco as well. Holmberg SD and others. The spectrum of medical conditions and symptoms before acquired immunodeficiency syndrome in homosexual and bisexual men infected with the human immunodeficiency virus. American Journal of Epidemiology. 141(5):395-404. March 1, 1995. Holtzman DM and others. New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases. American Journal of Medicine. 87:173-177, 1989. Solomon BA and others. Neurotoxic reaction to lindane in an HIV-seropositive patient, an old medication's new problem. The Journal of Family Practice. 40(3):291-296. March 1995. ------------------------------------------------------------------ The National Task Force on AIDS Drug Development: A Progress Report Jules Levin Jules Levin is an AIDS treatment advocate living in New York City. In early 1994, President Bill Clinton requested that Donna Shalala, Secretary of the Department of Health and Human Services, appoint a National Task Force on AIDS Drug Development. The purpose of the Task Force is to identify obstacles to the development of drugs for the treatment of AIDS and to formulate ways to address those obstacles. The ultimate goal is to facilitate AIDS drug research and development. In April 1994, the Task Force had its first meeting. Since then, it has been meeting for 2 days every few months. At the urging of AIDS community treatment advocates, the Task Force met February 23-24, 1995 in Washington, D.C., to discuss the new class of AIDS drugs called protease inhibitors. The March 1995 issue of BETA contains a detailed report on the proceedings of that meeting (BETA March 1995, p. 31-36). One clear benefit to the AIDS community that emerged from the February conclave was Merck and Company's announcement of an expanded access/open-label program for its protease inhibitor drug Crixivan (formerly called MK-639) for people with CD4 cell counts below 50. Merck's decision to establish this program was due to AIDS community representatives' public demand that Merck broaden access to its protease inhibitor drug for people with low CD4 counts. The Task Force met again April 25-26, 1995 in Bethesda, MD, to identify incentives and disincentives for private investment and collaboration in drug discovery and development for HIV/AIDS and other life-threatening diseases. Discussion centered around proposals on incentives for the development of more and better drugs for AIDS and other life-threatening diseases. Changes in tax and patent laws and FDA regulatory reform were also discussed. Other suggestions for incentives to AIDS research included product liability reform and extending and restructuring the Orphan Drug Act. Biotechnology and pharmaceutical companies want the Task Force to support their efforts to enact these proposals. Industry representatives are now lobbying Congress; they say at stake is the very survival of the biotechnology industry and AIDS research and development. The first day of the April Task Force proceedings began with presentations on industry, economics, community and government, followed by panel discussions on these topics. Presenting proposals for the pharmaceutical industry were the leaders of 2 trade associations: Carl Feldbaum, President of the Biotechnology Industry Organization; and Gerald Mossinghoff, President of the Pharmaceutical Research and Manufacturing Association. Presenting the economics perspective were Peter Arno, PhD, of the Albert Einstein School of Medicine; Joseph DiMasi, PhD, Director of Economic Analysis for the Tufts Center for the Study of Drug Development; and Mark Simon of the brokerage firm Robertson, Stephens and Company. AIDS community perspectives were represented by Mois‚s Agosto of the National Minority AIDS Council, Derek Link of the AIDS Action Council, Martin Delaney of Project Inform and Abbey Meyers of the National Organization for Rare Disorders. The biotechnology and pharmaceutical industries hope to secure financial incentives for their development of AIDS drugs. Industry lobbyists contend that the industry needs financial incentives in order to create more and better AIDS drugs. According to industry representatives, there are 115 biotechnology companies now involved in AIDS research in the U.S. The success of these research efforts depends heavily on attracting investment capital and establishing an economic environment in which research and development can flourish. Industry representatives describe the current economic climate as one in which capital is scarce; they characterize it as a "severe capital drought." The industry is in the midst of a "financial crisis," according to drug manufacturers, after losing $4.1 billion in 1994 and more than $11 billion over the past 3 years. The biotechnology industry raised only $278 million during the 1st quarter of 1995, compared with $762 million in the 1st quarter of 1994. Collectively, the value of biotechnology company stocks has fallen precipitously. The decline stems largely from proposals for price controls on prescription drugs by the Clinton Administration and others during the health care debate, disappointing results from clinical trials, and regulatory, tax, patent and litigation issues. According to a 1994 report by Ernst & Young, biotechnology companies have on average 25 months of capital remaining at their current rate of expenditure. A report from the Gordon Public Policy Center at Brandeis University says that 75% of biotechnology companies have 2 or fewer years of capital remaining. Nine hundred eighty three (983) of the 1,311 biotechnology companies require more capital to continue research and development. Therefore, they will need to focus on projects that are most likely to produce short-term revenues rather than on longer-term projects such as AIDS-related research and development. The biotechnology industry is capital- and research-intensive. Industry representatives claim that their proposals for patent, tax, regulatory and other incentives will attract investors and allow the industry to devote more funding to AIDS research and development. Some of the specific incentives they are requesting include the following: market pricing for biopharmaceuticals, across-the-board capital gains tax reduction and improved targeted capital gains treatment (only for AIDS drugs), a permanent and restructured research and development tax credit, targeted tax credits to companies for collaboration with public and other private organizations, permanent and restructured Orphan Drug tax credit incentives targeted specifically to AIDS research, and improved shareholder suit and product liability protection. The question of product liability is particularly relevant to the development of vaccines for AIDS. In addition, the drug industry wants to enact patent proposals to strengthen intellectual property protection for biotechnology products. To ensure that companies do not lose patent term due to delays in approval of a product by FDA, the industry proposes to extend market exclusivity for all patents related to HIV/AIDS and other life-threatening diseases, and to dispense with the government's patent office requirement that biotechnology patent applications include clinical trial data. Several other patent proposals were also discussed. Industry representatives also urged the Task Force to support their proposals for substantive FDA reform. Industry guidelines for FDA reform include the following:  Make less restrictive the process by which FDA reviews and approves manufacturing procedures. FDA guidelines in this area are commonly referred to as Good Manufacturing Procedures (GMP). Drug companies are expected to follow GMP in order to receive FDA approval. But GMP review is costly and time-consuming to the drug companies and to FDA. The industry wants FDA to utilize experts from outside the agency to review certain GMP, including toxicology, assay validation and environmental issues;  The industry supports proposals for Phase I study review and approval by local institutional review boards (IRB), instead of by FDA;  The industry wants to modify current FDA regulations that restrict the use of non-prescription drugs; and  In order to discourage U.S. companies from going abroad to build manufacturing facilities, the industry wants to liberalize laws governing exportation of products used overseas but not yet approved in the U.S. Finally, the industry is requesting support for the enactment of securities litigation and product liability reform legislation. Frivolous shareholder suits and the requirements for carrying product liability insurance are financially burdensome, according to industry lobbyists. Plaintiffs seeking excessive punitive damages awards further deprive companies of capital that could be used for research. There were objections to these proposals, including some from task force members, Clinton Administration representatives and economics experts. Abbey Meyers, of the National Organization for Rare Diseases, stated that the lack of more and better AIDS drugs is due solely to a deficiency in the progress of the science of AIDS. She said the problem is simply that there aren't any good drugs, and that the industry does not need incentives. There is certainly widespread support for efforts to further our understanding of the science of AIDS, but in my opinion, improved scientific understanding and more effective AIDS drugs will emerge from more spending on AIDS research and development. Some participants objected to broad-based drug industry incentives, e.g., incentives offered to encourage all drug development. They preferred to target assistance to research for AIDS and other life-threatening diseases. Personally, I question whether such an approach will be adequate. Some drugs may be developed for other illnesses and later may be recognized as useful for the treatment of AIDS. Clearly, a financially healthy environment for the biotechnology and pharmaceutical industry will help the development of new drugs for AIDS. In addition to broad-based incentives, we also need specifically targeted incentives for AIDS drug development. One approach is to offer broad-based incentives with the provision that, in order to qualify for them, a company must be conducting research for AIDS and/or other life-threatening diseases. In the AIDS community, there has been considerable outspoken criticism that the Task Force has not accomplished much, and may not be capable of accomplishing anything significant. After participating in 2 Task Force meetings, it seems to me that the group lacks sufficient authority and doesn't focus well enough on the issues it could affect. Other observers point out that since its inception, the Task Force has produced no significant initiatives. What contribution will the Task Force make toward a resolution of the debate on incentives for the development of AIDS drugs? Will it assist in speeding patient access to the protease inhibitor drugs? The next meeting of the Task Force will be held June 29-30, 1995, at which time its members are expected to make preliminary recommendations regarding industry incentives and the development of and access to protease inhibitor drugs. BETA will report on these developments in the September 1995 issue. ------------------------------------------------------------------ An Open Letter To Abbott Laboratories The following letter was sent by BETA and the San Francisco AIDS Foundation to the management of Abbott Laboratories to encourage the company to establish an expanded access program as soon as possible for its protease inhibitor drug ABT-538. Abbott has repeatedly rejected community requests for such a program. The company's response follows the text of the Open Letter. We at the San Francisco AIDS Foundation are saddened that Abbott has chosen not to establish an expanded access program for its protease inhibitor drug ABT-538 for people with AIDS who have fewer than 50 CD4 cells/mm3 and no other treatment options. While we realize that supplies of ABT-538 are limited, we see no compelling reason why such a program cannot be established in the near future for at least a few hundred people with AIDS. As you are aware, both Hoffmann-La Roche and Merck and Company have managed to overcome supply problems with their protease inhibitor drugs, and will institute expanded access programs this summer. Once again we call on Abbott to implement a similar program for ABT-538 before the end of 1995. Without this action, we are forced to believe that the company has no compassion for the thousands of people with AIDS who have exhausted standard therapies. We urge you to reconsider your position on this issue, and to join with us in seeking to provide the promising protease inhibitor drugs to people who are dying for lack of an effective treatment. Abbott Laboratories' Response Abbott is currently implementing 3 important clinical trials to determine the safety and efficacy of its protease inhibitor compound [ABT-538] in a large patient population. All of the bulk drug that has been manufactured to date is required for completion of these trials. While these trials are underway, we are continuing to solve the problems associated with large-scale manufacturing of bulk drug. ABT-538 is difficult to synthesize and produce in large quantities. In several months, we hope to be in a better position to evaluate the prospects for broader availability of the compound. As we have with our antibiotic Biaxin [clarithromycin], Abbott will seek avenues for broader distribution of ABT-538 once it is clinically proven to be acceptably safe and beneficial to AIDS patients. ------------------------------------------------------------------ The Inter-Company Collaboration for AIDS Drug Development: Boon or Bust? Jules Levin Jules Levin is an AIDS treatment advocate living in New York City. On May 11, I attended a joint meeting in New York City between AIDS community representatives and officials of the Inter-Company Collaboration for AIDS Drug Development (ICC). Formed in April 1993, the ICC is a consortium of 15 international pharmaceutical companies that have agreed to conduct combination and comparative studies of antiviral agents for the treatment of HIV infection and AIDS. ICC membership includes the pharmaceutical giants Hoffman-La Roche, Merck, Glaxo Wellcome, Bristol-Myers Squibb and others. Conspicuously absent is Abbott Laboratories, which refuses to join. Present or participating by conference call were about 20 representatives from different AIDS community organizations, including Gay Men's Health Crisis (GMHC), Project Inform, ACT UP/New York and the San Francisco AIDS Foundation. Chairing the meeting was David Barry, MD, of Glaxo Wellcome. Also in attendance were officials from Hoffman-La Roche and Merck. The ICC called the May meeting to discuss the start of the first triple-combination study of antiretroviral drugs conducted under the collaboration's master multi-drug protocol. The implementation of its first combination protocol (001) has been delayed almost an entire year due to disagreement about the design of the trial. Protocol 001 will examine the antiviral and immunologic effects of 2 different 3-drug combinations AZT plus ddC plus saquinivir (Roche's protease inhibitor) and AZT plus ddC plus nevirapine and compare the 3-drug combination to the 2-drug combination of AZT plus ddC. This study has been enrolling participants since earlier this year. Protocol 002 is being finalized for a starting date in June 1995. This protocol will also compare the 3-drug combination AZT plus ddI plus nevirapine to AZT plus ddI plus 3TC. I am not particularly excited about these protocols. I expressed my opinion at the meeting, but ICC officials avoided addressing this concern. The protocols do not include the most promising new experimental treatments for HIV infection, i.e., the Merck and Abbott protease inhibitor drugs. In addition, these protocols are very traditional in their approach to study design. Several preeminent AIDS researchers and forward-thinking community treatment advocates have called for more innovative approaches to trial design. For example, at the February meeting of the National Task Force on AIDS Drug Development, several well-known scientists supported creating new strategies for AIDS trial design. Stephen Carter, MD, of Bristol-Myers Squibb and Deborah Cotton, MD, former chair of FDA's Antiviral Drugs Advisory Committee, both expressed dissatisfaction with current approaches. They said we don't seem to be able to get the answers we need using traditional strategies. At this same meeting, Michael Saag, MD, a leading AIDS researcher, offered an innovative, alternative approach to AIDS trial design. Following his presentation, many scientists who were present expressed a strong interest in his approach. At the February meeting, I and other community representatives called for implementation of important new initiatives. One of our demands was for the ICC to begin uncontrolled, small, quick studies to screen new multi-drug combinations to discover the strongest possible antiviral effect as measured by polymerase chain reaction (PCR) and CD4 cell testing. At the ICC meeting, Bill Bahlman, an activist with ACT/UP New York, presented a proposal for small, quick, non-randomized combination "screening" studies to discover the combination(s) that offer the most significant reduction in viral load [see below]. These studies would attempt to find a drug combination that produces a reduction in viral load far superior to what we can achieve with currently-used treatment combinations. After identifying the superior combinations, we would study them in longer-term trials to further evaluate their potential benefits and safety profiles. This approach is most appealing to those of us with advanced HIV disease who have the least amount of time to wait for the results of long-term, traditionally designed studies. We need a way to quickly find the most effective regimens. At the meeting I made a presentation strongly advocating this new approach. In addition, I presented a concept sheet (authored by Drs. Fred Valentine and Roy Gulick of New York University and myself) proposing to quickly initiate a study to examine a combination of 2 protease inhibitors Roche's saquinavir and Merck's MK-639. It is urgent that we discover as soon as possible if this combination holds promise for a significant clinical benefit. Again, this is most vital to those of us with advanced disease. If the combination of these 2 protease inhibitor drugs is not promising, it's better to find that out sooner rather than later. Dr. Barry of Glaxo Wellcome, chairperson of the ICC subcommittee on clinical trials, supported both proposals. He welcomed the approach of screening combinations for their ability to reduce viral load. He offered his own thoughts on how he would like to conduct similar studies to examine changing treatment among individuals who have developed drug resistance. Responses from some community representatives to these new proposals were noteworthy. Peter Staley of the Treatment Action Group (TAG) criticized the absence of a control arm in the proposal for small, quick screening studies. TAG's Lynda Dee also objected to the study design. This same concern from TAG members was responsible for delaying the original ICC protocols from implementation for almost a year. In addition, some TAG members are questioning the reliablity of PCR testing and its lack of validation as a marker for viral burden. In response, I said that we must and, in fact, we are already using PCR technology to measure viral load as a marker for drug efficacy (or lack of efficacy). I pointed out that David Ho's and George Shaw's recently published papers [in Nature magazine] support the use of PCR technology to evaluate drug effectiveness. In addition, many other prominent scientists support the utilization of PCR technology to evaluate the effect of anti-HIV drugs. At the Task Force meeting in February, Dr. Carter said that the very multiplicity of possible antiretroviral combinations cries out for smaller, faster trials that can evaluate combinations quickly on the basis of viral and immunologic markers. He continued, "if we want to have an impact, we must begin to talk about [trial] strategies that are different from the strategies that we've followed up to now." At the same meeting, Dr. Cotton, well known for her skepticism about viral load and CD4 counts as reliable markers, said the time had come for her to reconsider the utility of these markers in AIDS clinical trial design. Unquestionably, like many scientists, I want to see studies conducted that will evaluate the ability of PCR testing to predict clinical outcome. But we cannot afford to wait several years for these results while thousands of people with AIDS get sicker and die. We need to utilize PCR technology in drug trials at the same time as we validate its effectiveness. In fact, some antiviral drug trials are doing just that. In addition, FDA has agreed to accept the results of PCR testing as a marker for efficacy in the ongoing Phase III trials of the 3 leading protease inhibitors drugs. FDA's new attitude toward PCR technology is a strong indication that AIDS clinical trial design is already changing. Those who subscribe to the same old, tired approaches are stuck in the past. Staley and Dee of TAG were the only community members (or industry people) who expressed objections to the proposal for small, quick screening trials. Other community representatives at the meeting supported these proposals, and Dr. Barry promised to present them to the ICC clinical trials subcommittee meeting in June 1995. I hope that these proposals will receive a fair and thoughtful hearing. In July, another joint meeting between the ICC and AIDS community representatives will be held to discuss the outcome of the June ICC deliberations. Also vital to the best interests of the AIDS community, particularly to those with advanced disease, is a clinical study combining 2 protease inhibitor drugs Roche's saquinavir (Invirase) and Merck's indinavir sulfate (Crixivan) [aka MK-639]. Almost everyone present at the May ICC meeting agreed on the importance of implementing this proposed study. Mickey Salgo, MD, of Roche acknowledged its significance, but said it could not be initiated immediately because Roche wants to use a new formulation of saquinavir in the study. Unfortunately, he said, certain safety and bioequivalence studies need to be carried out to qualify the new formulation of saquinavir for such a study. However, Dr. Salgo promised that in the fall of 1995 Roche will be ready to conduct the combination protease trial with Merck's Crixivan. Dr. Barry also acknowledged the importance of conducting this protease inhibitor combintion study as soon as possible. It is vital that we hold the drug companies to this commitment. We must follow up in the fall and insist that they conduct this critically important study. After the 3-hour ICC meeting ended, I walked across the street to the main ballroom of the Waldorf-Astoria hotel where Mother's Voices, an organization of mothers of people with AIDS, was holding its annual fundraising event. They filled the huge ballroom with over 1,000 people. From the moment I walked in, I could see tears in everyone's eyes, and I couldn't help but contrast this event to the relatively cold, dispassionate atmosphere I had just left. At the Mother's Voices event, compassion, worry and love were openly expressed; there were touching, kissing and embracing, while across the street it was business as usual. For me the contrast was sad, because it highlighted how the AIDS community's gains in fighting the disease and dealing with the drug companies and the government are so few and so hard fought. ------------------------------------------------------------------ Expanded Access to the Protease Inhibitor Drugs Ronald Baker, PhD Over the past 6 months, the Protease Working Group, a coalition of AIDS treatment advocates, has lobbied pharmaceutical giants Hoffmann-La Roche (Roche), Merck and Company and Abbott Laboratories to establish expanded access programs (open label safety studies) for the 3 protease inhibitor drugs now in Phase III testing. The primary objective of these proposed programs is to provide early access to the promising protease inhibitor drugs for people with AIDS and low CD4 cell counts who have exhausted the benefit from standard therapies. AIDS treatment advocates have called on the manufacturers of the 3 leading protease inhibitor drugs to implement expanded access programs as soon as possible, and no later than the end of 1995. Below is the most recent information available on these programs. Saquinavir (Invirase) from Hoffmann-La Roche Roche made a commitment in July 1994 to establish a limited saquinavir expanded access program in 1995 for 4,000 people with AIDS worldwide. The company has publicly pledged to increase enrollment in the saquinavir program as drug supply increases. Registration for enrollment of 2,280 people in the U.S. (57% of the total enrollment worldwide) is set to begin by early July 1995. Saquinavir will be shipped to physicians for distribution to patients in late August or early September. In order to supply saquinavir to those people with AIDS most in need of an alternative therapy (and in keeping with AIDS community input to Roche), about 60% of the U.S. participants will have 50 or fewer CD4 cells/mm3; 40% will have 51-300 CD4 cells/mm3. Since the number of people with AIDS in the U.S. qualified to receive saquinavir will no doubt exceed 2,280, a lottery system will determine who will receive the drug initially. To be considered for the expanded access, patients must be registered by their physicians. For more information about the saquinavir expanded access program in the U.S., physicians and patients may call 1-800-332-2144. Residents of Canada may call 1-800-257-3741 for information on that country's saquinavir program, which differs in size (slots for about 100 participants) and eligibility requirements from its U.S. counterpart. Indinavir sulfate (Crixivan) from Merck and Company Formerly called MK-639, Merck's protease inhibitor drug recently received a generic and brand name: indinavir sulfate (Crixivan). At a special February 1995 meeting of the National AIDS Drug Development Task Force, Merck officials heard stinging criticism from the treatment activist community about the company's decision in February not to sponsor an expanded access program for Crixivan in 1995. However, in a March 10, 1995 letter to AIDS community representatives, Merck officials announced a change in policy: unexpected "advances in manufacturing" would make possible a modest expanded access program for 1,700 people with 50 or fewer CD4 cells/mm3 by the end of 1995. The first 300 patients will be enrolled in June 1995. In August 1995, when more drug becomes available, enrollment will increase. BETA asked Merck officials in early June for a statement describing enrollment procedures for the Crixivan expanded access program. "We are still in the planning stages," said John Doorley, Executive Director of Corporate Communications at Merck, "and we have no new information to announce since our letter to community representatives in March." Sources inside Merck say that the Crixivan expanded access program will likely require patients to arrange to sign on to a waiting list through their individual physicians. After screening applicants for CD4 cell counts and other medical information, participating physicians will receive Crixivan directly from Merck and dispense it to patients. A lottery system will determine which 1,400 patients will receive Crixivan before the end of 1995. Abbott Laboratories' ABT-538 Abbott's protease inhibitor drug ABT-538, now in Phase III testing, has shown promising results in early studies. AIDS community representatives have repeatedly asked Abbott to establish an ABT-538 expanded access program. The company refuses to do so (see Open Letter to Abbott on page 64). Some AIDS community groups want to mount a boycott of Abbott products to draw public attention to the company's refusal to establish an expanded access program for ABT-538. Community representatives are scheduled to meet again with Abbott officials in July. ------------------------------------------------------------------ Pain Management in AIDS The following is an edited transcript of 2 BETA LIVE! national telephone conference calls held April 18 and April 20, 1995. BAKER: Welcome to the April edition of BETA LIVE! I'm Ronald Baker, editor of BETA, the AIDS treatment news magazine published by the San Francisco AIDS Foundation. Today's BETA LIVE! features 2 subjects. First, we'll discuss "Pain Management in AIDS," with pain experts Dr. William Breitbart and Dr. Matthew Lefkowitz. In the second part of the program, we'll be talking with AIDS community activist Jules Levin about protease inhibitor drug development. Let me introduce you to our guests. Dr. William Breitbart is Associate Attending Psychiatrist at Memorial Sloan-Kettering Cancer Center in New York City, and Associate Professor of Psychiatry at Cornell University Medical College. Dr. Matthew Lefkowitz is Clinical Associate Professor of Anesthesiology at the State University of New York Health Science Center at Brooklyn, and Director of the University's Pain Management Service. Dr. Lefkowitz, what is your working definition of pain? LEFKOWITZ: That's a good question. When we try to define what pain is, I usually go to the definition formulated by the International Association for the Study of Pain: pain is an emotional and also a sensory experience that can be described as if it were like tissue damage. So it's basically an emotional and sensory experience. Another useful definition of pain is whatever the patient says he or she has. BAKER: What are the major pain syndromes associated with AIDS? LEFKOWITZ: The 3 most common, which occur in 20-25% of patients, are abdominal pain, peripheral neuropathy and oropharyngeal pain. There is a 15-20% incidence of headache, related to an opportunistic infection or an AIDS-related tumor, or related to some of the HIV therapies. There's also a fairly significant incidence of headache which is not related to HIV disease. There is an approximately 5-10% incidence of post-herpetic neuralgia, which is pain that occurs after a shingles [herpes zoster] infection. There's also a 5% incidence of musculoskeletal pain, which is bone pain, joint pain and muscle pain, and about a 5% incidence of lower back pain. BAKER: What's the typical profile of an HIV positive person who's experiencing pain? LEFKOWITZ: The typical patient with HIV disease that I see probably has some kind of abdominal pain or peripheral neuropathy. In the past 6 or 7 years doctors and other healthcare providers have learned more about pain medications that are available. When we did studies a couple of years ago [described by Breitbart below], we found that patients were inappropriately treated with lots of different medications, and there didn't seem to be any rhyme or reason in the way that they were being treated. But in the past couple of years, I have see a much more logical approach to the treatment of pain in this population. BREITBART: Maybe I can add to that answer. In our work we find that the more advanced their disease is, the more likely someone with HIV disease is to have a problem with pain. Earlier in the disease it's less problematic, later in the disease pain syndromes are more common. Earlier in the disease, you're more likely to develop some iatrogenically produced pain difficulty. We see pain syndromes that are produced by treatments for HIV, such as the antiretroviral drugs, treatments for TB [tuberculosis], pentamidine prophylaxis, chemotherapy or radiation treatments. Some of the pain syndromes we see in AIDS patients are a direct result of the HIV virus' invasion of the nervous system (some of the HIV-related neuropathies) or a result of immunosuppression, opportunistic infections or opportunistic cancers. These make up about 40-50% of the pain syndromes we see, and are more typical of a person in later stages of disease. So a lot of the pain syndromes, about 30%, are related to therapy for HIV or AIDS or opportunistic infection. ddI and ddC commonly cause painful neuropathy, and many of our patients with neuropathy improve when they are taken off these drugs. Some of our patients who get chemotherapies like Vincristine, for instance, for Kaposi's sarcoma [KS], can develop peripheral nerve damage and peripheral neuropathic pain. Different kinds of pain problems can occur at different stages of disease. BAKER: Dr. Breitbart, how adequately do you think pain is treated, generally, in patients with HIV disease? BREITBART: We've been conducting some studies of pain experienced by AIDS patients in New York City. Of about 500 patients in our study, about 60% have pain. As it turns out, the vast majority of those patients have pain that's chronic and persistent, lasting for a couple of weeks or more. They usually have multiple pains (2 or 3) at any one time. Often they'll have some neuropathic pain and headache, and some musculoskeletal pain, joint or muscle aches. The pain severity is usually in the moderate to severe range in the majority of our patients. These kinds of numbers of pain, prevalence, and pain intensity in AIDS patients is very comparable to pain in cancer patients. In fact, pain intensity is slightly higher in patients with AIDS, I think, because pain in AIDS is vastly undertreated, dramatically more so than even cancer pain. We use some of the same methodology used in some cancer pain studies to assess the adequacy of analgesic medication prescribed for patients with AIDS who have pain. The first thing we looked at was the percentage of patients who are prescribed various analgesics and the potency of the analgesics. In our patients, about 40% get no analgesic medication whatsoever, or just get a nonsteroidal anti-inflammatory drug [NSAID] for moderate to severe pain, which is relatively inadequate. Only 6% of our AIDS patients have been given a strong opioid medication like morphine for severe pain. Some of the published guidelines, for example, those issued by the Agency for Health Care Policy and Research and by the World Health Organization [WHO], suggest that for severe pain, everyone should get a strong opioid like morphine. We also looked at something called the Pain Management Index [PMI], which is an index of the adequacy of analgesic therapy that we devised. The relative strength of the analgesic prescribed compared to the intensity of the pain. Thus if you have severe pain and get prescribed a strong opioid that's equivalent to the intensity of the pain, you have a PMI score of 0. If you have only moderate pain and get a strong opioid, that would be a PMI score of +1. So patients who have a PMI of 0 or a positive number are described as having adequate treatment, and patients with a PMI that's below 0 are inadequately treated. When this kind of methodology was used recently to assess the adequacy of pain treatment in a group of cancer patients, about 52% of patients with cancer pain were getting adequate analgesic therapy. In our AIDS cohort we used the same methodology; only 15% of our patients were getting adequate treatment. BAKER: Dr. Lefkowitz, how do you go about assessing pain in people with HIV infection? LEFKOWITZ: There are various methods you can use to assess pain. In adults probably the best way to do it is to use a numeric rating scale where patients are asked to rate their pain between, say, 0-10 or 0-100. There are also colored rulers that can be used, going through the colors of the rainbow into the very red range when pain is very, very severe. One point I want to make is that pain is different for everyone. HIV-related pain can come from different sites and different origins. Pain related to a tumor is different from pain related to neuropathy, which might be different than headache pain. It's very important to be able to make a diagnosis and to distinguish the origin of the pain. Once that is determined, it's a little easier to gear the therapy to the particular type of pain. BREITBART: May I add one thing? I think one of the problems in terms of getting adequate treatment for pain is that most physicians forget about the importance of providing analgesic medication when they're investigating the cause of the pain. They'll allow patients to remain in pain while they're doing X-rays or CT scans or tests because they're so focused on finding the cause of the pain. It is of course true that if you can treat the cause, you'll reduce the pain, but you've got to provide comfort or analgesia during the period of diagnostic work-up. LEFKOWITZ: A very good example of this is the pediatric patient who has a headache which might be secondary to meningitis or encephalitis. We'll see quite often that the underlying opportunistic infection will be treated, but the pain won't be. So you have a situation in which there's a young child who's got a terrible headache for 10 days to 2 weeks while undergoing antibiotic treatment. It's something that we should not forget. I think that we all agree that the WHO ladder, which was developed about 10 years ago for the treatment of cancer pain, can be adapted to patients who have pain related to HIV disease. It is a titration method where patients are treated depending on the type of pain they have. If the pain persists or increases, then we increase the drugs that we use. In pain management we have a couple of specific drug classes that are used very commonly. There are the nonsteroidal anti-inflammatory drugs [NSAID], which are the aspirin-like drugs used for mild to moderate pain. There is the whole class of opioids, and we have short-acting and long-acting opioids. I think that for mild to moderate pain or for moderate pain, the short-acting opioids are probably the drugs that should be used first. There are several choices of short-acting opioids. Certainly morphine is used quite commonly. There are the codeine mixtures such as acetaminophen [Tylenol] and codeine. There are the oxycodone mixtures, such as oxycodone and acetaminophen or oxycodone and aspirin. It is certainly an option to use oxycodone [Roxicodone] alone. We can also use hydromorphone or Dilaudid, which is another short-acting opioid. But when a patient finds themselves using an excessive amount, somewhere in the neighborhood of about 10-12 pills per day of, say, an oxycodone mixture or morphine, that's the time the patient should probably be switched over to a long-acting opioid. What's nice about the long-acting opioids is that the dosing interval is lessened so that patients take fewer pills or use the systems less often; they also allow for more stable blood levels. The drugs that we have available as long-acting opioids would be sustained-release morphine sulfate, compounds such as Oramorph SR or MS Contin; basically, this is morphine in a polymeric matrix that will slowly melt in the gut so that a constant, continuous amount of drug is released and absorbed into the bloodstream. There's also the transdermal fentanyl system such as Duragesic, which comes in patches of different sizes. Fentanyl is a very powerful short-acting opioid and lends itself very well to this type of system. The patch is put on and there are 3 days of analgesia. And, of course, there is methadone as well. Methadone was developed a very long time ago and is a very good pain reliever. It is probably the longest acting opioid, with a long half-life of about 36 hours. This is what makes it useful for substance abuse maintenance it will prevent opioid withdrawal for 36 hours. But the analgesic duration of action of methadone is about 6 hours. It is in many ways a nice drug to use when you are opting for a long-acting opioid. There are a couple of particular problems with methadone, especially when you start using it. In the acute stages patients can develop some side effects, such as respiratory depression, because the drug has a tendency to accumulate. When physicians use it and are careful to titrate in a logical way, these side effects should not occur. So you see that there is a very logical approach in starting with a nonsteroidal and then perhaps progressing to a short-acting opioid, and then going on to a longer-acting opioid. There is another class of drugs, the adjuvant analgesics, which includes the tricyclic antidepressants and the anticonvulsants. There is a whole group of drugs which are used as adjuvants to control some of the side effects of some of the pain drugs that we use, for example adjuvants to relieve nausea and vomiting or constipation or itching. Something you have to keep in mind is that opioids are different than a lot of other medications in that there is no ceiling effect, that is, a dose beyond which it is no longer effective. If you find yourself on a long-acting opioid, that can be increased until adequate pain relief is obtained or until a patient can no longer tolerate the side effects. You can continue to build up and continue to titrate the drug until the desired effect is obtained. BAKER: What have you seen as the impact of pain on quality of life for people with HIV infection? Is it appropriate to give pain medication to improve the sense of well-being or quality of life of the patient? BREITBART: We've been looking carefully at the impact of pain on quality of life and psychosocial adjustment in our patients with HIV disease, and we've compared our patients who have pain to those who do not, in terms of various aspects of quality of life. We found that pain has an enormous impact on quality of life and psychosocial adjustment in a variety of domains. For instance, you're twice as likely to have serious depression if you're also struggling with a pain problem than if you don't have pain, independent of the stage of the illness. You're more likely to have a major depressive syndrome that would require treatment, such as an antidepressant medication or psychotherapy. Our patients with pain are typically much more hopeless about the future, psychologically distressed, highly anxious and worried. They are much more likely to feel like life is not worth living. They have more suicidal ideation than the patients without pain. The intensity of pain is highly correlated with interference in various domains of quality of life, and is very much related to the degree of functional impairment in various domains. We typically measure 7 areas of quality of life, including overall mood, ability to interact with others, ability to walk, ability to work and a variety of others. For patients with mild pain, pain that patients rate as 2, 3 or 4 on a 0-10 numerical rating scale, for instance, only a few domains of function are interfered with, generally areas that are more psychological and mood-related. Overall enjoyment in life or overall mood tends to be most sensitive to pain interference; those are the kinds of domains that are interfered with even at mild levels of pain. As pain becomes more intense, more and more domains become interfered with, like ability to interact with others socially or to work. In the severe range of pain, patients have significant interference in almost every area of function that we measure. It's very important to try to get the severity of the pain down, because as you get the intensity down, you open up more and more areas of quality of life to return to normal. It's interesting that as a goal of therapy, physicians often try to get rid of the pain completely, and that's obviously the optimal goal, but even if you're able to lower the pain level from a moderate to a mild level, or from severe to moderate, you're able to improve areas of functioning. By moving the pain intensity level down you are having a great impact on all sorts of areas of quality of life. BAKER: It appears from what you said earlier that many clinicians neglect pain management in their AIDS patients. Why do otherwise sensitive and competent clinicians fall short in this area? LEFKOWITZ: Well, I think you're really looking at barriers to pain management. Why aren't patients with HIV disease adequately treated? I think the reasons are basically divided into 3 general areas. There are reasons that are associated with healthcare providers, reasons that are associated with patients themselves, and issues that are concerned with regulatory agencies. I think that doctors sometimes dismiss reports of pain or give pain a low priority because doctors and other healthcare providers are very concerned with treating opportunistic infections and important, life-threatening illnesses rather than focusing on quality of life issues. When we talk about quality of life issues, we certainly talk about pain, but quality of life also includes things like nausea and vomiting, itching and constipation. These things are very annoying and truly do affect the patient's quality of life. I think that sometimes patients are afraid to talk about their pain because they sometimes equate pain with progression of disease, so there is that denial aspect of it. I think that doctors need to educate patients about pain and they need to educate them about what pharmacological and nonpharmacological options are available. One thing that's very important is that pain control really is not only a reasonable expectation that patients have, but it's also a patient's right. I think that family and lovers and friends need to be a part of this whole process. BREITBART: I agree. I think that the barriers to treatment relate to physicians, the health care system and patients themselves. We've actually begun to look at some of these barriers. For instance, in our study of adequacy of treatment for pain in AIDS, we found that certain characteristics of our population were predictive of undertreatment. Women with HIV disease were twice as likely to be undertreated for their pain then men with HIV. Patients with less education were much more likely to be undertreated. Patients who had a history of injection drug use as an HIV transmission risk factor were much more likely, almost twice as likely, to be undertreated. BAKER: You mentioned undertreatment of women with HIV disease. Are there special concerns in managing pain in women with HIV disease? BREITBART: I think there are. Women with HIV disease have certain unique painful syndromes, obviously, that men don't have, such as gynecological sources of pain, pelvic pain and infections and cancers in the gynecological tract. We've also found that some of our women patients are more likely to have rheumatological sources of pain, muscle pain and joint pain, myopathy and myositis and various types of arthritis. We've also discovered that our women patients have some unique concerns about taking pain treatment. They're very concerned about issues related to taking these drugs and pregnancy. They're concerned about these drugs interfering with their ability to take care of their children. One of the patients I interviewed recently was very concerned that if she took morphine, it would be used as one more reason by some child welfare agencies to take her children away. So there are some special concerns that women have about pain treatment. BAKER: What about pain treatment for children? BREITBART: We didn't study children, so I can't comment directly on that, but I would guess that children with AIDS-related pain are very undertreated because children with cancer pain are tremendously undertreated. We have a program here at Memorial Sloan-Kettering, a National Cancer Institute-funded Cancer Pain Education Program, and I see clinicians who come here to learn about pain management who treat kids with cancer, kids with AIDS. They describe it as sort of a vast wasteland from the point of view of pain management. One of the things that we've done is surveyed physicians about what they think are the barriers to pain management in AIDS, and the big concerns from the physicians' perspective is that they don't know very much about pain, pain assessment or pain treatment in AIDS patients. For the most part, the AIDS care providers haven't had to deal with pain as an issue in their practices previously, and so they don't know very much about this area of specialty and they need to learn more about it. They're also concerned about prescribing controlled substances like opioids, morphine. They're concerned about the state regulatory agencies that monitor their prescribing patterns. They're concerned about opioids causing or contributing to addiction. They're afraid of the side effects of opioids like sedation and confusion. They think they're going to make their patients stop breathing if they give them opioid medications for pain. There are a lot of misconceptions about the side effects and addiction potential of these drugs. We've also surveyed patients about what patient-related barriers might occur. We found that the more patient-related barriers there are, the more undertreated patients tend to be. Patients are also concerned about the side effects of opioid drugs. They're afraid they're going to become addicted. They're afraid the side effects are going to be terrible, that they are going to become confused or incompetent. As I mentioned, some women patients are concerned about losing custody of their children. Our patients are also taking so many medications for all sorts of problems that there's a real resistance to taking more medicine for pain control. They prefer nonpharmacologic therapies for pain. Actually almost 75% of the patients we surveyed preferred nonmedication kinds of interventions for pain control. BAKER: We'll talk about some of those interventions shortly, but now let's take a few questions. NEW BEDFORD, MA: A large part of our population is IV drug users, and we have clients who are HIV positive on methadone. How does methadone impact or change the pain management of clients with, say, neuropathy pain? LEFKOWITZ: It doesn't necessarily change the treatment. If patients have neuropathic pain, there are certain medications that can be used, most notably the tricyclic antidepressant drugs, like Elavil and Pamelor, can be very effective in the treatment of neuropathic pain. There are also some anticonvulsant medications like Tegretol or Dilantin or valproic acid which can also be used in the treatment of neuropathic pain. BAKER: More broadly, there are special concerns related to managing pain in people with substance abuse problems and AIDS. What are some of those considerations? LEFKOWITZ: I think that the question is very important and it's something that we get asked a great deal, "How do you treat a substance abuser for pain management?" People are sometimes afraid or reluctant to adequately treat these patients because the whole issue of substance abuse, whether it's ongoing or there is a prior history of it, seems to cloud the issue of pain management. I think that certainly this is a very difficult patient population to treat, but remember that there are different kinds of substance abusers. There are patients who are no longer abusing drugs, there are patients who are currently abusing drugs and there are patients who are on methadone maintenance, such as the population the caller described. What I actually do is keep patients on the medications that they are already on, let's say methadone. I will start with that as a baseline and then I will usually add my medications from there. So if we opt for sustained-relief morphine sulfate or transdermal fentanyl, we might do that in addition to the methadone. Or we can even just increase the dosage of methadone, which is a powerful opioid. It's a narcotic and a very good analgesic and can be a very good option in the treatment of certain types of painful states. BREITBART: I just wanted to make one additional comment. The biggest misconception about methadone is that methadone, as it's used in methadone maintenance programs given as a once-a-day dose, would provide adequate analgesia for someone who has a chronic pain of moderate to severe intensity. As Matt pointed out, methadone is an opioid drug that's a very good analgesic agent. The problem is, the analgesic duration of a dose of methadone is only about 4-6 or 6-8 hours, while the half-life of the drug is very long, about 24-36 hours. Methadone given once a day is useful in preventing opioid withdrawal, but once a day is not adequate as an analgesic regimen. If you use methadone as an analgesic regimen, you've got to give it every 6 hours or so, sometimes every 8 hours and sometimes every 4 hours, depending on the individual. So when you use methadone for analgesic purposes, you're going to be giving it several times a day, around the clock, as opposed to the once a day dose used for methadone maintenance. So you have a choice. You can either keep the methadone as a once-a-day drug and start your analgesic regimen independent of it, which I think is the simplest route to take, or you can use methadone in a different kind of dosage regimen for pain. WILTON, NY: I was interested to know if there is a clinical pain scale instrument that's easily available and would work, for example, in prisons where it's sometimes difficult to assess the validity of answers. BREITBART: Well, there are some clinical scales that are available. It's very hard in the short time we have to teach everybody everything they need to know about prescribing pain medication or what they should be able to tell their doctor about how to prescribe analgesics for them, but there are some materials that are quite extensive and understandable for patients as well as doctors, that people can get free of charge. The Agency for Health Care Policy and Research [AHCPR] recently published 2 sets of guidelines on pain, 1 for acute and post-operative pain and 1 for cancer pain. The cancer pain guidelines have a section on pain in HIV and AIDS as well. While the text mainly focuses on cancer pain, the principles of analgesic drug use and the principles for pain management are very similar to those that would apply to patients with HIV and AIDS with some minor, subtle differences. There are 3 parts to the guidelines. There is a book for clinicians, a brief pocket version of the text for clinicians and a version for patients. The patient version is very helpful it's chock full of all sorts of understandable information. In both the patient and clinician versions there are examples of useful clinical assessment tools such as the Memorial Pain Assessment Card, which is a series of 3 visual analog scales and a categorical word rating scale, something called the Brief Pain Inventory. These are tools that are commonly used both clinically and in research settings. You can get free copies of these materials by calling 1-800-FOR-CANCER. You asked a slightly different question, which is how to verify a pain complaint in a patient for whom you're not quite sure whether the pain complaint is truthful or not. That's a more complex issue. My general strategy in those kinds of situations is to believe a patient's report of pain and to provide analgesia during an appropriate pain assessment. That assessment might include diagnostic tests to verify the etiology of the pain. An example might be an individual in a prison system who's complaining of symptoms of burning, tingling and numbness in the hands and feet, symptoms that are very consistent with neuropathic pain or peripheral neuropathy of AIDS. One can believe the patient, provide some analgesia and then do some diagnostic tests; in this particular circumstance, EMG nerve conduction tests are very sensitive at picking up peripheral nerve damage. One can corroborate the presence of the neuropathic syndrome with that test, giving you some objective evidence that there is indeed a peripheral neuropathic process going on. Matt, do you have any further comment on that issue? LEFKOWITZ: There are lots of different assessment tools that you can use. Sometimes patients don't understand the tools. Sometimes doctors don't understand them. What I use most often is the 0-10 scale, which is really very helpful. This questioner is really asking 2 different questions. The question about assessment is very easy use different pain scales. But to be able to validate or verify the patient's complaint of pain is much more difficult, and this is truly where the art of pain management comes in. Remember that pain is a subjective experience, not an objective experience. A very good example of that is headache. There are no objective tests MRIs, CAT scans, X-rays, etc. that can verify the patient's complaint of pain, and yet we all know that when we have a headache it can be very painful. BREITBART: Another thing that sometimes helps is once a patient brings a pain complaint to you, you begin the process of treating that patient, providing analgesia and trying to make the pain diagnosis through a process of assessment. You then engage with the patient in the process of treatment. Very often how the patient deals with you is an indicator of what their goal is in the interaction. If the patient is noncompliant, if the patient disappears from your clinic, etc., if any drug behaviors begin to emerge in the process of the treatment process, then you have more clues that something else is going on besides just the straightforward pain problem. NEW YORK, NY: There is also a lack of knowledge of controlled substances. Sometimes doctors don't even know the kind of dose they're writing a prescription for. How do you deal with that? LEFKOWITZ: The question is what if doctors don't know the right dose. Well, if doctors don't know the right dose to write, there are lots of manuals that are available. There's the Physician's Desk Reference (PDR) and, as Bill mentioned, there's the Cancer Pain Guidelines. A lot of pharmaceutical companies will publish equivalencies, so if it's a question of equivalence how many Percocet are equal to how many milligrams of morphine, or Tylenol with codeine is equal to how much Dilaudid, etc. those equivalencies are available. Something else that's of concern is that a lot of physicians and patients are unaware of the different kinds of formulations of opioids that are available and unaware of other drugs and delivery systems that are available, such as the nonsteroidal anti-inflammatory drugs, some of the psychotropic medications, the antidepressants and the anticonvulsants. Certainly in the past 10 years we have developed different ways of delivering opioids, for example sustained-release morphine forms, or transdermal systems, or infusion pumps which can be controlled by the patient. There are epidural catheters we use which are very similar to the catheters that are used in obstetrics. BREITBART: Let me add a few more points. I think the solution is education, both professional and patient education. Matt and I have been going around the country lecturing to physicians. We've been working with drug companies trying to create professional education material on pain management in AIDS so that physicians, especially AIDS care providers, can learn more about pain management. We've been trying to provide courses on pain management in AIDS at various AIDS care provider conferences, and we've been trying to foster links between the AIDS care-providing community and the pain community. We're trying our best to get the word out to professionals about AIDS pain management. There is also a series of conferences in New York City on June 13th at St. Vincent's Hospital. There's going to be an evening conference on pain management in AIDS. On September 29th at Memorial Sloan-Kettering, there's going to be another large educational conference on pain management in AIDS. In addition, I think patients with AIDS must become more educated consumers about the issues related to pain treatment. I've also been working with drug companies to create patient education materials so that patients can know more about the problem of pain in AIDS, the common pain syndromes and what reasonable treatments should be provided, because often it can be the case that if the doctor doesn't know how to treat something, the patient does. Finally, I think that if you're a patient with AIDS and you have a pain problem and you're not getting adequate treatment in your care setting, it's worth asking if there's anyone in the institution or setting who has pain expertise, or if there's a specialty pain service in the hospital or health care center. Often it's useful to get a consultant or specialist involved in your care if you have a pain problem. BAKER: How should a patient who feels that he or she is not receiving adequate pain management approach this problem with their care provider? BREITBART: It's interesting that among our patients polled about their feelings about pain and reporting it to their doctors, there's an enormous resistance to bringing up the issue of pain with their physician in the first place. In fact, the majority of patients in our study who have pain, reported that they delayed bringing the issue to their doctor's attention for many months on average. Two main things prevented patients from bringing up the issue of pain. One was the concern not to overburden their physician with too many problems; they were afraid that they wouldn't be "good patients" if they brought this additional problem to the physician's attention. The second was concern about distracting the doctor's attention away from treating life-threatening problems. It's important that patients bring up pain issues, because the physicians that we poll tell us that they're unaware that pain is such a big problem, and they report to us that their patients don't complain that much about pain. The response I get from most of the physicians we speak to is that, if they knew about it, they would try to deal with it. So I would encourage patients to bring up pain with their physician. I think they will be surprised at the positive response and the concern and attention that will be directed toward the problem. I think the fears about bringing it up are greatly exaggerated. AKRON, OH: I was wondering if you could talk about some specific therapies. One is the new Ultram, or tramadol, which is used as an analgesic. I'm not familiar with it. Also, a lot of people have been using Neurotin, one of the antiseizure drugs. Could you comment on these please? LEFKOWITZ: Well, I can comment on tramadol, the first drug you mentioned, a brand-new drug which was released on the market a couple of weeks ago. Tramadol is an analgesic that is not quite an opioid. It does bind to some opioid receptors, but it also increases levels of serotonin, similar to Prozac or Zoloft. So you have a dual effect. It's a different kind of analgesic, and this drug is the first of that type of analgesic that has ever been on the market. I have only used it once and I'm not quite sure of the results, but I think that physicians are going to be using it more and more often. COVINA, CA: Would you all discuss the assessment of a patient with peripheral neuropathy what stage of disease it usually occurs in, how it presents itself, and what the medical management is? LEFKOWITZ: That's a pretty big question. There is a way to control neuropathy pain, there just has to be a logical approach in the pain management. There are different types of neuropathy in HIV disease which can occur at different stages of the disease. Certainly in the asymptomatic phase we'll see patients with Guillain-Barre Syndrome. As the disease progresses we may see mononeuritis multiplex, inflammatory demyelinating neuropathy, chronic Guillain-Barre and post-herpetic neuralgia, which is a pain after shingles. I think that the most common is probably the distal sensory axonopathy in which the axon is slowly destroyed, which is very similar to diabetic neuropathy. To treat neuropathic pain we usually start with a tricyclic antidepressant or an anticonvulsant, depending on the type of pain. If the patient is complaining of a burning, aching type of pain or paresthesia, then we'll start them on a tricyclic antidepressant such as amitriptyline and nortriptyline, which can be very effective for neuropathic pain. If there is a sharp, shooting component to the pain, then we will add an anticonvulsant. I would say about 20% of patients can be treated adequately using a tricyclic alone. If that is inadequate, I will usually start my titration of opioids and nonsteroidals, perhaps start the patient on a nonsteroidal plus a short-acting opioid and then, if the pain continues, I will add a long-acting opioid and try a tricyclic antidepressant, and later start an anticonvulsant. When using long-acting opioids, one must always have breaks from medication. If the patient has particular times during the day that might be more painful than others, the patient should have a rescue medication to fall back on. Morphine or Percocet are probably are the most common rescue medications. As mentioned, there is no ceiling effect for opioids, so you can increase the dosage and number of opioid medications until the desired relief is obtained. There are ways of controlling a lot of the side effects of the opioids so that you don't feel "out of it," or euphoric or sedated all the time. That depends on the choice of narcotic and on the choice of the added medications that are used. BREITBART: If you can do something about the cause of the neuropathy, that often helps decrease the amount of neuropathic pain. If neuropathy is due to HIV, then you may be limited in what you can do. But in addition to neuropathies that are caused by the virus or the immune-mediated process, there are toxic, drug-induced neuropathies that are quite common in patients with AIDS; I frequently see patients develop painful neuropathies from ddI or ddC. Patients can also develop neuropathies from nutritional deficiencies; make sure you don't have a vitamin deficiency. Alcohol is a toxin; if you're drinking much alcohol, you should probably limit that. Some of the anti-TB drugs are toxic to nerves and can cause peripheral neuropathy. Very often in the process of treating a neuropathic pain syndrome in a patient with HIV or AIDS, one has to think about when the painful neuropathic syndrome started. Is it temporary, related perhaps to antiviral treatment? Do we think it's drug-induced? Should we think about stopping an antiretroviral as part of managing neuropathic pain? If you're on an antiretroviral that's known to cause neuropathy, like ddI or ddC, it's reasonable to discuss with your doctor the possibility of trying a period of time off the drug to see if neuropathy improves. In terms of making the diagnosis of a neuropathic pain problem or neuropathy in patients with HIV or AIDS, the typical description of burning, numbness, tingling or sometimes electric, shooting pains in the hands and feet is very common. When you examine the hands or feet you may detect decreased sensation or a decreased response to pin pricks and evidence that nerves have been damaged in these areas. Very often there are diminished ankle reflexes and other signs of neurologic damage. One can conduct some diagnostic tests such as EMG nerve conduction tests. Finally, one thing to emphasize is that although adjuvant analgesic drugs, like the antidepressants and the anticonvulsants, play an important role in managing pain related to neuropathy, if you're dealing with moderate to severe pain, even if it's a neuropathic pain, you're probably going to have to utilize adjuvant analgesic drugs in combination with opioid drugs, either weaker opioid drugs like codeine or oxycodone, or stronger opioid drugs like morphine or Dilaudid, if the pain is very severe. In my experience, it's rare for any of my patients who have severe, intense neuropathic pain to be able to get relief with a single drug. Most of our patients who get adequate relief are on some combination of a nonsteroidal anti-inflammatory drug, an antidepressant or anticonvulsant drug and an opioid drug, often in relatively high doses. It's not uncommon for me to have to try a number of different adjuvant analgesic drugs, different antidepressants, until we find one that's useful in that combination of medications. GULF SHORES, AL: I want to find out about numbness in the hands from HIV infection and what that could be? LEFKOWITZ: Numbness in the hands can be related to a couple of things. Probably the first thing you want to look at is some of the medications that you're taking. As Dr. Breitbart mentioned before, ddI, ddC and d4T can all cause this particular type of sensation. If the patient doesn't have diabetic neuropathy, then one would begin to consider some of the other common HIV-related neuropathies. The most common HIV neuropathy is something that we call a distal symmetric demyelinating axonopathy [or distal symmetric polyneuropathy], in which the nerves are basically slowly dying, starting from out in the periphery. This occurs in about 30% of patients with AIDS. As these nerves are destroyed, patients can certainly start developing numbness, but it is remarkable that the pain component is usually much more impressive than either the sensory loss or the motor loss. This more commonly happens in the feet, but can certainly happen in the hands. LITTLE ROCK, AR: I wondered if either of the gentlemen had any experience in treating HIV-related arthritis, and if so, were the treatment strategies different? LEFKOWITZ: The most common arthritis is reactive arthritis, or Reiter's Syndrome. Usually it involves the large joints, and may be associated with diarrhea as well. It is associated with patients who are HLAB27 [human leukocyte antigen, a genetic marker] positive. This particular arthritis is NSAID-resistant; we don't really know why. Certainly I tend toward trying to use the nonsteroidals more often with some of the arthritides and the arthralgias, and I try to push as far as possible, watching for emerging side effects, because the nonsteroidals are excellent drugs for arthritis. If that doesn't work, then I start on my usual WHO ladder titration method of short-acting opioids, then going to the long-acting opioids, and I usually add some kind of adjuvant analgesic medication such as a tricyclic antidepressant. In my practice we have cancer patients and HIV patients; we have many low-back patients, patients with specific pain syndromes. I would say approximately 80% of these patients are treated with tricyclic antidepressants. They're also probably excellent analgesics for HIV-related arthralpathies. STATEN ISLAND, NY: When a person takes 10 or 20 pills a day of all different kinds, and then if they have pain and take some of these drugs you mention, what is the reaction towards their regular pills such as ddI or AZT? What's going to happen if they start putting methadone or morphine into their body on top of that? BREITBART: I think just the sheer number of pills that many of my patients are taking becomes insurmountable for them; it becomes something that distresses and depresses them. That's why sometimes delivery systems for opioids that are not by the oral route, like the fentanyl patch, are useful for them psychologically, because they don't have to keep taking pills all the time. But there are some specific concerns related to using these medications in patients with HIV disease. For instance, one must be somewhat cautious about using some of the nonsteroidal anti-inflammatory drugs which are used for mild to moderate pain because of the side effects of these drugs, which include things like platelet problems. In some of our patients with very low platelet levels, NSAID are probably something you don't want to use. Some of our patients have kidney disease, and one must also be cautious about using the nonsteroidal anti-inflammatory drugs in those circumstances. Nonsteroidal anti-inflammatory drugs are carried in the proteins in the blood, and if levels of these proteins are very low because of wasting and dehydration, there's really more drug in the patient's system then there would be in a healthy person; with higher levels of drug, there may be more toxicity. With just a few exceptions, most of the opioid drugs are quite safe and can be very useful even in many of our patients with HIV disease who are on multiple medications. Opioids can be sedating; if you're on other sedating medications, you have to be cautious about additive sedation. But for the most part, many of my patients who have pain and get these medications do very well and don't have any major problems in terms of interactions with other drugs. LEFKOWITZ: I'm very cautious in the use of nonsteroidals because of all the side effects, ranging from upset stomach and gastritis to some patients developing renal failure. I also see that when acetaminophen plus codeine is used. I don't particularly like using codeine because I don't think that the small amount of analgesia that you get from codeine is worth the number of side effects, such as nausea, vomiting and constipation. I see that many times patients are given prescriptions for acetaminophen plus codeine and they take so many of them that they can actually develop an acetaminophen overdose. LEFKOWITZ: Also, TB medications will increase the metabolism of methadone, so don't be surprised if some patients have increased methadone requirements if they are taking a TB medication. Some of the anticonvulsants have the same effect. PHOENIX, AZ: My question is about the effect of opioids on the immune system. How might they interact in combination with antivirals and interleukin 2? Could there be any benefit? LEFKOWITZ: It's an interesting question. I'm not quite sure if I know the answer, how the immune system is affected by some of the opioids. And I don't think that anything is proven. BREITBART: It's a very complex issue because we know that pain has negative effects on the immune system, and there's some evidence in laboratory experiments that opioids can also have some negative effects on the immune system. This issue has been debated strongly in cancer pain. For instance, John Liebeskind's laboratory at the UCLA Department of Psychiatry has been studying pain and immunology and the effects of opioids on the immune system, and his feeling is that the benefits of treating pain far outweigh any of the negative consequences of opioids on the immune system. In other words, uncontrolled pain is worse for your immune system than having no pain and being on some opioid drugs. I've seen a few reports and literature on opioids and their effect on viral replication in test tubes, and there's some evidence that there may be some increase in viral replication when opioids are added to cells that are infected with HIV in vitro. These are just preliminary studies, and there's really no way to know yet whether this has any clinical relevance to the use of opioids as pain medication in people whose uncontrolled pain may have effect on their immune system as well. JACKSONVILLE, FL: It seems to me that the speakers are trying to make a strong argument for the use of opioids. But they are not mentioning what the other aspects of comprehensive pain control should be. I'd like for them to mention the role of nonpharmacologic alternatives for pain management. Also, it seems to me that they're grouping all the nonsteroidals in the same group, but there are nonsteroidals that have different potencies in their analgesic effects. Finally, they briefly mentioned that one of the reasons why primary care physicians don't usually prescribe narcotics or adequately manage pain syndromes is because they do not know much about prescribing narcotics or opioids. So I think they should try to give us definite guidelines for using these drugs, including issues such as PRN [as needed] as opposed to around-the-clock dosing and time limits for chronic management with these medications. BREITBART: Chronic pain in patients with AIDS is a complex, multidimensional experience that involves not only physical aspects of pain, but an interaction of the physical, the psychological and the emotional. Optimal treatment for chronic pain in AIDS would involve approaches that appreciate all of these interacting components so that treatments that are applied towards the physical aspects are as important as treatments that are applied towards the psychological, social and emotional aspects. We often, in my practice, use analgesic drugs but we also try to provide psychosocial support, use psychotherapy and use specific cognitive or behavioral techniques, such as distraction or relaxation exercises, or various forms of imagery. We also use physical rehabilitation, acupuncture and other nonpharmacological interventions. LEFKOWITZ: I agree with Bill regarding the use of nonpharmacologic approaches. Those are very important and should be used. I think that the danger sometimes comes in when we use one modality exclusively, when we use one type of medication or one type of nonpharmacological approach. I think that all of these approaches to treating pain should be used until the right combination is found. In terms of the nonsteroidal anti-inflammatory drugs, there are lots of different drugs and classes of these drugs. There are different doses and different dosing intervals. What I usually say is that a physician should probably use the nonsteroidal that they are most comfortable with. Some NSAID drugs have a few more side effects than others. Whatever physicians are most comfortable with is what they should use, then when side effects appear they'll be able to treat them. Toradol, or Ketorolac, is the first injectable nonsteroidal available in the United States. It also exists in a pill form. It's a very powerful analgesic as well as an anti-inflammatory. It is a NSAID and can be used in the same way that you'd use any other nonsteroidal anti-inflammatory drugs. It's a very effective pain killer, but the company suggests that it only be used for about 3 weeks because of emerging side effects. The other comment that the caller had was about using medications around the clock and using PRN [as needed] medications. I think that whenever we're using any of these pain killers, they should in fixed doses and on a fixed schedule of regular time intervals. There should also be PRN medication, or breakthrough, rescue medication, so that if the patient has more pain at a particular time of the day, there is a rescue medication available to him or her to treat the acute pain episode. When using a long-acting opioid such as Oramorph SR, MS Contin or the Duragesic patch, some kind of short-acting opioid, say 15 milligrams of morphine or oxycodone, should always be made available to the patient on a PRN basis. BAKER: Thank you very much Dr. Breitbart and Dr. Lefkowitz. This is an important area that deserves more investigation. I appreciate your efforts. I would urge everyone to get the March issue of BETA which contains a lengthy article on "Pain in AIDS," coauthored by Drs. Lefkowitz and Breitbart. Our next guest is Jules Levin. Jules is a person living with AIDS and a community activist in New York City. He is coordinator of the Protease Inhibitor Drug Working Group, a coalition of community-based AIDS organizations that's working to speed up the testing and approval of the new protease inhibitor drugs. Jules, why does the AIDS community consider the protease inhibitor drugs so important? LEVIN: Well, we have been using all the other available drugs for a number of years, and most people with AIDS have used up all their treatment options. For many of these people there is nothing available that may have a sufficient impact on the virus except the protease inhibitor drugs. In addition to that, we are finding that the protease inhibitors seem to have a much more dramatic impact on the virus than the previously used and available drugs. We are also finding that people with advanced AIDS, with very low CD4 counts, are responding well to protease inhibitors. Many people are dramatically improving from very low T-cells to much higher levels and many of these people have been able to maintain this increase for a fairly long period of time; their symptoms are going into remission. We've never seen such a response from any other antiviral drugs. BAKER: What about the toxicity of these compounds? Is that of any concern? LEVIN: To the best of my understanding, the toxicity concerns with this class of drugs is less than with the other antiviral drugs. BAKER: Could you tell us briefly where these drugs are now in the development process and what their availability is? LEVIN: That is what the Protease Working Group has been primarily concerned with. We're very unhappy and dissatisfied that people with lower CD4 counts don't have access to these drugs now and will not in the very near future in the quantities that they need. There are many, many thousands of people that want and need access to these drugs immediately. There are 3 protease inhibitor drugs right now that are the most developed in terms of what stage they're at the Roche drug, the Merck drug and the Abbott drug. The Merck drug and the Abbott drug are entering Phase III trials right now. And Roche has promised us their drug [saquinavir]. They are planning an expanded access program for 4,000 people by the end of the summer or the early fall. The Merck drug is in Phase III right now; you can enter a Phase III trial. In the near future, probably in the middle of June, Merck will be starting, as a result of our pressure on them, an advanced AIDS program. They will do a small trial for people with under 50 CD4 cells/mm3 starting in mid-June, and that will be accompanied by a larger open label program for at least 1,400 patients. And we're hopeful that they will double that number. Abbott has told us that they will not give us an expanded access program now or in the near future. We are upset about this and have met with Abbott to discuss it. BAKER: All of these companies have indicated that they will apply for accelerated approval. When is that expected to happen, and after the application, how long would it be before these drugs are available by prescription? LEVIN: We expect Roche's application for approval to occur in the early fall [1995] and we expect to have the drug [saquinavir] available sometime in the mid-to-late fall. I expect the application for approval of the Abbott drug at the very end of 1995, maybe January 1996. And I would say the same is true for Merck, too, late 1995 or early 1996 for application, and approval by March or February of 1996. One of the reasons that the drug companies are unwilling to meet our demands [for earlier access], so they claim, is the difficulty in manufacturing these drugs. BAKER: Once the applications [for accelerated approval] are submitted, how long does it take for FDA to make a decision? LEVIN: It can take a number of months before the approval actually happens. And in this case, that's just unacceptable. There are people who are very sick. There's no reason why this process can't be shortened considerably. BAKER: Is there something that people can do in terms of communicating with the FDA about this situation? LEVIN: Yes. In the AIDS game it takes 3 to tango: FDA, the drug companies and the AIDS community. And it's very important for the community to repeatedly, unrelentingly let FDA know that they're watching, and that they expect FDA to work as diligently as possible toward approving these drugs as quickly as possible, and not to let unnecessary delays get in the way. One thing that the community everyone listening can do is call or fax or write FDA. The office to call is the FDA Office of AIDS and Special Health Issues. Tell them that you're anxiously awaiting approval of the protease inhibitor drugs and that you are watching FDA in hopes that they will speed this up as quickly as possible. Their telephone number is 301-443-0104 and their fax number is 301-443-4555. BAKER: You mentioned open-label programs for the protease inhibitor drugs. What does that mean? LEVIN: "Open label" basically means that certain people would be able to have direct access to the use of the protease inhibitors [outside of the clinical trials]. What we would like is for people below 50 CD4 cells/mm3 and people who are intolerant to other antivirals to have access. They wouldn't be randomized or blinded. They just get a protease inhibitor in addition to whatever other approved antiviral they may be taking. BAKER: As you know, in February [1995] there was a meeting in Washington, DC, of the National Task Force on AIDS Drug Development. I understand that there was a lot of discussion about protease inhibitor drug development. LEVIN: We did convince the authorities to devote the entire Drug Development Task Force meeting to the subject of protease inhibitors, and many of the important players were invited to this meeting from drug companies as well as from governmental agencies and from the AIDS community. Going into the meeting we were negotiating with Merck about an open-label access program for crixivan (formerly called MK-639) for people with advanced AIDS, and what they were willing to offer us at that time was very meager. As a result of the presentations that we made at the Task Force meeting, Merck later responded with a much larger open-label program for crixivan. BAKER: If people are interested in signing up for these programs or trials, here are some phone numbers. The Merck toll free number for enrollment in trials of crixivan is 1-800-379-1332. For the Roche protease inhibitor, the number to call is 1-800-526-6367. And for Phase III trials of the Abbott protease inhibitor, which are currently enrolling, the number is 1-312-755-1241. There's another coalition that you've spoken about, Jules, called the Protease Consensus Coalition. What is the purpose of that group? LEVIN: That's a smaller group of people, some of whom are in the Protease Working Group and some of whom are not. In order to attempt to influence the participants at the National Task Force on AIDS Drug Development meeting in February, we started networking nationally [with other activists]. We formulated a consensus statement that asks for faster and broader access to the protease inhibitor drugs. We put together a document with individual signatures and endorsements from organizations and presented it at the Task Force meeting to FDA Commissioner David Kessler. Any organization or person that would like to get a copy of the consensus statement and sign on can do so, and we encourage people to do this. We're still collecting signatures. The fax number to request a copy of the statement is 310-371-4565; send it to the attention of Linda. BOSTON, MA: Has there been any progress made with the drug companies on working on cross-resistance among the protease inhibitor drugs? I know that was part of the consensus statement, and I wondered if the drug companies had responded to that at all. LEVIN: Well, you may know about an article that came out in Nature magazine last week. The information came from Merck's labs. Based upon test tube information from the blood of 4 or 5 people, they found evidence of cross-resistance between all the protease inhibitors. There was a lot of controversy about this paper because many people thought that particular finding by Merck was premature, preliminary at best, and may not occur when utilizing higher dosages of these drugs. BAKER: Was there anything else you wanted to add, Jules, about protease inhibitor drug development? LEVIN: Well, I think that we have covered most of the issues. I would just, again, encourage the community to take an interest in this issue. The subject does not get enough attention, and I hope that people out there listening will take a greater interest. BAKER: Thank you, Jules. We will be doing periodic updates on the status of the protease inhibitor drugs in future BETA LIVE! conference calls. We'll have you back again to give us a progress report. People contact us from time to time with suggestions for future conference calls. If you'd like to comment on any of our programs or offer suggestions for future programs, please write to us at BETA LIVE!, P.O. Box 426182, San Francisco, CA 94142. The BETA LIVE! fax number is 415-552-9762. On behalf of BETA and the San Francisco AIDS Foundation, thanks for participating in today's BETA LIVE! teleconference. Goodbye for now. ------------------------------------------------------------------ Selected Open Clinical Trials for HIV/AIDS Treatments Leslie Hanna For further information, call the number provided with the individual listing. If no telephone number is listed, call the AIDS Clinical Trials Information Service (ACTIS), toll-free, at 1-800-874-2572 (1-800-TRIALS-A) for information about site locations. This government-sponsored service can provide information about most of the following trials, but can only provide information about early-phase privately sponsored trials when the sponsor has elected to give that information to ACTIS. Treatment for HIV Infection ABT-538 (Abbott protease inhibitor) Phase III trials have begun. Abbott protocol number M94-247, for people with fewer than 100 CD4 cells/mm3 and prior antiretroviral experience, is taking place at 30 sites nationwide; only 2 sites are still enrolling: Los Angeles and Chicago. Participants will be randomized to receive the protease inhibitor plus their current (approved) antiretroviral therapy, or placebo and their current antiretroviral. Those who experience a new AIDS-defining event while in the study will be offered open-label ABT-538. For more information about the 2 open sites, contact: Dr. Peter Ruane at Cedars-Sinai Medical Center, Los Angeles: 310-358-2300; and Dr. John Pottage at the Chicago Center for Clinical Research, Chicago: 312-494-2204. Protocol number M94-245, involving antiretroviral-naive people with greater than 200 CD4 cells/mm3, is fully enrolled and underway. Additional protocols including the finalized 246 will be added later this summer. ABT-538 and AZT This Phase III, double-blind, 3-arm study will compare (1) ABT-538 monotherapy to (2) AZT monotherapy to (3) ABT-538 plus AZT. Participants with 200-700 CD4 cells/mm3 will be randomized to 1 of the 3 arms. At the end of the 12-month study, those showing benefit may receive open-label ABT-538. For more information on ABT-538 trials, call Mabrey Whigham: 312-755-1241. indinavir sulfate (Crixivan), formerly called MK-639 (Merck protease inhibitor) Merck has begun enrolling participants in several phase III studies to test the safety, tolerability and effectiveness of Crixivan at a dose of 800 mg, 3 times daily. Studies include:  Open-label enrollment of up to 1,400 people (by the end of 1995) with fewer than 50 CD4 cells/mm3 begins in August.  A 12-month surrogate marker (CD4 and viral load) study in 780 AZT-naive patients with CD4 counts between 50-500 cells/mm3. Participants will be stratified by CD4 cell count (50-250 and 250-500 CD4 cells/mm3) and randomized to receive Crixivan, AZT or the combination. The study began enrolling in April 1995 in the U.S. The study will also take place in Europe, and possibly in Canada and Australia.  A 12-month pilot surrogate marker study in 540 AZT-experienced patients with CD4 counts between 50-500 cells/mm3. Participants will be randomized to Crixivan, d4T or the combination. The study began in May in the U.S. and will also take place in Europe.  A 12-month pilot surrogate marker study in 90 AZT-experienced patients with 50-400 cells/mm3. Participants will be randomized to Crixivan, AZT/3TC or the triple combination. The study began in April in the U.S.  A surrogate marker study in 300 patients with CD4 counts less than 50 cells/mm3. Participants will be randomly assigned to (1) AZT plus 3TC, (2) AZT plus 3TC plus Crixivan, (3) Crixivan monotherapy or, if randomization proves medically inappropriate (e.g., AZT intolerance or with excessive prior 3TC use), (4) open-label Crixivan. Enrollment for this study begins in June.  A clinical endpoint (new opportunistic infections or death) study is underway in 750 AZT-naive, Brazilian patients with CD4 counts between 50-250 CD4 cells/mm3. Patients are randomized to Crixivan, AZT or the combination. For more information about Merck trials, call 1-800-379-1332. KNI-272 (Japan Energy protease inhibitor) This open-label Phase I study takes place at the National Cancer Institute (NCI) in Bethesda, MD. The 4-week study gives the protease inhibitor in intravenous (IV) and oral forms at intervals throughout the 4 weeks. Call Kathleen Wyvill, RN: 301-496-8959. Saquinavir (Hoffmann-La Roche protease inhibitor), nevirapine, AZT and ddI ICC 001 is a Phase III double-blind trial of the comparative efficacies of different combinations of the 4 antiviral agents, sponsored by the Inter-Company Collaboration. Participants (200-500 CD4 cells/mm3) will be randomized to receive either (1) AZT, ddI and placebo, (2) saquinavir, AZT and ddI or (3) nevirapine, AZT and ddI. The study lasts 48 weeks. PCR tests of viral load are performed at each clinic visit. For more information, contact Cassandra Sanders, PA, at Beth Israel Medical Center, NY: 212-420-4519; or Richard Hutt, RN: 212-561-4439. Saquinavir, nevirapine, AZT and ddC This Phase II multicenter study will evaluate the safety and efficacy of the following 3 combination regimens: AZT/ddC/saquinavir vs AZT/ddC/nevirapine vs AZT/ddC. The study is open to people with 200-500 CD4 cells/mm3 and no prior antiretroviral treatment. For more information, call 1-800-526-6367. Saquinavir and ddC FDA 229A is a Phase III study that will involve 1,000 participants. The trial is open to people with 50-300 CD4 cells/mm3 who have failed on AZT. Prior use of ddC, ddI or d4T must not be greater than 2 weeks. There are 3 treatment arms: (1) saquinavir monotherapy, (2) ddC monotherapy and (3) ddC plus high-dose saquinavir. (A fourth arm, ddC plus low-dose saquinavir, has been dropped.) Saquinavir, AZT and ddC In this Phase III double-blind, placebo-controlled trial, people with 50-350 CD4 cells/mm3 will be randomized to receive various combinations of these anti-HIV agents. The 4 treatment arms are: (1) saquinavir plus AZT plus ddC, (2) saquinavir plus AZT, (3) AZT plus ddC and (4) AZT. Prior use of antiretrovirals other than AZT is excluded, and previous use of AZT must not exceed 4 months. For more information about international and North American trials of saquinavir, call 1-800-526-6367. MDL 28,574A plus AZT MDL 28,574A is a new anti-HIV drug from Marion Merrill Dow. This Phase II 24-week study will evaluate the antiviral activity of MDL 28,574A alone and in combination with AZT, in 2 demographic groups, i.e., CD4 cell ranges 100-300 and 301-500 cells/mm3. There are 25 sites in the U.S. For more information, contact Ruth Ann Burk at the Stoneybrook HIV Treatment Development Center, NY: 516-444-1658 or Nelson Murcar, RN, at the University of California/San Francisco AIDS Program, CA: 415-476-9296, extension 84092; or call 1-800-TRIALS-A. Combination vs alternating antiretroviral treatment for advanced HIV infection ACTG 193A is a Phase II/III double-blind study comparing combination nucleosides to alternating nucleosides to triple-drug therapy for people with fewer than 50 CD4 cells/mm3. Investigators will evaluate efficacy and the relative abilities of the different regimens to minimize toxicity as well as resistance. Participants are randomized to receive (1) AZT plus ddC, (2) AZT plus ddI, (3) AZT alternating monthly with ddI, or (4) AZT plus ddI plus nevirapine. Multiple sites. Hydroxyurea and ddI This pilot study will evaluate the safety, tolerability and antiviral effects of hydroxyurea as monotherapy vs hydroxyurea combined with ddI. The 24-week study is open to people with 400 or fewer CD4 cells/mm3. For more information, call Larry Mole, PharmD, at the VA Palo Alto/AIDS Research Center, CA: 415-493-5000, extension 4694. Sulfasalazine Sulfasalazine is approved for the treatment of arthritis, an autoimmune disease. Like aspirin, it reduces pain and inflammation; unlike aspirin, it is not known to cause gastrointestinal problems. This placebo-controlled, dose-ranging, 16-week study will evaluate the potential of the drug to elevate CD4 cell counts in people with HIV and seek to establish optimal doses. Participants must not have arthritis, severe liver or kidney disease, or active major opportunistic infection(s). In New York, call Dr. Eddy Disla at Cabrini Medical Center: 212-995-6996. Hydroxychloroquine and AZT This double-blind Phase II open-label safety and efficacy trial will evaluate the anti-HIV potential of these 2 agents in those with 200-500 CD4 cells/mm3. Participants will be randomized to receive either the combination of the 2 agents, or AZT alone. Call Kurt Sperber, MD, at Mt. Sinai Medical Center, NY: 212-241-0764. Glutathione Glutathione is a naturally occurring protein that detoxifies waste in the body; glutathione deficiencies are associated with HIV infection. This study will test the safety and pharmacokinetics of different doses of glutathione (up to 1.5 g twice daily), to evaluate its potential to counteract HIV-related deficiencies. Study requirements include having a CD4 cell count greater than 500 CD4 cells/mm3, no prior use of antiretrovirals and no cigarette smoking. For more information call Paul Prosser at the Pacific Oaks Medical Group, Los Angeles, CA: 818-906-6279. 935U83 This Phase I multicenter trial looks at the pharmacokinetics, safety and efficacy of 4 different doses of the non-nucleoside reverse transcriptase inhibitor 935U83. The study is open to people without hepatitis who have 200-500 CD4 cells/mm3 and less than 1 month prior use of nucleoside therapy. 935U83 plus AZT plus 3TC This Phase I/II study will evaluate the safety and efficacy of 935U83 in combination with AZT and 3TC vs the combination of AZT and 3TC. The 12-week study is open to people with 100-500 CD4 cells/mm3 and no prior antiretroviral treatment. For more information, call Peter at ViRx, San Francisco Bay Area, CA: 415-353-5623. GEM 91 This open-label Phase IB/II trial will evaluate the safety, pharmacokinetics and anti-HIV properties of GEM 91, an antisense drug. Sixty people will receive intravenous GEM 91 for 2 to 4 weeks. Viral RNA plasma concentrations will be measured by bDNA. This trial requires 2 weeks of hospitalization. In New York, call Dr. Giordano: 212-746-4177. In Birmingham, Alabama, call Dr. Saag: 205-934-7349. Delavirdine, AZT and ddI ACTG 261 is a Phase II, double-blind trial of delavirdine combined with AZT and/or ddI, vs AZT and ddI in people with 100-500 CD4 cells/mm3 and less than 6 months of prior monotherapy with AZT or ddI. Treatment lasts 48 weeks; participants are randomized to 1 of 4 treatment arms. Investigators are evaluating the various combinations and doses. For more information, call Upjohn: 800-432-4702. OPC-8212 OPC-8212 (vesnarinone) is an oral medication used in Japan to treat congestive heart problems. This Phase I study evaluates the safety, tolerance and antiviral potential of 6 different doses of OPC. The study lasts for 12 weeks and is open to people with asymptomatic HIV infection and greater than 300 CD4 cells/mm3. Call University of California/Los Angeles Center for AIDS Research and Education (CARE): 800-UCLA-MD1 or 310-206-1960. In Atlanta, 2 similar Phase I studies but with 4 different doses of OPC are enrolling people with (1) 50-300 CD4 cells/mm3 and (2) greater than 300 CD4 cells/mm3. Call Scott Godwin at the AIDS Research Consortium of Atlanta: 404-876-2317, extension 327. SVP-30 SVP-30 is an extract obtained from the boxwood tree, a type of evergreen. In France, the manufacturer is conducting Phase II/III studies. Informal studies underway in the U.S. provide SVP-30 free to all participants. Each study last 6 months. Requirements include blood tests at entry and each 2 months thereafter, including PCR. For more information, call David Stokes, Boston, MA: 617-424-9195. SC-49483 vs AZT for inhibition of syncytia formation ACTG 259 is a Phase II double-blind multicenter study of SC-49483, a new drug that may help prevent the formation of syncytia. Syncytia formation is associated with disease progression. Participants will be randomized to receive either (1) low-dose SC-49483 plus AZT, (2) high-dose SC-49483 plus AZT or (3) AZT plus placebo. Requirements include 50-350 CD4 cells/mm3 if no prior antiretroviral use and 150-350 if participants have past antiretroviral use. BMS 180194 for HIV and CMV This Phase I/II study will compare the safety, tolerance, anti-CMV and anti-HIV activity of the new oral antiviral drug BMS 180194. Two research clinic visits are required each week for 8 weeks, plus 3 hospital stays of 1 day each. Requirements include a CD4 count below 200 CD4 cells/mm3 and no history of CMV disease. In San Francisco, call Mt. Zion Hospital: 415-476-6356; in Minnesota, call 612-624-6489; and at John Hopkins University in Maryland, call 410-955-7704. PMEA plus AZT The National Cancer Institute (NCI) is conducting a Phase I/II dose-ranging study of the safety and efficacy of the combination of AZT and PMEA. PMEA is active against herpesviruses and HIV. PMEA is given in IV form 3 times a week. Participants have less than 500 CD4 cells/mm3. Call Sergio Bauzo at the NCI, Bethesda, MD: 301-496-8959. GS-840 A Phase I/II study of the oral drug GS-840 is underway at multiple centers in the U.S. Manufactured by Gilead Sciences, GS-840 is a prodrug of another Gilead Sciences product, GS-393, or PMEA, which is also in ongoing clinical trials. AZT effect on viral load in lymph nodes This 9-week multicenter study will evaluate the effect of AZT on the amount of HIV in blood and lymph tissue. All participants will receive AZT for 8 weeks and will have 2 lymph nodes biopsied, at the beginning of the study and then 8 weeks after treatment ends. The 2 lymph node biopsies will not cause long-term health problems. Study requirements include having 100-500 CD4 cells/mm3. Exclusion criteria include prior use of any antiretroviral drugs, chemotherapy and current opportunistic infections (except mild Kaposi's sarcoma or candidiasis). In the SF Bay Area, contact the AIDS Community Research Consortium (ACRC): 415-364-6563. Treatment for Opportunistic Infections Aspergillosis: amphotericin B lipid complex (ABLC) This Phase III open-label study is evaluating the safety and efficacy of ABLC for treating definite or probable invasive aspergillosis. Eligibility requirements include severe immunosuppression, culture-proven aspergillosis (within 14 days of beginning treatment) and lack of response to conventional amphotericin B treatment. For more information, call Brian Camp, RN, at ACRC, San Francisco Bay Area: 415-364-6563. Amphotericin B lipid complex (ABLC) is available on an emergency basis to people with life-threatening fungal infections. Nationwide, call the Liposome Company: 800-422-5279. Candidiasis: fluconazole (Diflucan) oral suspension A Phase II/III open-label safety and efficacy trial of an oral suspension formulation of fluconazole for the treatment of esophageal candidiasis is ongoing. There are 2 sites. In Houston, call Dr. Lahart: 713-791-1414, extension 3653; in Los Angeles, call Dr. Leedom: 213-343-8281. Candidiasis: itraconazole (Sporanox) oral solution A Phase III open-label safety and efficacy trial of an oral solution of itraconazole for refractory oropharyngeal candidiasis is ongoing. Participants receive 100 mg twice daily. Candidiasis: itraconazole and fluconazole This blinded, randomized multicenter pilot study will evaluate the safety and efficacy of itraconazole and fluconazole for oropharyngeal candidiasis. Participants will receive 1 of 2 doses of oral itraconazole or oral fluconazole for 2 weeks. Periodic physical exams and blood tests will be performed throughout the 5-7 week study and 4 weeks after treatment. Participants must have oral candidiasis (thrush or oropharyngeal candidiasis) and at least 100 CD4 cells/mm3. Exclusion criteria include esophageal or disseminated candidiasis. Candidiasis: liquid itraconazole This Phase III open-label safety and efficacy study will evaluate itraconazole for oral Candida infections (thrush) that cannot be treated successfully with fluconazole. Liquid itraconazole is administered like a mouthwash for 14-28 days with 6 weeks of follow-up. Study length depends upon efficacy. Participants have thrush that has not responded to fluconazole for 14 days. There are several sites across the U.S. Cryptococcal meningitis: amphotericin B plus flucytosine plus fluconazole ACTG 202 is a Phase II multicenter double-blind trial of amphotericin B plus flucytosine plus fluconazole, with or without IV dexamethasone, for the treatment of cryptococcal meningitis. Participants are randomized to 1 of 2 arms. Amphotericin and dexamethasone (or placebo) are given intravenously; flucytosine and fluconazole are taken orally. Cryptococcal meningitis: RMP-7 plus amphotericin B Another ongoing cryptococcal meningitis trial is a Phase I double-blind dose-escalating trial of the safety and pharmacokinetics of RMP-7 plus amphotericin B (all agents are given intravenously). Participants are randomized to 1 of 5 arms. Cryptococcosis: fluconazole plus flucytosine This Phase II trial evaluates the safety and efficacy of oral fluconazole plus oral flucytosine for preventing cryptococcosis. The study is open to people with HIV infection and a positive response to a test for the cryptococcal antigen. The study lasts one year; study visits occur each month. Cryptosporidiosis-associated diarrhea: bovine immunoglobulin concentrate (BIC) This study will prospectively evaluate the ability of bovine immunoglobulin concentrate (BIC) to alleviate severe diarrhea resulting from cryptosporidial infection or other causes, that has failed to respond to other treatments. Participants are randomized to receive either BIC powder or BIC capsules. The study lasts 7 weeks. Entrance requirements include 10 days of diarrhea within the past month and exclude milk protein or severe lactose intolerance. In the SF Bay Area, call Dr. Paul Greenberg: 415-206-8824. Cryptosporidiosis-associated diarrhea: IGX This Phase I open-label trial is evaluating IGX, hyperimmunized chicken egg yolk, for the treatment of cryptosporidiosis. The treatment is drunk in an eggnog-like formulation. At Cornell Medical College, NY, call Rosemary Soave, MD, or Lawrence Davis, MD: 212-746-6320. Cytomegalovirus (CMV) retinitis: ganciclovir and intravitreal implants This Phase III multicenter study will evaluate the safety and efficacy of ganciclovir in conjunction with intravitreal ganciclovir implants. Participants will be randomized to 1 of 3 treatment arms: IV ganciclovir; implant plus oral ganciclovir; or implant plus placebo. Those whose regimen includes IV administration will have a central line placed, which will be removed at the end of study. Participants must have had CMV in only one eye. Exclusion criteria include current or past presence of CMV disease in other parts of the body, and more than 2 induction phases of therapy for CMV retinitis. CMV retinitis: cidofovir (HPMPC) FDA 216B is an open-label study of the safety and efficacy of intravenous cidofovir, or HPMPC. Entrance requirements include ophthalmologically proven CMV retinitis and unsuccessful ganciclovir and/or foscarnet treatment (for at least 4 weeks). Retinal photographs will be used to evaluate efficacy. There are 6 sites in the U.S. and 1 in Great Britain. Histoplasmosis prophylaxis: itraconazole An ongoing histoplasmosis prophylaxis trial is randomizing participants to receive either 200 mg daily itraconazole or placebo. Treatment as well as follow-up both last 12-24 months. Most sites are in the midwest. Mycobacterium avium complex (MAC): azithromycin (Zithromax), clarithromycin (Biaxin) plus ethambutol (Myambutol) This double-blind study compares 2 combinations of anti-MAC agents for the treatment of disseminated MAC. Participants will be randomized to take 250 or 650 mg azithromycin plus 800-1200 mg ethambutol daily or clarithromycin 500 mg twice daily and 800-1200 mg ethambutol once a day. At the end of 24 weeks, participants may be evaluated for entry into an open-label maintenance protocol. The study is open to people with HIV and a positive MAC blood culture within 2 months prior to study entry. A total of 300 people will be enrolled at 25-30 sites nationwide. In the SF Bay Area call the ACRC: 415-364-6563. Mycobacterial infections and/or HIV: thalidomide (Synovir) FDA 133A is a Phase I/II trial of the safety and efficacy of thalidomide in people with HIV and/or mycobacterial infections, including MAC and tuberculosis. Clinical examinations and laboratory tests will be used to evaluate the impact of thalidomide on reducing symptoms and improving immune responses in participants. The trial is open to people with proven mycobacterial infection (culture or smear), with or without documented HIV infection. HIV positive participants must have fewer than 500 CD4 cells/mm3 and must be taking one or more antiretroviral. Recent fever, weight loss and night sweats are also required. Participants will be randomized to receive oral thalidomide or placebo the night before beginning anti-tuberculosis treatment, to continue for 7 nights. Follow-up continues for a total of 28 days. Pneumocystis carinii pneumonia (PCP) treatment: trimetrexate glucuronate (TMTX) plus leucovorin (LCV) plus dapsone vs trimethoprim/sulfamethoxazole (TMP/SMX) This randomized, Phase I study will compare the safety and efficacy of the combination TMTX, LCV and dapsone to TMP/SMX (Bactrim or Septra) for the treatment of PCP. Participants will be hospitalized for the first 10 days of the 24-day study. Requirements include AIDS and active PCP. Exclusion criteria include more than 24 hours of systemic anti-PCP therapy within 2 weeks of start of study, pregnancy, anti-HIV drugs (AZT, ddI, ddC, d4T), pulmonary Kaposi's sarcoma or active pulmonary tuberculosis and current use of clarithromycin. This is a multicenter study. In the SF Bay Area contact Lisa Turner at San Francisco General Hospital (SFGH): 415-476-9296, extension 84093. Treatment for Malignancies and Cancers Anal cancer: isotretinoin, interferon alfa-2a This dose-escalating study of isotretinoin in combination with interferon alfa-2a will assess the ability of the combination to prevent anal neoplasia (secondary to anogenital human papillomavirus infection) in people with HIV infection. Participants will be taught to self-inject. Treatment will last 12 weeks with 36 weeks of follow-up. Requirements include biopsy-confirmed Grade I or treated Grade II or III anal intraepithelial neoplasia (AIN, a type of anal cancer). No opportunistic infections or cancers requiring chemotherapy are allowed. This is a multicenter study. In the SF Bay Area contact Sue Forstat at the University of California, San Francisco AIDS Clinic: 415-476-3226. Kaposi's sarcoma (KS): interleukin 4 (IL-4) ACTG 224 is a Phase I/II open-label, dose-ranging study of IL-4 for treating KS. In Boston call Dr. Scadden: 617-632-8895; in Los Angeles call Dr. Miles: 310-206-6414. For more information about a Phase II open-label trial of IL-4 for KS, call Dr. Gill in Los Angeles: 213-343-8275. KS: OPC-8212 OPC-8212 (vesnarinone) is an oral medication that is also being studied for its antiviral properties. It inhibits TNF-alpha and IL-6, cytokines that may be growth factors for KS cells. This 16-week, Phase I study will evaluate the safety and effects of 4 different doses of the agent on KS, and is open to people with HIV and biopsy-proven KS, without other current opportunistic infections. Use of antivirals is allowed. Call the UCLA CARE Center: 310-206-1960. KS: topical gel This Phase I/II, multicenter study is looking at the efficacy of a topical medicine called LGD1069. People with KS can apply the medicine, which comes in gel form, to their lesions themselves. A natural retinoic hormone (9-cis-retinoic acid), LGD1069 is related to vitamin A, which plays various roles in immune system responses and in protecting body tissues. The study will last for 4 weeks. If appropriate, participants may be eligible to continue using the agent after the end of the study. In the SF Bay Area call St. Francis HIVCare: 415-353-6215. KS: tretinoin (AR-623) This Phase II/III dose-escalating study will evaluate the safety and efficacy of tretinoin for KS treatment. Tretinoin will be injected 1 or 3 times a week for 24 to 32 weeks. To participate one must have diagnosed KS of the skin but no chemotherapy, immunotherapy, hormone or radiation therapy, and no opportunistic infections (except candidiasis) within 3 weeks. This is a multicenter study. KS and solid tumors: tecogalan sodium This Phase I, dose-escalating multicenter study will evaluate the safety, efficacy and pharmacokinetics of tecogalan sodium. Tecogalan sodium will be infused 2 times a week for 3 weeks. Participants will be hospitalized for the first infusion, and will continue treatment on an outpatient basis. Requirements include confirmed KS with at least 4 skin lesions. Exclusion criteria include prior anti-KS therapy for 3 weeks or more, an opportunistic infection other than KS within 4 weeks before the study, a history of acute or chronic GI bleeding or inflammatory bowel disease. Requirements for solid tumor participants include a confirmed solid tumor with metastatic disease or a tumor unresponsive to standard investigational therapies and no anti-cancer therapy for 3 weeks. In the SF Bay Area call Michael McKeehen, RN, at San Francisco General Hospital: 415-476-9296, extension 84101. Treatments for Wasting Syndrome and Myopathy AIDS-related diarrhea: diethylhomospermine (DEHSPM) This is a Phase I study of the efficacy of DEHSPM for treating refractory AIDS-related diarrhea. To participate one must have uncontrolled diarrhea (defined as more than 500 ml/day of liquid stool for 4 weeks duration despite high-dose, non-specific antidiarrheal therapy). Exclusion criteria include use of anti-diarrheal drugs. For more information, contact Dr. Charles Sninsky or Barbara Fitz-Williams at the University of Florida Clinical Research Center: 904-392-2877. Chronic diarrhea: oral rehydration therapy Chronic diarrhea results in depletion of water and nutrients. This study will compare 2 oral rehydration solutions (ORS): a standard glucose formula vs a newer one containing oligosaccharides, "shorter" sugars, which may reduce diarrhea in addition to rehydrating the participant. Chronic diarrhea, an entrance requirement, is defined as 3 or more episodes, 3 times a week, for 3 weeks. For more information, call the AIDS Treatment Data Network in New York: 800-858-2111. Diarrhea related to HIV-associated fat malabsorption: enzymes This study will evaluate the ability of giving exogenous enzymes to people with HIV and severe diarrhea that has no identifiable, treatable cause but is related to fat malabsorption. Pancrelipase supplements are already approved for the treatment of non-HIV-related fat malabsorption. The study involves a special diet and 12 days of hospitalization. Body composition tests will be performed. In San Francisco call Yvette Garcia: 415-206-4748; or Johannes Koch: 415-206-4753. Bowel syndrome: glutamine Glutamine is an amino acid that may help repair damaged intestinal linings (contributing to "leaky bowel syndrome," associated with HIV infection). Participants will be randomized to receive 1 of 2 doses of glutamine or placebo for 28 days. Various tests are performed to measure the integrity of intestinal linings as well as absorption and treatment efficacy. Call the AIDS Treatment Data Network, NY: 800-858-2111 or 212-260-8868. Wasting syndrome: thalidomide (Synovir) FDA 230A is a Phase II placebo-controlled study of the safety and efficacy of thalidomide for treating HIV-related wasting syndrome. In particular, investigators will be examining the effect of thalidomide on reducing weight loss and on antiviral and anti-tumor necrosis factor-alpha potential. The study is open to people with HIV and wasting, or greater than 10% loss of normal/prewasting body weight in the absence of another infection that might account for such weight loss. Participants will be randomized to receive low- or high-dose thalidomide (100 mg or 200 mg/day) or placebo for 8 weeks, and may continue for an additional 4 weeks. Immune Enhancement HIVIG plus AZT vs IVIG plus AZT for pregnant women HIVIG, a solution of concentrated antibodies, is a type of passive immunotherapy. ACTG 185 is a Phase III multicenter trial that compares HIVIG to IVIG for efficacy in preventing transmission of HIV from mother to infant. Participants are randomized to take either HIVIG or IVIG; all participants take AZT. Infants receive the same treatment as mothers. Mothers are given AZT intravenously during labor. Newborns also receive either IV HIVIG or IVIG within 12 hours of birth, and a syrup formulation of AZT for 6 weeks. Interleukin 2 (IL-2) This randomized, unblinded Phase II study of high- and low-dose subcutaneous injections of IL-2 will evaluate its safety and efficacy. The study is open to people with asymptomatic HIV infection and 300-700 CD4 cells/mm3. All participants will receive d4T for at least 2 weeks prior to initial dosing. During the study, participants will receive 5 days of subcutaneous injections per 8-week cycle, with a total of 3 cycles. Exclusion criteria include prior IL-2 therapy and a history of AIDS-defining conditions. Antiretroviral agents other than d4T must be discontinued 2 weeks prior to study. For more information, call Nelson Murcar at the UCSF AIDS Program: 415-476-9296, extension 84092; and in Atlanta, Dr. Melanie Thompson at the AIDS Research Consortium: 404-876-2317. Interleukin 12 (IL-12) This double-blind, placebo-controlled, dose-escalating study of the safety of subcutaneous recombinant human IL-12 is sponsored by Genetics Institute, Inc. Inclusion criteria are 100-500 CD4 cells/mm3 and an HIV RNA level greater than or equal to 5,000 (bDNA testing will be part of the screening procedure). Participants must be on a stable combination of antiretroviral agents for a minimum of 6 weeks before beginning the study. Exclusion criteria include AIDS-defining opportunistic infections (minor infections are permitted). A history of PCP is acceptable, if resolved. Neuropathy, central nervous system pathology and cardiac history are excluded. The current Phase I study is taking place at 2 sites. In San Francisco, call Nelson Murcar at the UCSF AIDS Program: 415-476-9296, extension 84092. In Los Angeles, call Dr. David Hardy at UCLA: 310-206-6414. For additional information, including information about upcoming Phase I/II trials of IL-12, call Dennis Harp of Genetics Institute, MA: 617-876-1170. Thymopentin (TP5) Thymopentin, or TP5, is derived from a natural hormone and stimulates the immune system. This Phase III double-blind, placebo-controlled trial will evaluate the safety and efficacy of thymopentin (Timunox) in HIV positive individuals taking one or more anti-HIV drugs. Participants are randomized to receive thymopentin with AZT or ddI, or AZT combined with ddI, or AZT combined with ddC. A previous study indicated that the combination of thymopentin and AZT was more effective than AZT alone in slowing HIV disease progression. A related Phase II placebo-controlled trial will look at the impact of various doses of thymopentin on viral load; the study is open to people with less than 400 CD4 cells/mm3. Children and Adolescents Accessing experimental therapies not in pediatric trials Although most adult studies are only open to persons over the age of 18 years, several adult studies now also include adolescents 13-17. Representatives at 1-800-TRIALS-A can identify which adult studies permit adolescents. For children with limited therapeutic options, many pharmaceutical companies will allow compassionate use of therapies not yet in pediatric trials. Such use is determined on a patient-by-patient basis and may depend upon the availability of dosing information or a liquid formulation of the drug. Pediatricians should contact the company directly and request the department or investigator handling the drug in question. [Virginia Parks] Virginia Parks is an AIDS treatment activist and a member of the Pediatric Community Constituency Group of the ACTG. 3TC and AZT Approximately 600 children ages 3 months to 15 years, with less than 56 days previous use of an antiretroviral will be enrolled in this double-blind efficacy study. Children will be randomized to receive either 3TC and AZT or placebo and AZT. The study, considered pivotal for FDA approval of the drug, may be revised if data from current pediatric studies suggest that the combination of AZT and ddI is preferable to AZT alone (see below). This study is scheduled to enroll at 74 sites nationwide including all ACTG and National Institute of Child and Human Development (NICHD) sites [VP]. 3TC, AZT and ddI This study will evaluate the safety, efficacy and pharmacokinetics of 3TC, AZT and ddI in children with HIV. Participants enrolled in Arm A will receive all 3 drugs concurrently, but will be assigned to 1 of 2 different AZT dose levels. Those in Arm B will be assigned treatment based on their past medical history. Participants must be between 3 months and 18 years old. Exclusion criteria include opportunistic infections requiring treatment. For more information, contact Susan Sandelli, RN, at NCI, Bethesda, MD: 301-402-1391. AZT and ddI ACTG 152 compares AZT or ddI vs AZT plus ddI in children with previous AZT experience. Based upon interim data, the monotherapy AZT arm has been closed; children on that arm will be unblinded and offered the best available care as determined by parent/guardian and physician. Children on the ddI monotherapy or AZT/ddI combination arm will remain on study until it ends in August 1995 [VP]. All-trans-retinoic acid and interferon-alpha This summer, the NCI plans an open enrollment for a 2-part study of the natural history of lymphoproliferative disorders in children (enrolling primarily HIV-infected children but also pediatric transplant recipients). The first part of the study will be an observation period, without therapeutic intervention. The second part will be a 6-month treatment period with all-trans-retinoic acid and interferon-alpha, plus concurrent antiretroviral treatment in HIV-infected children. Clinic visits are required at specific intervals during the 48-week-long study. Call the NCI: 301-402-1391, extension 1387. Amphotericin B lipid complex for fungal infections Last November, a pediatric study began at the National Cancer Institute (NCI), using a lipid complex formulation of amphotericin B for treating splenic and/or liver candidiasis following cancer treatment. Amphotericin B lipid complex is given intravenously. Call Dr. Walsh at the NCI: 301-402-3527. Antibiotics for prevention of multiple opportunistic infections ACTG 254 will compare trimethoprim/sulfamethoxazole (TMP/SMX) to the combination of azithromycin and atovaquone as prophylactic regimens against PCP, MAC and other AIDS-related infections. The nationwide study seeks to enroll 680 children aged 2 to 13 years [VP]. Crixivan This study will evaluate the safety, tolerance and preliminary efficacy of the Merck protease inhibitor, Crixivan, alone for 12 weeks, then in combination with AZT and 3TC. The study is open to children with asymptomatic HIV infection who are at risk for opportunistic infection(s), based on CD4 cell counts as follow: for children 6-12 months of age, fewer than 1500 CD4 cells/mm3; for those 1-6 years, fewer than 1000 CD4 cells/mm3; for those greater than 6 years old, fewer than 500 CD4 cells/mm3. Another inclusion criterion is history of refractory disease or intolerance to antiretroviral therapy. For more information, call the NCI: 301-402-1391, extension 1387. The study is scheduled to begin this summer. Fluconazole vs amphotericin B for life-threatening candidiasis Another pediatric trial (only in Los Angeles) randomizes children with life-threatening candidiasis to receive either fluconazole, IV or oral, (12 mg/kg/twice daily) or amphotericin B (1 mg/kg/day). For more information, call Dr. Kovacs at the Los Angeles County/University of Southern California Medical Center: 213-342-3732 or 3733. HIV-1 immunogen This summer, the NCI plans a Phase I study of the safety, tolerance and immunogenicity of HIV-1 immunogen (gp120-depleted, inactivated HIV-1 preparation in an adjuvant, IFA) in HIV-infected children. Treatment arm A, consisting of children with no or mild symptoms but no signs of immunosuppression, will receive no antiretroviral therapy, and will be randomized to receive either HIV-1 immunogen or IFA. Treatment arm B, consisting of children with no or mild symptoms and moderate immunosuppression, will receive combination AZT/ddI and will be randomized to receive HIV-1 immunogen or adjuvant in the same manner as arm A. Eligible children are 3 months to 18 years old, with vertically acquired HIV. Call NCI: 301-402-1391, extension 1387. Interleukin 2 (IL-2) NCI plans a pilot study of recombinant IL-2, combined with antiretroviral therapy. Participants will receive AZT and ddI for 8 weeks before receiving high- or low-dose IL-2, which is administered subcutaneously twice a day for 5 days, every other month. After 24 weeks on study, based on safety and preliminary efficacy, participants may continue IL-2 therapy. The study is open to children aged 2 to 21 years. Those 2-5 must have 500-1000 CD4 cells/mm3, and those 6-21 must have 200-500 CD4 cells/mm3. Enrollment will begin this summer. Call the NCI: 310-402-1391, extension 1387. Levamisole, AZT and ddI The NCI also plans a pilot Phase I study to evaluate the safety, tolerance and immunomodulatory effects of levamisole, in combination with AZT and ddI, by looking at immune function changes and viral burden. The study seeks to establish maximum tolerated dose. The study is open to children and adolescents 2-21 years old with moderate to severe symptomatic HIV disease. Those less than 6 years old have under 500 CD4 cells/mm3, and those 6-21 have fewer than 200 CD4 cells/mm3. Call the NCI: 301-402-1391, extension 1387. Non-Hodgkin's lymphoma The NCI is conducting a pilot study of 2 drugs, systemic cyclophosphamide and methotrexate, for the treatment of HIV-related non-Hodgkin's lymphoma in children aged 3 months to 18 years. The drugs under study are considered the 2 most effective drugs for treating childhood lymphomas. During the 2-month study, participants will continue to use antiretrovrial therapy as well as IV gamma globulin, acyclovir and PCP prophylaxis to minimize the risk of complicating infection. For more information, call the NCI: 301-496-2321. Off-study access to 3TC Glaxo Wellcome, the manufacturer of 3TC, will provide free drug to patients for whom other antiretrovirals have failed. This expanded access program includes adults and children over the age of 2 years. Glaxo Wellcome also has been receptive to requests for compassionate use in children less than 2 years old. Call 800-248-9757 for more information on expanded access or compassionate use of 3TC [VP]. Oral ganciclovir (cytovene) ACTG 225 is a study of oral ganciclovir in children with asymptomatic CMV infection and low CD4 cell counts. Four different doses will be evaluated for pharmacokinetics and long-term safety in children. The study will enroll 32 children at several ACTG sites [VP]. Protease inhibitor (KNI-272) The National Cancer Institute (NCI) is conducting a Phase I study of the safety, toxicity and antiviral potential of a new protease inhibitor, KNI-272, in HIV positive children ages 3 months to 18 years. Children with no prior antiretroviral treatment will comprise arm A, and children intolerant to antiretroviral therapy will comprise arm B. For more information, call: 301-402-1391. Recombinant human growth factor vs growth hormone This Phase I/II NCI study compares the safety and tolerance of recombinant human growth hormone (rHGH, Nutropin) and recombinant human insulin-like growth factor (rhIGF-1), in combination with antiretroviral therapy, in children with HIV and growth failure. Investigators will also collect preliminary data on the effects of the growth factor and growth hormone on growth, immune function and viral burden. Eligible children are 6 months to 18 years old, have used antiretroviral therapy in the past, and have experienced growth failure. Exclusion criteria include diabetes and malnutrition. Initially, all children will receive AZT and ddI for 12 weeks. They will then be randomized to receive either rHGH or rhIGF-1 for 12 weeks. Children who benefit from the regimen may continue for another 12 weeks (36 total). For more information, call the NCI: 301-402-1391 or 301-402-1387. Serono Laboratory study of rHGH Serono has just begun a Phase II randomized dose-finding study, designed to determine the short-term safety and efficacy of HGH in children with HIV-associated failure to thrive. Eligible children will receive subcutaneous injections of rHGH for 6 weeks; those who complete the study may continue for another 12 months. Call 800-283-8088. Women Cervical dysplasia ACTG 200, a Phase II/III open-label trial, is enrolling HIV positive women with cervical dysplasia. Investigators will evaluate the safety and efficacy of 5-FU for maintenance treatment of cervical dysplasia. Participants will be randomized to a treatment or an observation arm. Those in the treatment arms will apply topical 5-FU twice a week for 6 months. There are multiple sites. Cervical intraepithelial neoplasia (New York only) In New York, this information-gathering study will look at the relationship between HIV-related immunosuppression and cervical intraepithelial neoplasia, or CIN. Clinical data will be collected through the provision of routine gynecological care to female participants. For more information, call Mary Jo Hoyt, principal investigator: 212-604-8038. Megace oral suspension FDA 025C is open-label Phase IV study provides 2 different doses of Megace to women with HIV-related weight loss. Weight gain, appetite and other measures will be compared between the low-dose and the high-dose groups. Those on low-dose who do not improve will have their dose increased. Natural history of HIV infection in women Sponsored by the National Institute of Allergy and Infectious Disease (NIAID), the Women's Interagency HIV Study (WIHS, pronounced "wise") is a large prospective observational study of the natural history of HIV infection in women. Investigators will be evaluating clinical manifestations, immunologic markers and virologic parameters, the roles in disease progression of cofactors such as nutrition, endocrine influences (hormones), socioeconomic status and substance use, and more. Designed to last 4 years, the study involves clinic visits every 6 months. Each visit, participants will have physical/gynecological exams and blood draws (for laboratory tests). Eligible HIV positive women are 13 years or older. The 6 study sites are: New York City (Bronx-Lebanon Hospital Center and State University of New York at Brooklyn); Washington, D.C. (Georgetown University Medical Center); Chicago (Cook County Hospital); San Francisco (University of California at San Francisco Medical Center) and; Los Angeles (University of Southern California School of Medicine). For information in English and Spanish, call the National WIHS Hotline: 800-665-1855. Nutrition (San Francisco) This 4-hour study at San Francisco General Hospital will measure body fat, bone density, dietary intake and energy expenditure in women with HIV. Call Viva Tai, RD, at 415-206-4090 or Dr. Kathy Mulligan: 415-206-5882. Vaginal candidiasis prevention: fluconazole A Phase I open-label multicenter trial randomizes women to receive either 200 mg weekly or 50 mg daily fluconazole as prophylaxis against vaginal candidiasis. Vaginal candidiasis treatment: fluconazole This ongoing open-label Phase I/II multicenter trial randomizes women to receive either 200 mg fluconazole a week or 100 mg daily as a treatment for vaginal candidiasis. Miscellaneous Acitretin for severe psoriasis In New York, there is an open-label, dose-escalating trial of the efficacy of oral acitretin for the treatment of psoriasis in people with HIV. Acitretin is known to clear psoriasis and is considered an effective treatment in HIV negative people; this will be the first thorough study of its use in people with HIV. Eligible participants are 18-55 years of age with psoriasis that affects at least 10% of their bodies (as measured by the Psoriasis Area and Severity Index, or PASI). For more information, contact Dr. Bradford Katchen at the Department of Dermatology, Beth Israel Medical Center: 212-420-2184. Delavirdine for AIDS dementia complex (ADC) This Phase II placebo-controlled study will look at the safety and efficacy of delavirdine (DLV) for treating ADC. DLV, a non-nucleoside antiretroviral also under study for its anti-HIV effects, may improve neurological function. There are no CD4 cell requirements. People using AZT, ddI or ddC must have been doing so for a minimum of 90 days before the study begins. If the treatment appears promising, participants may be eligible to take DLV indefinitely. Intramuscular testosterone replacement This pilot study evaluates the safety and efficacy of intramuscular testosterone replacement in men with HIV and loss of sex drive or depression. In New York, call Judith Rabkin, PhD, at the NYS Psychiatric Institute: 212-960-5762. Methionine for HIV-related myelopathy AIDS-related myelopathy is a central nervous system disorder that causes degeneration of the spinal cord. A lack of methionine, a natural protein, may play a role in this disease. This 6-month study will provide methionine as a dietary supplement to replete the substance and will evaluate the effects on myelopathy. Eligible participants are men and women over the age of 18 years with HIV-associated myelopathy, with or without neuropathy and dementia. Exclusion criteria include Kaposi's sarcoma, lymphoma and cervical cancer. Symptoms of myelopathy must have been present for at least 6 weeks; they include weakness of the limbs, especially the legs; unsteady, stiff and/or poorly coordinated walk; frequent urination, and; impotence in men. Call Jessica Moise at Mt. Sinai Medical Center: 212-241-0784. Neutropenia prevention: filgrastim (Neupogen) This randomized, controlled multicenter trial will evaluate filgrastim for the prevention of serious (Grade IV) neutropenia, or low numbers of white cells in the blood. Participants will receive 1 of 2 doses of filgrastim or placebo by subcutaneous injection. Requirements include a white blood count between 750 and 1000 cells/mm3. No treatment with filgrastim or growth factors for 14 days, active CMV retinitis or cancer (except for stable KS), allowed. Participants receiving ganciclovir must wait 3 weeks after starting ganciclovir. OPC 14117 for ADC This Phase II double-blind trial is evaluating the use of a vitamin E-like compound, OPC 14117, to treat HIV-associated cognitive changes. OPC 14117 may protect nerve cells from HIV-related damage. For the first 12 weeks, participants will be randomized to receive either OPC or placebo; for the next 12, open-label drug will be provided. Seventeen (17) clinic visits are required during the 24-week study. Eligible participants include HIV-infected men and women, 18 or older, experiencing difficulty with short-term memory concentration. Seizure disorders and opportunistic infections of the central nervous system are disallowed. For more information, call Ronda Friedman at Columbia University, NY: 212-960-2230; Charlyne Hickey at the University of Rochester, NY: 716-275-5130; or Deborah Hasenauer at Johns Hopkins University, Baltimore, MD: 410-955-1852. Peptide T for ADC This Phase II study will evaluate Peptide T for the treatment of dementia, especially to alleviate symptoms such as memory lapses, and difficulty with thinking and concentration. Participants have symptoms of ADC. Peptide T is given as an intramuscular injection; participants or their caregivers will be taught how to give the daily injections. Call Julie Grinnell at the Mt. Sinai Medical Center, NY: 212-241-0784; or Deborah Hasenauer at Johns Hopkins University, Baltimore, MD: 410-955-1852. Standard antibiotics vs Chinese medicine for chronic sinusitis This 12-week study compares the efficacy of traditional Chinese medical to standard antibiotic treatment of HIV-related chronic sinusitis, a condition often unresponsive to standard Western treatments. Participants will be randomized to receive acupuncture and Chinese herbs or an antibiotic for 8 weeks. Eligible participants have CT scan-confirmed sinusitis and have used neither acupuncture nor herbs in the month before beginning the study. In the SF Bay Area contact Thomas Sinclair or Elyse Graham at the Immune Enhancement Project: 415-252-8711. Thalidomide (Synovir) for aphthous ulcers ACTG 251 is a multicenter study of the safety and efficacy of thalidomide for the treatment of oral and esophageal aphthous ulcers and HIV viremia. Investigators will look at viral load and tumor necrosis factor (TNF) levels. To participate, people with HIV need to have had a biopsy within 8 weeks prior to study entry that documents the presence of aphthous ulcers lasting at least 2 weeks, as well as a negative culture for herpes (within the same period). Participants will be randomized to receive 4 weeks of either 200 mg oral thalidomide or placebo once daily. Tuberclosis (Tb) prophylaxis ACTG 177/CPCRA 004 is a Phase II open-label trial that will evaluate the safety and efficacy of 2 different drug regimens for the prevention of Tb. Participants will be randomized to receive either rifampin and pyrazinamide for 2 months, or isoniazid and vitamin B6 for 1 year. Persons with active Tb, acute hepatitis and/or severe peripheral neuropathy and pregnant women will be excluded. There are multiple sites. Clinical Trials Information by Region SOUTHERN CALIFORNIA HIV TREATMENT DIRECTORY 213-469-5888 AIDS/HIV TREATMENT DIRECTORY FOR NEW ENGLAND 617-566-4004 NEW YORK, CONNECTICUT, NEW JERSEY AND PHILADELPHIA 212-268-4196 AIDS Institute Experimental Treatment Infoline in New York state: 800-MEDS-4-HIV outside New York: 212-239-5523 DIRECTORY OF WISCONSIN HIV/AIDS CLINICAL TRIALS in Wisconsin: 800-359-9272 outside Wisconsin: 414-291-2799 NORTHERN GEORGIA and ALABAMA 404-874-7926 SOUTH FLORIDA Community Research Initiative of South Florida, Inc. 305-667-9296 GULF COAST REGION 504-584-3605 HOUSTON CLINICAL TRIAL NETWORK 713-520-2083 CANADIAN HIV TRIAL NETWORK 604-631-5327 ACTIVELY RECRUITING U.S. TRIALS AmFAR Treatment Directory 212-682-7440 SAN FRANCISCO BAY AREA 415-476-9554 ------------------------------------------------------------------ GLOSSARY A ACCELERATED APPROVAL: FDA regulations governing early marketing approval of promising drugs for life-threatening illnesses. To receive accelerated approval a drug need not show evidence of clinical benefit (e.g., increased survival or decreased disease progression), but rather "reasonable promise" of benefit based on surrogate marker data such as CD4 cell count and HIV burden (viral load). ACTIVE IMMUNIZATION: a process by which a person is innoculated with an antigen with the expectation that the body's own immune system will mount an immune response to that antigen. ACUTE: rapid in onset, aggressive; opposite of chronic. ADJUVANT ANALGESIC: a drug (e.g., antidepressant, steroid) that increases the pain-relieving effects of opioid analgesics or which is used as a principal analgesic for neuropathic pain. ADOPTIVE IMMUNE TRANSFER (ADOPTIVE IMMUNOTHERAPY): the use of a graft of immune tissue (e.g., bone marrow) from a healthy donor to build a replacement immune system in an individual whose immune system has been damaged or destroyed. ADRENAL GLAND: an organ located above each kidney that produces various hormones. The medulla (inner part) of the adrenal gland secretes adrenaline (epinephrine). The cortex (outer part) secretes steroids such as cortisol and certain androgens. AIDS CLINICAL TRIALS GROUP (ACTG): a NIAID-sponsored group of medical centers, known as AIDS Clinical Trials Units (ACTU), that evaluate treatments for HIV disease and associated illnesses. There are 36 adult ACTG sites and 24 ACTG pediatric sites. ALDOSTERONE: a steroid hormone produced by the adrenal gland that is important in potassium and sodium regulation. ALLOGENIC: refers to a graft or transfer from a non-genetically identical but HLA-matched (protein marker-matched) individual. AMEBIASIS: infection with amebas, especially Entamoeba histolytica, which invade the bowel mucosa causing ulceration and bloody diarrhea. Transmission is by contaminated water, oral-anal contact or hand-to-mouth transfer of feces. ANABOLISM: the cellular synthesis of organic molecules; the building of proteins and muscle mass in the body. Anabolic steroids are hormones that promote this process. ANALGESIA: relief from pain. An analgesic is a drug that reduces sensibility to or perception of pain. ANAPHYLACTIC SHOCK: a life-threatening allergic reaction characterized by a swelling of body tissues and a sudden decline in blood pressure. ANDROGEN: a hormone (e.g., testosterone) that has masculinizing effects, including stimulation of the male reproductive organs and development of secondary sex characteristics. ANEMIA: an abnormally low number of red blood cells or a decreased concentration of hemoglobin, resulting in a reduced supply of oxygen to cells and tissues. ANERGY (adjective ANERGIC): the lack of an immune response to a foreign antigen. Anergy may indicate an inability to mount a normal allergic or immune response. ANGULAR CHEILITIS: inflammation, fissures and/or dry sore plaques at the corners of the mouth caused by nutritional deficiencies, candidiasis, etc. ANOREXIA: the lack or loss of appetite for food. ANTIBIOTIC: an agent that inhibits the growth of or destroys microorganisms. ANTIBODY (AB): an immunoglobulin protein secreted by activated plasma cells, which evolve from B-cells, in response to an antigen. The antigen/antibody reaction forms the basis of humoral (TH2) immunity. Neutralizing antibodies destroy or inactivate infectious agents while enhancing antibodies promote infection. ANTICONVULSANT: a drug that reduces or prevents convulsions (seizures or fits) and may be used as an adjuvant analgesic. ANTICYTOKINE: a substance that inhibits the production or action of cytokines. ANTIDEPRESSANT: a drug that acts to elevate the mood and prevent, cure or alleviate mental depression. Antidepressants are also sometimes used as adjuvant analgesic to relieve neuropathic pain. Heterocyclic and tricyclic refer to specific chemical structures. ANTIGEN: any agent or substance that stimulates an immune response. Antigens are often foreign microorganisms such as bacteria or viruses, or the substances they produce. ANTIGENEMIA: the presence of an antigen in the blood. ANTIOXIDANT (DEOXIDANT): a substance that inhibits the oxidation reaction by binding with and neutralizing free radicals and other highly reactive molecules, thus reducing oxidative damage. Some antioxidants are produced by the body, others are available in foods and supplements (e.g., beta carotene, Vitamin E, selenium). ANTIRETROVIRAL: an agent (e.g., AZT, d4T) used to suppress the activity or replication of retroviruses such as HIV. ANTISENSE: a complementary piece of genetic material (DNA or RNA) that binds to another piece of DNA or RNA by base-pairing, and thus prevents that DNA/RNA from being used to synthesize new proteins. HIV antisense therapy (e.g., GEM 91) uses molecules that bind to HIV messenger RNA and block viral replication. ANTISERUM: immune serum; serum that contains antibodies specific to a single antigen. ANTIVIRAL: an agent that interferes with the life cycle of a virus and suppresses its replication. APHTHOUS ULCER: a "canker sore"; a small often painful shallow lesion on the mucous membranes lining the mouth, esophagus or rectum. APOPTOSIS: premature programmed cell death. ARM: a group of participants in a research trial who all receive the same treatment (treatment arm) or placebo (control arm). ARTHRALGIA: pain in a joint. ARTHRALPATHY: destruction or necrosis of the tissues of a joint. ARTHRITIS (plural ARTHRITIDES): inflammation of a joint; rheumatism. ASPERGILLOSIS: a life-threatening infection caused by the fungus Aspergillus. Aspergillosis typically infects the lungs and sinuses, but can spread through the blood to other organs including the brain. Symptoms include fever, chills, difficulty breathing, coughing up blood and possibly dementia. ASSAY: a test used to detect the presence and/or concentration of a drug, substance or microorganism in body fluids or tissues. ASYMPTOMATIC: not feeling or showing outward signs of disease despite the presence of a disease-causing agent. ATAXIA: reduced voluntary muscle coordination and ability to control movement, possibly indicating a nerve disorder. ATROPHY (adjective ATROPHIC): progressive degeneration or wasting, especially the loss of muscle tissue. ATTENUATE: to weaken or reduce virulence. An attenuated virus has a diminished ability to cause disease. AUTOIMMUNE RESPONSE (AUTOIMMUNITY): a condition in which an individual's immune system fails to recognize its own biochemical markers as being "self" and attacks body tissues as if they were foreign matter. AXONOPATHY: destruction or death of the axon, the long structure of nerve cells that acts as a pathway for nerve impulses. AZOLE DRUG: a class of drugs (e.g., itraconazole, fluconazole, ketoconazole) used to treat fungal infections. B B-CELL (B-LYMPHOCYTE): an immune system cell that carries out the humoral immune response. B-cells are produced in the bone marrow and spleen, and mature into plasma cells that produce antibodies. BACTEREMIA: the presence of bacteria in the blood. BASELINE: a known value to which later measurements can be compared, e.g., baseline CD4 cell count. BETA-2 MICROGLOBULIN (B2M): a cell surface protein that is released into the bloodstream when cells die. Elevated blood levels are associated with immune activation and HIV replication. BIOAVAILABILITY: the extent to which a substance (e.g., a drug) is absorbed and circulated in the body; the physiological availability of a drug, as distinct from its chemical potency. BIOPSY: the surgical removal of a small piece of tissue for microscopic examination and/or culture. BIOTECHNOLOGY: industrial processes that involve the use of biological systems, including the use of genetically engineered organisms and recombinant molecules. BLASTOMYCOSIS: an uncommon infection caused by the fungus Blastomyces dermatitidis. Infection typically begins in the lungs and may become disseminated; symptoms may include skin lesions and fever. BLINDING: the process of preventing patients and/or healthcare providers from knowing whether the patient is taking active drug or placebo in order to reduce bias in drug trials. BONE MARROW TRANSFER (BMT): a graft of bone marrow, the spongy tissue in the interior of bones that is responsible for producing blood cells, from one individual to another to reconstitute the recipient's damaged immune system. BRANCHED DNA ASSAY (BRANCHED CHAIN DNA, bDNA): an assay (test) for measuring viral load in plasma or tissue by measuring a chemical signal produced by viral RNA. bDNA testing can be used to evaluate the effectiveness of anti-HIV drugs and to gauge disease progression. C CACHEXIA: a condition of body wasting and general ill-health. CAMPYLOBACTER: a family of bacteria that may cause acute illness in the small intestine characterized by diarrhea, abdominal pain, nausea, vomiting, fever and bloody diarrhea. Campylobacter is frequently found in undercooked poultry and in raw or unpasteurized milk and milk products. CANDIDA: A genus of yeast-like fungi. Several species can cause infection in humans, including C. albicans, C. glabrata, C. parapsilosis, and C. krusei. CANDIDIASIS: a fungal disease caused by a Candida species, typically C. albicans. Candidiasis can affect the skin, nails and mucous membranes throughout the body including the mouth, esophagus, vagina, intestines and lungs. Oral and vaginal candidiasis may be early signs of immune impairment in HIV positive individuals. CATABOLISM: the breakdown of bodily proteins for energy and raw materials. CD4 CELL (CD4 LYMPHOCYTE, T-HELPER CELL, T4 CELL): a subset of white blood cells that carry the CD4 cell surface marker and help the body fight infection. CD4 cells engulf and process invaders (e.g., viruses) and display pieces for recognition by disease-fighting cells (e.g., cytotoxic T-lymphocytes). CD4 cells release cytokines that coordinate a broad range of immune activity including killer cell activation and antibody production. HIV invades CD4 cells, typically resulting in their dysfunction or destruction. CD4 CELL COUNT (T-HELPER CELL COUNT): the number of CD4 lymphocytes present in a cubic millimeter (mm3) of blood. The CD4 count is one indicator of the severity or progression of HIV disease and is sometimes used as a surrogate marker. In healthy adults CD4 cell counts range from 400-1800 cells/mm3; counts are considerably higher in healthy children. In adults, severe immune suppression is associated with CD4 cell counts below 200 cells/mm3. CD4 (OR CD8) CELL PERCENTAGE: the number of CD4 (or CD8) cells as a percentage of all lymphocytes. Cell percentage is a more consistent and reliable measure than absolute cell count. CD4/CD8 RATIO: the ratio of CD4 cells to CD8 cells. In healthy individuals the CD4/CD8 ratio is about 2; in individuals with HIV disease the ratio typically eventually drops below 1. CD8 CELL (CD8 LYMPHOCYTE, T8 CELL): a type of white blood cell that helps regulate and/or carry out the body's immune response. There are 2 major subsets of T-cells that express the CD8 surface marker: T-suppressor cells and cytotoxic T-lymphocytes (CTL). CEILING EFFECT: the phenomenon in which a drug reaches a maximum effect, so that increasing the amount of drug taken does not increase its effectiveness. CELL-MEDIATED IMMUNITY (CELLULAR IMMUNITY, TH1 RESPONSE): the immune response mediated by the TH1 subset of CD4 cells. Cell-mediated immunity is stimulated by the cytokines IL-2, IL-12 and gamma interferon and carried out by CD8 cytotoxic T-cells (CTL) and macrophages. Contrast with humoral immunity. CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC): the U.S. federal government agency within the Department of Health and Human Services that monitors disease occurrence and develops policies for preventing diseases and maintaining the health of the population. CENTRAL NERVOUS SYSTEM (CNS): the brain and spinal cord. CEREBROSPINAL FLUID (CSF): a clear, nutrient-rich fluid that circulates around and through the brain and around the spinal cord. CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN): abnormal growth of cells of the uterine cervix; may be an early stage of cervical cancer. HIV infection is associated with an increased risk of CIN. CERVICITIS: inflammation of the uterine cervix. CHANCRE: a primary sore or lesion that forms at the site of entry of a microorganism. CHANCROID: a sexually transmitted disease, caused by infection with Haemophilus ducreyi, that results in soft chancres or ulcers. CHEMOTHERAPY: the use of chemical agents to treat disease. CHLAMYDIASIS (CHLAMYDIA): an infection, usually sexually transmitted, with the bacterial parasite Chlamydia trachomatis. The infection may be asymptomatic or include symptoms such as genital inflammation and discharge, pelvic pain and fever. If left untreated, it may result in pelvic inflammatory disease (PID), ectopic pregnancy and death. CHRONIC: less intense, slow, persisting over a long period of time; opposite of acute. COCCIDIOIDOMYCOSIS: a fungal disease acquired by inhaling dust particles containing spores of Coccidioides immitis characterized by lesions in the upper respiratory tract and lungs. The disease sometimes disseminates to visceral organs, bones, skin and other tissues. The infection may be benign and self-limited or virulent and severe. COFACTOR: a substance, microorganism or environmental factor that activates or enhances the action of a disease-causing agent. Some possible cofactors in AIDS are mycoplasma, herpesviruses and age. COHORT: a group of individuals in a study who share a statistical factor. COLITIS: inflammation of the colon, or large bowel. COLONY STIMULATING FACTOR (CSF, G-CSF, GM-CSF): a cytokine responsible for controlling the production of white blood cells. Types include granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are used to relieve neutropenia caused by drugs such as AZT and ganciclovir. COLPOSCOPY: examination of a tissue surface (particularly the uterine cervix) with a low-power microscope (colposcope) to identify abnormal cell growth and, if necessary, remove a tissue sample for biopsy. COMPASSIONATE USE: an FDA classification that allows the use of an experimental drug for a serious illness for which there is no other suitable treatment. CONDYLOMATA ACUMINATA: genital and/or anal warts caused by infection with the human papillomavirus (HPV). Condylomata acuminata is typically sexually transmitted and may be particularly aggressive (more numerous and/or more frequent) in people with HIV disease. CONTRAINDICATION: any circumstance or symptom that makes a method of treatment inadvisable in a particular case. CONTROLLED TRIAL: a clinical trial in which a group receiving an experimental therapy is compared to a control group that is not given the intervention under study. In a placebo-controlled trial the control group is given an inactive substance (placebo); in an active control trial the control group is given the best existing proven therapy. CORTICOSTEROID: one of a group of steroid hormones produced by the cortex (outer part) of the adrenal gland or manufactured synthetically. Corticosteroids have anti-inflammatory and immunosuppressive effects. CORTISOL: a steroid hormone secreted by the adrenal cortex as part of the body's response to stress. Cortisol promotes the breakdown of bodily tissues and high levels are associated with reduced immune function. Synthetic cortisol (hydrocortisone) is used to reduce inflammation and lessen allergic reactions. CPCRA (TERRY BEIRN COMMUNITY PROGRAMS FOR CLINICAL RESEARCH ON AIDS): a community-based clinical trials network sponsored by NIAID. CPCRA conducts Phase II and III studies in community settings with a focus on new treatments for opportunistic infections, particularly in underserved populations. CROHN'S DISEASE: a type of enteritis, an inflammation of the intestines. CROSS-RESISTANT: development of resistance to one agent which also confers resistance to another (often similar) agent. CRYPTOCOCCOSIS: an infection caused by a yeast-like fungus, typically Cryptococcus neoformans, which is found in soil and bird excreta. A common manifestation is cryptococcal meningitis (CM), an inflammation of the membranes surrounding the brain and spinal cord; cryptococcosis may also become disseminated. Symptoms may include nausea, fever, headache, vision and speech difficulties, changes in mental status. Untreated CM can lead to coma and death. CRYPTOSPORIDIOSIS: a disease caused by the protozoa Cryptosporidium parvum, which is transmitted to humans by contact with animal feces, ingestion of contaminated food or water or oral-anal sexual contact (rimming). The protozoa grows in the intestines and bile ducts and causes severe, chronic diarrhea, gas, weight loss and lymphadenopathy. Cryptosporidiosis may be persistent and life-threatening in immunosuppressed individuals. CUTANEOUS: pertaining to the skin. CYTOKINE: an intercellular hormone or chemical messenger protein (e.g., interleukin, monokine) released by white blood cells including macrophages, monocytes and lymphocytes. Cytokines facilitate communication among immune system cells and between immune system cells and the rest of the body. CYTOMEGALOVIRUS (CMV): a virus of the herpes family. CMV infection often occurs in healthy individuals without causing symptoms. In individuals with HIV disease, CMV may cause serious illness including retinitis, pneumonia, colitis and encephalitis, sometimes resulting in blindness or death. CYTOPATHOGENICITY: ability to cause disease in cells. CYTOTOXICITY: the quality of being toxic to or killing cells. CYTOTOXIC T-LYMPHOCYTE (CTL, T-KILLER CELL): an immune system white blood cell that targets and kills cells infected with viruses, bacteria, parasites and other microorganisms. CTL action is coordinated by CD4 cells via the production of cytokines. D DEHYDROEPIANDROSTERONE (DHEA): a weak androgenic steroid produced by the adrenal cortex. DHEA is decreased in people with HIV disease and is under study as an anti-HIV treatment and as a therapy for wasting syndrome. DELAYED-TYPE HYPERSENSITIVITY (CELL-MEDIATED HYPERSENSITIVITY): a cell-mediated immune response that produces a local reaction characterized by redness and induration (hardness) 48-72 hours after exposure of the skin to an antigen. DEMENTIA: chronic loss of mental capacity that affects a person's ability to function in a social or occupational setting, including the progressive deterioration of thinking, memory, behavior, motor skills and possibly associated psychological symptoms such as depression and apathy. DEMYELINATING NEUROPATHY: a type of nerve damage that involves demyelination, the destruction or loss of the lipid myelin sheath that surrounds and insulates the axons of nerve cells and is necessary for the proper conduction of nerve impulses. DENDRITIC CELLS: immune system cells found in the skin and mucosal linings. Dendritic cells are the first to arrive at sites of injury or infection, where they bind to invaders and transport them to the lymph nodes. Dendritic cells may be the first to be infected by HIV during primary infection. DERMATITIS: inflammation of the skin. DERMATOPHYTOSIS: a variety of infections (e.g., tinea pedis, or athlete's foot) caused by dermatophytes, a type of fungal organism. DESENSITIZATION: the reduction of sensitivity or allergic reactions to an antigen or drug by administering a very small amount and gradually increasing the dose. DIABETES: a disease characterized by excessive urination. Diabetes mellitus is caused by lack of insulin production or lack of responsiveness to insulin, resulting in hyperglycemia (high blood sugar). Diabetes insipidus is typically due to hormonal dysregulation. DISSEMINATE: to spread; a disseminated infection is distributed throughout the body, possibly causing symptoms in multiple sites. DNA (DEOXYRIBONUCLEIC ACID): a molecule found in the nucleus of cells that encodes genetic information. The particular sequence of the 4 chemical building blocks (nucleotides) that make up a DNA chain determines the unique genetic code of an individual. See also RNA. DOUBLE-BLIND: a type of clinical trial in which neither the subject nor the observer knows what treatment, if any, the subject is receiving. At the end of the experiment the "code" is broken and data are analyzed. Double-blinding is done to minimize bias due to the expectations of the patient, the investigator and healthcare providers. DYSPAREUNIA: painful sexual intercourse. DYSPHAGIA: difficult or painful swallowing. DYSPLASIA: abnormal development or growth of cells and tissues; precancerous tissue changes. DYSPNEA: difficult or labored breathing. DYSREGULATION: interruption of, or interference with, normal processes. DYSURIA: difficult or painful urination. E EDEMA: swelling caused by an abnormal accumulation of fluid in body tissues. EFFICACY: effectiveness, efficiency; the ability to achieve a desired effect. ELECTROLYTE: an electrically charged compound (e.g., sodium, potassium) found in body fluids, tissues and cells. An imbalance of electrolytes can result from prolonged vomiting and diarrhea and may lead to the disruption of many bodily processes. ELECTROMYOGRAPHY (EMG): a method of recording the electrical activity of muscles. -EMIA: suffix referring to the presence of a substance or component in the blood, e.g., hypocalcemia (low levels of calcium in the blood), viremia (presence of virus in the blood). ENCEPHALITIS: inflammation of the brain. ENCEPHALOPATHY: any disease of the brain. ENDOCARDITIS: inflammation of the inner membranes of the heart. ENDOCRINE SYSTEM: a system of ductless glands that regulates bodily functions via hormones secreted into the bloodstream. The endocrine glands include the hypothalamus, pituitary gland, thyroid, adrenal glands and gonads (ovaries and testes). ENDOMETRIUM: the mucous membrane that lines the uterus. ENDOSCOPY: a method of examining the interior of a body cavity or hollow organ (e.g., upper gastrointestinal tract) using a flexible fiber optic instrument (endoscope) that transmits light. ENDPOINT: a direct marker of disease progression, e.g., disease symptoms or death. The effectiveness of drug therapies is often determined by observing the clinical endpoints that develop over time in patients undergoing experimental treatment. Contrast with surrogate marker. ENGRAFTMENT: transfer of tissue or organs from one individual to another; transplant. ENTERITIS: inflammation of the intestines, especially the small intestine. EOSINOPHIL: a type of white blood cell that plays a role in allergic reactions and defense against parasites. EOSINOPHILIC FOLLICULITIS: a rash of itchy pimple-like red bumps on the face, arms, chest and back. The cause is unknown, but has been associated with Demodex mites and Pityrosporum yeast. EPIDEMIOLOGY: the study of the frequency, distribution and behavior of a disease in a population. EPSTEIN-BARR VIRUS (EBV): a virus of the herpes family. EBV infection is common and usually asymptomatic in childhood, and may cause infectious mononucleosis in young adults. EBV is associated with hairy leukoplakia, some types of lymphoma and AIDS-related muscle cell tumors. ERYTHEMA (adjective ERYTHEMATOUS): an inflammatory redness of the skin. ERYTHROCYTE: a mature red blood cell that contains hemoglobin. Erythrocytes transport oxygen and carbon dioxide between the lungs and the tissues of the body. ESOPHAGEAL CANDIDIASIS: a fungal infection of the esophagus that may cause painful swallowing and lead to weight loss; an AIDS-defining opportunistic infection. ESOPHAGITIS: inflammation of the esophagus; symptoms may include "heartburn" (regurgitation of stomach acid) and painful or difficult swallowing. ESOPHAGUS (adjective ESOPHAGEAL): the swallowing tube, the portion of the digestive canal between the oral cavity and the stomach. ESTROGEN: the female sex hormone; a natural or synthetic substance (e.g., estradiol) that stimulates the development of secondary sex characteristics and regulates the reproductive cycle in women. ETIOLOGY: the cause of a disease; the study of causes of disease. EXPANDED ACCESS: an FDA program that distributes experimental drugs free of charge through physicians to people with life-threatening illness who have failed on, or are intolerant of, approved therapies and have no other treatment options. F FALLOPIAN TUBE: oviduct; 1 of the 2 tubes leading from the ovaries to the uterus through which an ovum (egg) travels. FIRST-LINE TREATMENT: the preferred standard therapy for a particular condition. FLORA: the plant and/or bacteria species that inhabit a particular environment, e.g., intestinal flora. FLORID: refers to a skin lesion having a bright red color. FOLLICLE STIMULATING HORMONE (FSH): a hormone produced by the pituitary gland that stimulates the ovarian follicles to mature and produce ova (eggs) in women and induces sperm production in men. FOOD AND DRUG ADMINISTRATION (FDA): the agency of the federal government responsible for regulating the development, use and safety of drugs, medical devices, food, cosmetics and related products. FUNGEMIA: the presence of fungi in the blood. FUNGUS: a class of organisms that includes yeasts, molds and mushrooms, several of which can cause disease in humans, e.g., candidiasis, cryptococcal meningitis and histoplasmosis. G GAMMA GLOBULIN (IMMUNOGLOBULIN G): a type of antibody that provides specific immunity against antigens and is used for passive immunization. GASTRITIS: inflammation of the mucosal lining of the stomach. GENE (adjective GENETIC): the unit of heredity. A gene contains hereditary information encoded in the form of DNA located at a specific position on a chromosome in a cell's nucleus. Genes determine many aspects of anatomy and physiology by controlling the production of proteins. GENE THERAPY: an approach to preventing and/or treating disease by replacing, removing or introducing genes or otherwise manipulating genetic material. Examples include adding a gene to a cell to produce a specific missing protein and using antisense molecules to prevent viral replication. GERMINAL CENTER: a part of the lymph node in which lymphocyte maturation takes place. GIARDIASIS: infection with the protozoan Giardia (e.g., Giardia lamblia), which is spread via contaminated food and water and by fecal-oral contact. Giardia infects the intestines and produces nausea, cramping and diarrhea. GLYCOPROTEIN (GP): a small unit composed of a sugar and a protein molecule that makes up the envelope of HIV (e.g., GP41, GP120, GP160). GONAD: an organ that produces sex cells (ova and sperm), e.g., an ovary or a testis GONADOTROPIN: a hormone (e.g., follicle-stimulating hormone) that acts on the gonads to promote their growth and function. GONOCOCCAL: related to infection with the organism that causes gonorrhea, e.g., gonococcal urethritis, gonococcal vaginitis. GONORRHEA: a sexually transmitted disease caused by the bacteria Neisseria gonorrhoeae. Gonorrhea may be asymptomatic or may include symptoms such as urethritis, discharge, pelvic pain and inflammation of the tissues of the genitals, rectum and/or throat. Untreated gonorrhea may lead to pelvic inflammatory disease in women and may affect other organs such as the heart and brain. GRAFT-VERSUS-HOST REACTION: a situation in which transplanted immune cells (e.g., bone marrow cells) attack the tissues of the new host's body. GROWTH HORMONE (GH, SEROSTIM): a peptide hormone secreted by the anterior pituitary gland. GH enhances growth by stimulating metabolism and protein synthesis and also stimulates the immune system. Recombinant human growth hormone (rHGH) is a genetically-engineered drug under study for the treatment of HIV-related wasting syndrome. GUILLAIN-BARR SYNDROME: an acute disease that produces weakness or paralysis, most commonly in the legs and feet. H HAIRY LEUKOPLAKIA: a condition caused by the Epstein-Barr virus (EBV) and characterized by small, white, hair-like projections on the sides of the tongue. HALF-LIFE: the time required for half the amount of an agent (e.g., drug, virus) to be eliminated from the body. HELPER T-CELL: see CD4 cell. HEMATOCRIT (HCT): the percentage of red blood cells in whole blood; a drop in hematocrit may indicate bone marrow dysfunction. HEPATITIS: an inflammation of the liver that may be caused by several agents including viruses and toxins. Hepatitis is characterized by jaundice, enlarged liver, fever, fatigue and abnormal liver function tests. Hepatitis A (infectious hepatitis) may be transmitted by contaminated food or by fecal-oral and/or household contact. Hepatitis B (serum hepatitis) is transmitted by sexual contact or contaminated blood or blood products. Other types include hepatitis C and alcoholic hepatitis. HEPATOTOXICITY: poisonous to the liver. HERPES SIMPLEX VIRUS (HSV): a herpes virus that causes blisters and recurring disease. HSV-1 usually produces lesions on the lips or in the mouth ("cold sores"). HSV-2 is usually sexually transmitted and its lesions generally occur in the anal and/or genital area. In immunocompromised individuals lesions may last longer and be more frequent and severe, and the virus may become disseminated. Symptomatic disease outbreaks occur at unpredictable intervals of weeks, months or years; reactivation may result from emotional stress, hormonal changes or other illnesses. HERPESVIRUS: a group of viruses that includes herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and human herpesvirus types 6 and 7 (HHV-6, HHV-7). Herpesviruses may act as opportunistic pathogens and/or cofactors in HIV pathogenesis. HERPES ZOSTER (SHINGLES): a skin condition characterized by painful blisters that appear in a linear distribution following nerve pathways. Shingles is caused by reactivation of the varicella-zoster virus (VZV) that causes chickenpox; VZV lies dormant in the nerves and reactivates when immune defenses are weakened. HISTOPLASMOSIS: a fungal infection acquired by inhaling spores of the fungus Histoplasma capsulatum, which are present in soil or dust. The disease is most often found in the lungs, where it produces a tuberculosis-like inflammation, but may also become disseminated; it may be life-threatening in individuals with suppressed immune systems. HLA (HUMAN LEUKOCYTE ANTIGEN): a genetic marker of "self". See major histocompatibility complex. HORMONE: a chemical messenger involved in the regulation and coordination of cellular and bodily functions. See also cytokine, endocrine system. HUMAN CHORIONIC GONADOTROPIN (HCG): a hormone secreted by the placenta that maintains pregnancy during the early development of the embryo. The beta subunit of HCG has been shown to suppress the development of Kaposi's sarcoma cells in vitro. HUMAN HERPES VIRUS-6 (HHV-6): a herpes virus that infects lymphocytes including CD4 cells. HHV-6 infection generally occurs early in life and may cause fever, roseola (a red skin rash) or brain inflammation. HUMAN PAPILLOMAVIRUS (HPV): a member of the papova family of viruses that causes warts, including the sexually transmitted disease Condylomata acuminata (genital warts). Certain strains of HPV (e.g., 16, 18) are associated with cervical, anal and oral cancer. HUMORAL IMMUNITY (ANTIBODY-BASED IMMUNITY, TH2 RESPONSE): the immune response mediated by the TH2 subset of CD4 cells. Humoral immunity is stimulated by the cytokines IL-4 and IL-10, and carried out by plasma cells (derived from B-cells) which produce antibodies. Contrast with cell-mediated immunity. HYPERPLASIA: excessive growth of normal cells (not tumor cells); an increase in the number of normal cells in a tissue or body part which may increase its size. HYPOADRENALISM (ADRENAL INSUFFICIENCY): inadequate adrenal function resulting in low levels of adrenal hormones. HYPOGONADISM: inadequate function of the gonads (ovaries or testes) characterized by deficient hormone secretion and gamete (ova or sperm) production. HYPOTHALAMIC-PITUITARY-GONADAL AXIS (HPG AXIS): a feedback loop that regulates hormone levels. The hypothalamus produces hormones that control secretion of hormones by the pituitary gland, which in turn regulates the activity of the gonads. HYPOTHALAMUS: a gland in the brain that controls and integrates the autonomic nervous system and regulates the production of hormones by endocrine glands. I IATROGENIC: refers to an unfavorable response to medical or surgical treatment or symptoms attributable to a medical therapy, e.g., peripheral neuropathy caused by an antiviral drug. IDIOPATHIC: referring to a disease or condition of unknown cause or origin. IDU (INJECTION DRUG USER): a person who administers a drug (e.g., heroin) with a needle and syringe. Sometimes also referred to as IVDU or intravenous drug user. IMMUNE-BASED THERAPY (IMMUNOTHERAPY, IMMUNE MODULATING THERAPY): a therapy that attempts to modify or enhance immune response or reconstitute a damaged immune system. Examples of immune-based therapies for AIDS include active immunization (vaccination), passive hyperimmune therapy, CD8 cell line expansion and cytokine therapy. IMMUNE MODULATOR (IMMUNOMODULATOR): a substance capable of modifying functions of the immune system. Immune modulators include cytokines (e.g., IL-2, gamma interferon) and broad-acting agents (e.g., hormones such as endorphins). IMMUNE SYSTEM: the body's natural defense system that protects against foreign invaders (e.g., microorganisms) and cancerous cells. Some immune defenses are nonspecific (e.g., phagocyte activity). Defenses against specific antigens are of 2 types: cell-mediated (TH1) and humoral (antibody-based or TH2). Organs of the immune system include the lymph nodes, spleen, thymus, tonsils and bone marrow. IMMUNE THROMBOCYTOPENIC PURPURA (IDIOPATHIC THROMBOCYTOPENIC PURPURA, ITP): an autoimmune disorder in which macrophages attack and destroy the thrombocytes (platelets), resulting in excessive bruising and uncontrolled bleeding. IMMUNIZATION: a process by which a person is protected against the adverse effects of infection by a disease-causing microorganism. IMMUNOENDOCRINOLOGY: a hybrid branch of medicine combining the study of the immune system (immunology) and the study of the endocrine glands and their hormones and effects (endocrinology). IMMUNOGEN: an antigenic agent or substance that stimulates an immune response. IMMUNOGLOBULIN (IMMUNE GLOBULIN, IG): see antibody. IMMUNOSUPPRESSION (IMMUNOCOMPROMISE): reduced function of the immune system; a state in which the immune system defenses have been suppressed or weakened. INFLAMMATION: the body's response to tissue injury or infection, which typically includes increased vessel dilation and permeability resulting in redness, swelling, heat and pain. INSULIN-LIKE GROWTH FACTOR (IGF-1): a substance naturally produced by the body that has many of the same effects as growth hormone. A genetically engineered form of IGF-1 is under study as a therapy for AIDS-related wasting. INTEGRASE: an enzyme produced by HIV that allows the integration of HIV DNA into the host cell's genetic material. INTERFERON: a cytokine (chemical messenger) that plays a role in immune response. Interferons are secreted by infected cells and help protect other cells from infection. There are 3 major classes: alpha, beta and gamma. Synthetic interferons are under study as treatments for HIV infection and other diseases. Interferons may cause flu-like side effects such as fever, aches and anorexia. INTERLEUKIN (IL): a cytokine (chemical messenger) secreted by immune system cells. Various interleukins (e.g., IL-1, IL-2, IL-6, IL-12) regulate a range of immune system functions. See also TH1/TH2 immune response. INTERLEUKIN 2 (IL-2, T-CELL GROWTH FACTOR): a cytokine produced by CD4 and CD8 cells that promotes the activity of natural killer and other cytotoxic cells and is associated with cell-mediated (TH1) immune response. Recombinant IL-2 is under study as a treatment for HIV disease. Side effects include flu-like symptoms and decreased blood pressure. INTOLERANCE: the inability of the body to appropriately metabolize an agent or drug. IN VITRO: Latin for "in glass"; refers to work done in a test tube or culture medium in the laboratory. IN VIVO: Latin for "in the body of a living organism"; refers to work done using human (or animal) subjects. INVOLUTION: shrinkage and decomposition, e.g., lymph node involution involves shrinkage and loss of normal shape and internal structure. K KAPOSI'S SARCOMA (KS): an abnormal proliferation of incomplete blood or lymph vessels of the skin, mucous membranes and/or internal organs. KS typically appears as pink or purple flat or raised lesions on the skin or in the mouth. The cause of KS is unknown, but has recently been associated with a herpesvirus (KSHV). KILLER T-CELL: see cytotoxic T-lymphocyte. L LEUKOCYTE: any white blood cell, including monocytes, CD4 cells, etc. Many leukocytes are involved in the body's defense against infection and disease. LEUKOPENIA: an abnormally low number of white blood cells in the circulating blood. LIPOSOME: a spherical particle of fat suspended in a liquid medium. Liposomes may be used to carry drugs or other substances to cells or tissues. LIVER ENZYME: a protein produced by the liver. Abnormally high levels of liver enzymes in the blood indicate liver damage or disease (e.g., hepatitis, drug-related liver toxicity). Liver enzymes include alanine transaminase (ALT, SGPT) and aspartate transaminase (AST, SGOT). LOG: refers to quantities in factors of 10. A log change is a 10-fold or order of magnitude increase or decrease (e.g., 10 to 100 is a 1 log increase). Changes in viral load are often expressed in terms of logs. LONG TERMINAL REPEAT (LTR): a segment of the HIV gene that must be activated to "turn on" viral replication. LONG-TERM NON-PROGRESSOR (LTNP): an individual who has been infected with HIV for many years (usually defined as 7-10 or more years) but who does not exhibit immune system decline or opportunistic infections. About 5% of persons with HIV disease seem to be LTNP. LTNP may have unusually strong immune responses (e.g., CD8 cell activity), may be infected with a weakened strain of HIV or may have genetic factors (e.g., HLA/MHC markers) that protect them. LONG-TERM SURVIVOR (LTS): an individual who has been infected with HIV for a long period of time (typically 7-10 or more years). The term long-term survivor includes both long-term non-progressors and individuals who live for many years with a damaged immune system and/or opportunistic infections. LUMBAR PUNCTURE (SPINAL TAP): insertion of a needle into the spinal column to remove spinal fluid for diagnosis or to inject anesthesia or medications. LUTEINIZING HORMONE (LH): a hormone that stimulates the final ripening of ova (eggs) and their release. LYMPHATIC SYSTEM (adjective LYMPHOID): a network of capillary-like vessels, ducts, nodes and organs that help maintain the fluid environment of the body and coordinate immune response. The lymphoid organs include the lymph nodes, spleen thymus, tonsils and adenoids. LYMPH NODE: a small, bean-sized organ located throughout the body with concentrations in the neck, groin and armpits. Lymph nodes are the sites of antigen presentation and immune activation. LYMPHOCYTE: a type of white blood cell (e.g., T-cell, B-cell) responsible for immune defense against particular antigens. LYMPHOKINE: a chemical messenger (e.g., interferon, interleukin) produced by lymphocytes that directs and regulates immune responses. LYMPHOPHOKINE-ACTIVATED KILLER CELL (LAK CELL): a type of lymphocyte (neither a T-cell nor a B-cell) that has cytotoxic activity against a broad range of cells. LYSIS: rupture and destruction, e.g., of a cell. M MACROPHAGE: a large scavenger white blood cell that ingests degenerated cells and foreign particles and secretes monokines (messenger proteins) involved in a variety of immune system responses. The long-lived macrophages are a major reservoir of HIV infection. MAINTENANCE THERAPY (SECONDARY PROPHYLAXIS): a preventive therapy that follows successful initial treatment of an illness. Maintenance therapy typically continues for the lifetime of an individual to prevent disease reactivation. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC): cell surface markers (also known as HLA markers) that determine receptor shape and allow immune cells to recognize components of the body (i.e., to distinguish "self" from "non-self"). MHC molecules are necessary for antigen presentation and recognition of antigens by immune system cells. MALABSORPTION: decreased intestinal absorption of nutrients due to damage to the tissues lining the intestinal tract. MARKER: a lab result or symptom observation used to measure a treatment's effectiveness or an individual's immune system status. MAST CELL: a basophil (white blood cell) that has left a blood vessel and entered a tissue. Mast cells release histamine and heparin as part of an allergic reaction. MEMORY T-CELL: a subset of CD4 and CD8 cells that are capable of mounting an immediate immune response to a specific antigen. MENINGITIS: inflammation of the meninges, the membrane envelopes that encase the brain and spinal cord. METABOLISM: the process of building the body's molecular structures from nutrients (anabolism) and breaking them down for energy production (catabolism). METASTASIS (adjective METASTATIC): secondary cancer that has spread from the primary or original site. METHADONE: an oral opioid drug used for pain therapy and to treat heroin and other opiate addictions by preventing withdrawal. MOLLUSCUM CONTAGIOSUM: raised, flesh-colored lesions that contain active poxvirus, appearing most often on the face, neck, arms, legs and anogenital region. The condition is common in HIV positive persons and may be due to a reactivation of an earlier infection. MONILIA: a group of yeast-like fungi related to Candida. MONOCLONAL ANTIBODIES: antibodies that are derived from a single cell or its identical progeny, and are specifically directed against a particular antigen, e.g., anti-cytomegalovirus antibodies. MONOCYTE: a type of white blood cell that plays a role in immune defense. Monocytes leave the bloodstream and migrate into the tissues where they become macrophages. MONONEURITIS MULTIPLEX (MONONEUROPATHY MONOPLEX): a type of neuropathy characterized by inflammation of or damage to several nerves in unrelated parts of the body, leading to asymmetric areas of movement and sensory disturbance. The condition tends to occur during the early stages of HIV infection. MONONUCLEAR CELL: a cell that has one nucleus. Usually refers to a subset of white blood cells, i.e., lymphocytes and monocytes. Peripheral blood mononuclear cells (PBMC) circulate in the blood. MONOTHERAPY: use of a single agent or drug for treatment. MUCOUS MEMBRANE (MUCOSA): a moist layer of semi-permeable tissue lining the gastrointestinal, respiratory and genitourinary tracts. MUTATION: a change in the character of a gene that is perpetuated in subsequent cell divisions. MYALGIA: pain in the muscles. MYCOBACTERIA: an category of gram-positive, acid-fast bacteria that cause diseases such as tuberculosis, leprosy and Mycobacterium avium complex (MAC). MYCOBACTERIUM AVIUM COMPLEX (MAC): a disease caused by Mycobacterium avium or Mycobacterium intracellulare (sometimes referred to as Mycobacterium avium-intracellulare or MAI), bacilli found in soil. In immunosupressed persons the bacteria can infect lymph nodes, bone marrow, liver, spleen, spinal fluid, lungs and the gastrointestinal tract. Symptoms include diarrhea, wasting, fever, fatigue and spleen enlargement. MYCOSIS (adjective MYCOTIC, MYCOLOGICAL): a disease caused by fungus, e.g., candidiasis, cryptococcal meningitis, histoplasmosis. MYELIN: a white fatty substance that forms a sheath around the axons of some neurons (nerve cells) and is necessary for proper neural transmission. MYELOSUPPRESSION: the inhibition of bone marrow activity, causing decreased production of blood cells. MYOPATHY: an abnormality or disease of the muscles that may cause pain or weakness. MYOSITIS: inflammation of skeletal muscle, which may involve muscle degeneration and weakness. N NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID): a component of the National Institutes of Health (NIH) that conducts federally-funded research aimed at preventing, diagnosing and treating illnesses such as AIDS and tuberculosis. NIAID conducts the majority of HIV/AIDS research in the U.S., including the AIDS Clinical Trials Group (ACTG), Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Vaccine Evaluation Group (AVEG). NATIONAL INSTITUTES OF HEALTH (NIH): a large biomedical research organization that is part of the federal U.S. Public Health Service. NIH includes 24 institutes, centers and divisions, several of which perform AIDS-related research. NATURAL KILLER CELL (NK CELL): a type of lymphocyte that attacks and kills cells infected with microorganisms. Unlike cytotoxic T-lymphocytes (CTL), NK cells are non-specific and attack infected cells without regard to their receptor or MHC/HLA configuration. NECROSIS: localized tissue death. NEF: a gene of HIV that influences viral replication; also the protein produced by that gene. NEOPLASM: a tumor or growth; tissue that develops abnormally or grows more rapidly than normal. A neoplasm that does not spread to other tissues is called benign; a neoplasm that has the potential to spread (metastasize) is called malignant or cancerous. NEOPTERIN: a substance produced by macrophages in response to a foreign agent. Neopterin levels are elevated as a result of immune system activation, and have been used to predict HIV disease progression. NEURALGIA: a sharp, shooting pain along a nerve pathway. NEURITIS: inflammation of the nerves accompanied by symptoms of pain and tenderness of surrounding tissue. NEUROPATHY (adjective NEUROPATHIC): any abnormal, degenerative or inflammatory condition of the nerves. See also peripheral neuropathy. NEUTROPENIA: an abnormally low number or a decrease in the number of neutrophils, a type of white blood cell that releases chemicals involved in inflammation and are the primary defense against bacteria and fungi. NEW DRUG APPLICATION (NDA): an application made by a drug sponsor to FDA to request marketing approval after a drug completes Phase III clinical trials. NF-KAPPA B (NF-kB): a regulatory protein that functions to increase cellular metabolic activity and cell division. NF-kB may induce increased HIV gene expression and viral replication. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI): a drug (e.g., nevirapine) that inhibits the action of the retroviral reverse transcriptase enzyme, thus blocking viral replication, yet works in a different way than nucleoside analog drugs. NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSAID): a drug that relieves pain and reduces inflammation and fever, but which is not a steroid or an opioid. NUCLEOSIDE ANALOG (NA): a synthetic compound (e.g., AZT, ddI, ddC, d4T, 3TC) that mimics one of the building blocks of DNA. These compounds suppress retroviral replication by interfering with the reverse transcriptase enzyme; the synthetic nucleosides cause premature termination of the viral DNA chain. O ODYNOPHAGIA: esophageal pain on swallowing. OFF-LABEL: use of an FDA-approved drug for an indication other than that for which the drug was approved. ONYCHOMYCOSIS: a fungal infection that causes the nails to thicken and split. OPEN LABEL: a drug trial in which both participants and investigators know what drug is being tested and what dose is being used. OPIOID (NARCOTIC): a class of drugs (e.g., heroin, codeine, methadone) that are derived from the opium poppy plant, contain opium, or are produced synthetically and have opium-like effects. Opioid drugs relieve pain, dull the senses and induce sleep. OPPORTUNISTIC INFECTION (OI): an illness caused by a microorganism that usually does not cause disease in persons with healthy immune systems, but which may cause serious illness when the immune system is suppressed. Common OI in HIV positive people include cytomegalovirus and Pneumocystis carinii pneumonia (PCP). ORAL CANDIDIASIS: a candidal infection in the mouth, typically characterized by white or red patches on the oral mucosa, tongue, palate or back of the throat. Types include pseudomembranous candidiasis (thrush), chronic atrophic candidiasis (e.g., angular cheilitis) and leukoplakia. OXIDATION: a chemical reaction in which another substance combines with oxygen by giving up an electron. Oxidants or pro-oxidants promote this reaction, while antioxidants inhibit it. OXIDATIVE STRESS: increased levels of free radicals and other oxidation-promoting molecules associated with disease, immune response and aging. When the production of pro-oxidants exceeds the cellular supply of antioxidants, harmful effects may result including cell membrane damage, cell death and damage to genetic material (DNA and RNA) resulting in mutations. P p24: a core protein of HIV produced by the gag gene. The p24 antigen test detects the p24 protein fragment in blood or tissues; a positive result indicates that HIV is actively replicating and predicts disease progression. The p24 antibody test measures the amount of antibodies against the p24 antigen; high levels of p24 antibody in the absence of p24 antigen may indicate that the immune system is successfully suppressing the virus. PANCREATITIS: inflammation of the pancreas, a digestive gland in the abdominal cavity. Symptoms may include intense pain, nausea, constipation and possibly jaundice. Pancreatitis is a side effect of some anti-HIV drugs (e.g., ddI). PAP SMEAR (PAPANICOLAOU SMEAR): a specimen of cells taken from the uterine cervix or anus, prepared on a slide and examined under a microscope for abnormal cell growth and development (dysplasia). PARALLEL TRACK: a system of distributing experimental drugs to individuals who are unable to participate in ongoing clinical trials. Parallel track drugs have completed Phase I safety testing and show enough evidence of efficacy to merit wider release. PARASITE: an organism that lives on or in the body of a host and derives nourishment from it. Some parasites can cause disease, especially in people with weakened immune systems. Human parasites include fungi, yeast, bacteria, protozoa, worms and viruses. PARESTHESIA: abnormal physical sensations, e.g., prickling or tingling. PARENTERAL NUTRITION: a regimen that delivers nutrients intravenously, bypassing the enteral (gastrointestinal) tract. Partial parenteral nutrition (PPN) delivers some nutrients orally and some intravenously; total parenteral nutrition (TPN) delivers all nutrient intravenously, typically via a chest catheter. PARONYCHIA: inflammation and separation of the skin from the base of the nails. PASSIVE IMMUNIZATION: a process in which a person is given antibodies (gamma globulins) produced by a source other than their own immune system, e.g., manufactured or transferred from individuals with active immunity. PATHOGEN (adjective PATHOGENIC): any disease-causing agent, especially a microorganism. PATHOGENESIS: the development of a particular disease, including the specific events involved, bodily tissues or systems affected, mechanisms of damage and timing of the course of disease. PATHOLOGY (adjective PATHOLOGIC): the study of disease, focusing on causes, development and progress, and how the body is affected. PELVIC INFLAMMATORY DISEASE (PID): a condition affecting the upper female reproductive tract including the uterus, fallopian tubes and ovaries. PID may result from untreated chlamydiasis or gonorrhea. Without treatment PID can become chronic and may lead to extreme pain, infertility, sepsis and death. PERINATAL: referring to the period around the time of birth. PERIPHERAL NEUROPATHY: a disorder of the nerves usually involving the feet and/or hands and sometimes the legs, arms and face. Symptoms may include numbness, a tingling or burning sensation, sharp pain, abnormal reflexes, weakness and partial paralysis. Peripheral neuropathy can be a side effect of some anti-HIV drugs (e.g., ddC, ddI, d4T). pH: a logarithmic scale used to describe the acidity or alkalinity of a solution. Water has a neutral pH of 7. A pH is below 7 is acidic; a pH above 7 is alkaline (or basic). PHARMACOKINETICS: the action of drugs in the body, including the processes of absorption, transformation, distribution to tissues, duration of action and elimination. PHARMACOLOGY: the science of drugs, their sources and how they work; the specialty of preparing and dispensing drugs. PHARYNGITIS: pain and inflammation of the pharynx (throat), the upper part of the gastrointestinal tract between the oral cavity and the esophagus. PHASE I TRIAL: the first step in human testing of a new drug; these trials evaluate drug safety and toxicity at different dose levels in a small number of volunteers. PHASE II TRIAL: the second step in the evaluation of a new drug in humans; these trials evaluate drug effectiveness and involve more participants than Phase I studies. Phase II studies proceed only if Phase I studies have shown that a drug is acceptably safe. PHASE III TRIAL: the third step in human drug testing; these trials are designed to support and verify information gathered in Phase I and II trials and involve many more volunteers (up to several thousand). Phase III trials may compare the drug being tested to other therapies or to placebo. PHOTOTHERAPY: treatment using light, typically ultraviolet light. PITUITARY GLAND: a small gland in the brain that produces several hormones that regulate bodily functions via their effects on other endocrine glands. PLACEBO-CONTROLLED TRIAL: a trial of an experimental therapy in which an inert, inactive substance (placebo) is given to one group while the treatment being tested is given to another, and the results for the different groups are compared. Placebo is used to make the experience of the treatment and control groups as similar as possible and to minimize bias due to the expectations of the patient. PLASMA: the fluid, non-cellular portion of circulating blood that carries blood cells and nutritive substances throughout the body, removes metabolic wastes and is a medium for chemical communications between different parts of the body. PLATELET: see thrombocyte. PNEUMOCYSTIS CARINII PNEUMONIA (PCP): a life-threatening type of pneumonia thought to be caused by a protozoan. PCP is a common opportunistic infection and a leading cause of death in people with AIDS. POLYCLONAL ANTIBODIES: antibodies derived from more than one clone of cells and having specificity for a variety of different antigens. POLYMERASE CHAIN REACTION (PCR): a highly sensitive test that uses an amplification technique to detect minute amounts of DNA or RNA in blood or tissue samples. POLYNEUROPATHY: damage to the peripheral nervous system. Two types are common in persons with HIV infection: inflammatory demyelinating polyneuropathy, which involves the destruction of the myelin sheath surrounding the neurons, and sensory axonal polyneuropathy. Symptoms may include weakness and painful tingling or burning sensations. See also peripheral neuropathy. POST-HERPETIC NEURALGIA (PHN): the often severe pain that sometimes follows the healing of herpes zoster (shingles) lesions. PPD TEST (PURIFIED PROTEIN DERIVATIVE): a test that uses an injection of tuberculin to test for prior exposure to Mycobacterium tuberculosis, which is indicated by induration (redness and swelling) at the injection site. PRIMARY INFECTION: the initial introduction of an infection into the body of a host. Primary (or acute) HIV infection may be characterized by flu-like symptoms including fever, malaise, enlarged lymph glands and possibly a sore throat or rash. PRN: given as needed (from the Latin pro re nata). PROCTITIS: inflammation of the mucous membranes of the rectum. PRODRUG: a drug that exerts its effects after metabolic changes within the body convert it to a usable or active form. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): a progressive brain disease thought to be caused by the Jacob-Creutzfeldt (JC) papovavirus. PML infects oligodendrocytes (support cells in the brain) and leads to defective nerve signal transmission. Symptoms include changes in mental status, speech and vision difficulties, limb weakness, partial paralysis and loss of coordination. PML progresses rapidly and is often fatal. PROPHYLAXIS: a treatment that helps to prevent a disease or condition before it occurs (primary prophylaxis) or recurs (secondary prophylaxis). PROSPECTIVE STUDY: a study that looks forward in time. Patients are selected and their progression is followed. A prospective cohort study follows a specific group of patients over a period of time. Contrast with retrospective study. PROTEASE INHIBITOR: a drug (e.g., saquinavir, Crixivan, ABT-538) that blocks the action of the protease (proteinase) enzyme that breaks up large proteins produced from viral RNA, thereby preventing HIV replication. PROTOZOAN: a group of acellular or one-celled microorganisms, some of which can cause disease in humans. PRURITUS: a condition characterized by itching. PSYCHONEUROIMMUNOLOGY (PNI): the study of how psychological processes, mental states and the nervous system affect immune system function. PSYCHOTROPIC: an agent (e.g., thorazine) that affects psychic or mental functioning, behavior or experience. PULMONARY: relating to the lungs. PURPURA: discoloration due to bleeding beneath the skin. PURULENT: characterized by the accumulation of pus. Q QUANTITATIVE COMPETITIVE POLYMERASE CHAIN REACTION (QC-PCR): a refined and more sensitive version of the PCR assay used to detect DNA or RNA. R RANDOMIZED TRIAL: an experiment arranged so as to produce a chance distribution of subjects into different treatment groups or arms. Randomization is intended to cancel out factors that aren't specifically being studied in an effort to obtain unbiased data. RECEPTOR: a specific protein-binding site on a cell's surface or interior. When chemical messengers bind to receptors, various cellular functions are activated or inhibited. Many drugs exert their effects by binding to receptors and altering normal cellular communication. Viruses enter cells by fusing with receptors on the cell surface and then passing into the interior of the cell. RECOMBINANT: produced by genetic engineering in the laboratory. REFRACTORY: resistant to treatment. REITER'S SYNDROME (REACTIVE ARTHRITIS): an autoimmune disorder characterized by the simultaneous occurrence of arthritis, urethritis (inflammation of the urethra) and conjunctivitis (inflammation of the outer membrane of the eye). The syndrome may occur following other diseases such as chlamydiasis or salmonellosis. REPLICATION: duplication or reproduction. RESCUE MEDICATION: a strong, short-acting analgesic given to control acute episodes of breakthrough pain in a patient on a continuous pain management regimen. RESISTANCE: the ability of a microorganism (e.g., a virus) to lose its sensitivity to a drug. Microorganisms mutate in a way that allows them to function and reproduce despite the presence of a drug. RETINAL DETACHMENT: a condition in which a layer of the retina separates from the underlying epithelium, allowing vitreous fluid to seep behind the retina, resulting in loss of vision. RETINITIS: inflammation of the retina, the light-sensitive tissue at the back of the eyeball that transmits visual impulses via the optic nerve to the brain. RETROSPECTIVE STUDY: a study based on the medical records of patients, looking backward in time at events that happened in the past. A retrospective cohort study uses the records of a specific group of patients. Contrast with prospective study. RETROVIRUS: a class of enveloped viruses that have their genetic material in the form of RNA and use reverse transcriptase to translate their RNA into DNA. The retrovirus family includes oncoviruses (e.g., HTLV-1) and lentiviruses (e.g., HIV-1, HIV-2). REVERSE TRANSCRIPTASE (RT): a viral enzyme that allows a retrovirus to translate its genetic material, in the form of RNA, into DNA which is then integrated into the chromosomes of the host cell. REVERSE TRANSCRIPTASE INHIBITOR (RTI): a drug that blocks retroviral replication by interfering with the reverse transcriptase enzyme. RTI include nucleoside analogs (e.g., AZT, ddI) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine). RHEUMATOLOGY (adjective RHEUMATOLOGICAL): the study of various conditions (e.g., arthritis) involving pain or other disorders of the joints, RIBOZYME: RNA with enzymatic activity that can break down (cleave) and piece together (splice) genetic material (DNA or RNA), thus modifying the genetic instructions it carries. Ribozymes are used as "molecular scissors" in genetic engineering. RNA (RIBONUCLEIC ACID): a single-stranded nucleic acid made up of nucleotides. RNA is involved in the transcription of genetic information from DNA; the information encoded in DNA is translated into messenger RNA (mRNA), which controls the synthesis of new proteins. RNA takes the place of DNA in retroviruses such as HIV. S SALMONELLOSIS: infection caused by Salmonella, rod-shaped bacteria commonly found in raw meat, poultry, eggs and raw or unpasteurized milk and milk products. The 3 forms of salmonellosis in humans are typhoid fever, septicemia and acute gastroenteritis (inflammation of the stomach and intestinal tract). SALVAGE THERAPY: emergency treatment with an experimental drug of a disease or illness that has not responded to standard therapy. SCABIES: an intensely itchy rash due to an inflammatory hypersensitivity reaction to the parasitic mite Sarcoptes scabieri. SEBORRHEA (SEBORRHEIC DERMATITIS): a common scaly eruption or rash, often itchy, that occurs on the scalp, face, chest or scrutum. Seborrhea may have an underlying fungal component, and may be severe in individuals with advanced HIV disease. SECOND-LINE TREATMENT: the second preferred therapy for a particular condition; used when the patient fails or cannot tolerate the first-line treatment. SEPSIS: the presence of pathogenic (disease-causing) organisms or their toxins in the blood or tissues, and the associated bodily reactions. SEQULAE: conditions resulting from a disease or injury. SEROCONVERSION: the change in a person's antibody status from negative to positive. SEROSTATUS (ANTIBODY STATUS): the presence or absence of antibodies in the blood serum. If antibodies are present, a person is said to be seropositive; if no antibodies can be detected, they are said to be seronegative. SEROTONIN: a neurotransmitter that has many effects, including blood vessel constriction and smooth muscle stimulation. SERUM: the fluid portion of blood after coagulation; lymphatic fluid. SHIGELLOSIS: infection caused by Shigella, a family of rod-shaped bacteria. Shigellosis can cause digestive disturbances ranging from mild diarrhea to severe dysentery. SHINGLES: see herpes zoster. SIMIAN IMMUNODEFICIENCY VIRUS (SIV): a viral infection endemic to African green monkeys and similar to HIV-2. SPECIFICITY: a statistical measure of the accuracy of a screening test, i.e., how likely a test is to label as negative those who do not have a disease or condition. Contrast with sensitivity. STANDARD THERAPY: a therapy that is FDA-approved for a given condition and is widely used as first-line treatment. STEM CELL: a precursor cell from which all blood cells are derived. As they mature, stem cells evolve into various types of red and white blood cells. Bone marrow, the site of blood cell production, is rich in stem cells. STEROID: a family of substances that share a similar chemical structure, including some hormones (e.g., testosterone), Vitamin D and various drugs. Steroid drugs are used to lessen inflammatory reactions. STEROIDOGENESIS: the production of steroid hormones. STRAIN: a specific genetic variant of a particular organism. SUBCUTANEOUS: beneath the skin; subdermal. SUBTYPE: a subspecies of microorganism. There are 8 known subtypes of HIV-1: A through G and O. SURROGATE MARKER: a marker or sign that can serve in place of a clinical endpoint. Surrogate markers for HIV disease may be virologic (e.g., p24 antigen level, viral load), immunologic (e.g., CD4 cell count, cytokine levels) or clinical (e.g., weight loss). SYNCYTIUM (plural SYNCYTIA): a mass of cells which fuse together to form one "giant cell." In HIV infection this may lead to direct cell-to-cell infection. Strains of HIV are classified as either syncytium-inducing (SI) or non-syncytium-inducing (NSI). SYNERGY (SYNERGISM): the action of 2 or more agents (e.g., drugs) working together that produce an effect greater than the combined effect of the same agents used separately. SYPHILIS: a disease caused by the spirochete bacterium Treponema pallidum. Stages of syphilis are primary (an initial chancre in the mouth or anogenital area) secondary (a generalized rash which occurs several weeks to a year later), dormant and tertiary (which may affect many organs including the brain, leading to dementia [neurosyphilis] and death). SYSTEMIC: affecting the whole body; not localized. T TAT: a gene of HIV that plays a role in viral replication; also the protein produced by that gene. T-CELL (T-LYMPHOCYTE): a type of white blood cell derived from the thymus that participates in a variety of cell-mediated immune responses. There are 3 major types of T-cells: T-helper (CD4), T-suppressor (CD8) and T-killer (cytotoxic T-lymphocytes or CTL). TERATOGENICITY: the ability to cause malformation of the fetus. TESTOSTERONE: a steroid hormone produced by the testes, essential for sperm production and the development of reproductive organs and secondary sexual characteristics in males. Testosterone is under study as a therapy for HIV-related wasting syndrome. TH1/TH2 IMMUNE RESPONSE: 2 branches of the immune system. The TH1 response involves a subset of CD4 lymphocytes called TH1 cells that secrete IL-1, IL-2 and gamma interferon, which enhance the cell-mediated immune response and inhibit both TH2 cell activity and the humoral immune response. The TH2 response involves the TH2 subset of CD4 cells that secrete IL-4 and IL-10; TH2 cells and their secretions are thought to inhibit cell-mediated immune response and enhance the humoral (antibody-based) immune response. See cell-mediated immunity, humoral immunity. T-HELPER CELL: see CD4 cell. THERAPEUTIC VACCINE (TREATMENT VACCINE): a vaccine given after infection to reduce or arrest disease progression. A therapeutic vaccine aims to produce or reinforce an immune response in a person who is already infected. THROMBOCYTE (PLATELET): a type of blood cell that facilitates normal blood clotting. THROMBOCYTOPENIA: a condition marked by an abnormally low number of platelets, which may result in abnormal bleeding and bruising. THRUSH: see oral candidiasis. THYMUS (adjective THYMIC): a lymphoid organ in the upper chest cavity that is the source of lymphocytes in children, but which generally shrinks during adolescence. The thymus is the site of lymphocyte differentiation where lymphocytes learn to recognize antigens. The thymus produces many thymic factors (e.g., thymodulin, thymopentin, thymostimulin) that are involved in the regulation of immune function. THYROID GLAND: an organ at the frontal base of the neck that produces thyroxin and other hormones. THYROID STIMULATING HORMONE (TSH): a pituitary hormone which stimulates the growth and function of the thyroid gland. TINEA: a group of infections of the skin, nails or hair caused by various fungal organisms. Types include tinea versicolor, tinea corporis (ringworm), tinea pedis (athlete's foot) and tinea cruris (jock itch). T-KILLER CELL: see cytotoxic T-lymphocyte. TOLERANCE: a condition in which the body becomes accustomed to an agent (e.g., drug) so that the previous dose no longer produces the desired effects. TOXICITY (adjective TOXIC): the state of being poisonous or harmful. TOXOPLASMOSIS: an opportunistic infection caused by the microscopic parasite Toxoplasma gondii, found in raw or undercooked meat and cat feces. Symptoms may include headache, lymphadenopathy, malaise, muscle pain, fever and dementia. Toxoplasmosis may lead to brain swelling, coma and death in persons with suppressed immune systems. TRANSDERMAL: passing through the intact skin. TREATMENT IND: an FDA classification that allows physicians to prescribe certain promising experimental drugs prior to marketing approval to patients with life-threatening diseases who lack satisfactory alternative treatments. TRICHOMONIASIS: infection caused by the protozoan parasite Trichomonas vaginalis. Trichomoniasis may be asymptomatic, especially in men; in women symptoms may include vaginal irritation, itching and discharge. TRIGLYCERIDE: a combination of glycerol and fatty acids. TROPISM: affinity for or the tendency to move toward something; the specific attraction of a virus or other microorganism to a particular host tissue, e.g., HIV has a tropism for CD4 cells. T-SUPPRESSOR CELL: a type of T-cell that bears the CD8 surface marker and helps to regulate the immune response. TUBERCULOSIS (TB): an infectious disease caused by Mycobacterium tuberculosis that typically affects the lungs but may occur in other organs (extrapulmonary TB). Transmission generally occurs through inhalation of aerosolized sputum droplets. Multidrug-resistant tuberculosis (MDR-TB) is resistant to some of the standard drugs and requires more aggressive treatment. TUMOR NECROSIS FACTOR (TNF, CACHECTIN): a cytokine produced by activated macrophages that can destroy tumors. When chronically elevated, TNF may promote wasting. In laboratory tests TNF has been shown to stimulate HIV replication. U UNCONTROLLED TRIAL: a research study in which there are no participants taking a placebo or alternative therapy. URETHRITIS: inflammation of the urethra, the canal that carries urine from the bladder to the outside of the body. V VACCINE: a preparation that contains an infectious agent or its components which is administered to stimulate an immune response that will protect a person from illness due to that agent. A therapeutic (or treatment) vaccine is given after infection and is intended to reduce or arrest disease progression. A preventive vaccine is intended to prevent initial infection. VAGINITIS: inflammation of the vagina, the passage from the uterus to the outside of the body. VARICELLA-ZOSTER VIRUS (VZV): a virus in the herpes family that causes chickenpox (varicella). VZV may lie dormant for years and reactivate later in life to cause herpes zoster (shingles), especially in immunosuppressed individuals. VECTOR: an agent used as a vehicle for transfer. A disease vector is an agent that transfers a pathogen from one organism to another (e.g., an insect). A viral vector is an engineered virus used to introduce genes into cells or a live virus used as an antigen delivery vehicle in a vaccine. VERTICAL TRANSMISSION: the transmission of an infectious organism from a mother to a fetus or neonate (newborn). Vertical transmission may occur in utero (in the womb), during the birth process or following birth via breastfeeding. VIRAL LOAD (VIRAL BURDEN): the amount of virus in the blood or other tissues. The presence of HIV RNA indicates that the virus is replicating; changes in viral load may be used to gauge drug effectiveness and disease progression. Viral load is expressed as the number of copies of viral RNA per cubic millimeter of blood (mm3). VIREMIA: the presence of virus in the blood or plasma. VIRULENCE (adjective VIRULENT): aggressiveness, ability to cause disease. VIRUS: a group of minute organisms that are unable to grow or reproduce outside the body of a host. During replication a virus integrates its genetic material (DNA or RNA) into a host cell and takes over the cell's biological mechanisms to reproduce new virus particles. VULVA: the external female genitalia, including the clitoris and the inner and outer labia (lips) surrounding the urethral and vaginal openings. VAGINAL CANDIDIASIS (VAGINAL THRUSH, YEAST INFECTION): infection of the vagina and/or vulva with a yeast-like fungus, typically Candida albicans. Symptoms may include pain, itching, redness and a white "curd-like" discharge. Vaginal candidiasis is more common and more difficult to treat in HIV positive women and recurrent episodes may be an early sign of HIV infection. W WASTING SYNDROME: a condition characterized by atrophy of lean body mass and involuntary weight loss of more than 10% of normal body weight. Other symptoms may include chronic diarrhea, fatigue or weakness and fever. WILD-TYPE: the normal, typical phenotype of a virus or other organism before genetic mutation or manipulation takes place. Copyright (c) 1995 - Bulletin of Experimental Therapies for AIDS; San Francisco AIDS Foundation. Noncommercial reproduction encouraged. Distributed by AEGIS, your online gateway to a world of people, information, and resources. 714.248.2836 * 8N1/Full Duplex * v.34