AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 December 15, 1995 Opportunistic Infections (Part XV) Tuberculosis [Oportunistic Infections and Related Disorders; From AmFAR's AIDS/HIV Treatment Directory, Vol. 7, No. 4 (January 1995) PATHOGEN: The mycobacterial organism M. tuberculosis. HIV-infected people are particularly susceptible to infection by M. tuberculosis, and the course of the disease is accelerated. One report (Daley et al.) described a tuberculosis outbreak among 30 HIV-infected residents of a group housing facility; active tuberculosis developed within four months in 11/30 (37%) and newly positive skin tests developed in 4/30 (13%). SITES OF INFECTION: Initially, the alveoli of the lungs. Extrapulmonary tuberculosis is unusual in non-HIV-infected patients but frequently occurs in HIV-positive people, especially in those with lower CD4 counts (Jones et al.). While most patients with AIDS-associated tuberculosis have pulmonary involvement, in at least half of these cases the disease is not confined to the lungs. The lymphatic system is frequently involved. Berenguer et al. report that while tuberculous meningitis occurs more frequently in HIV-infected people, clinical outcomes are similar to those in non-HIV-infected people. SYMPTOMS: The classic symptoms of tuberculosis (cough, weight loss, fever, night sweats, fatigue) are present but not necessarily indicative of TB in people with AIDS. DIAGNOSIS: The sensitivity of tuberculin skin tests is reduced in most cases of TB with severe immune suppression. Diagnosis of TB requires isolation of M. tuberculosis by culture. A new assay is in development which may accelerate the diagnosis of MDR-TB. Jacobs et al. report that inserting the light-producing luciferase gene into M. tuberculosis in culture allows for the rapid detection of resistant and susceptible strains after treatment with antituberculosis drugs [Editor's Note: See NIAID Press Release below]. TREATMENT: The CDC recently released new guidelines for the treatment of TB (Centers for Disease Control and Prevention, 1993). These guidelines address the growing prevalence of multi-drug resistant TB (MDR-TB). All patients with M. tuberculosis should have drug-susceptibility testing performed on their first isolate; the results of testing should provide the basis for clinical therapeutic decisions. Initial treatment should include four drugs; during the first two months the regimen should include isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin. Since data are not available to determine if a six-month regimen is sufficient for HIV-infected patients, they should be treated for a total of 9 months, and for at least 6 months after sputum conversion. CDC also recommends that directly observed therapy (DOT) be considered for all patients. Malabsorption of anti-mycobacterial drugs occurs relatively frequently in AIDS patients with TB (Berning et al., Gordon et al., Peloquin et al.). To prevent treatment failure, screening for drug malabsorption may be indicated. One recent report (Holt et al.) concluded that three-times-weekly therapy is equally effective in both HIV- positive and HIV-negative patients with tuberculosis. 423 patients in Haiti were enrolled in the trial, 176 (42%) of whom were HIV-positive. Patients received isoniazid, rifampin, pyrazinamide, and ethambutol administered three times a week for two months, followed by isoniazid and rifampin for four months. Improvement in symptoms and sputum conversion occurred equally frequently in both HIV-positive and HIV-negative patients. Mortality was more frequent in the HIV-positive subjects (9% vs. 1%). A randomized, placebo-controlled phase I study of aerosolized recombinant human interferon-alpha in combination with standard therapy (isoniazid, rifampin, ethambutol, pyrazinamide, vitamin B6) is about to begin enrolling subjects. Participants will receive aerosolized gamma interferon (1000 mg qd) for four weeks, with a follow-up of nine months. Unfavorable response to therapy and treatment-limiting toxicities will be the major study endpoints. MULTI-DRUG RESISTANT TUBERCULOSIS: Several outbreaks of multi-drug resistant tuberculosis (MDR-TB) among HIV-positive people in hospitals and prisons have been reported. Mortality among these patients is very high (approximately 80%) and the disease progression is extremely rapid. Edlin et al. and Fischl et al. studied outbreaks of MDR-TB in hospitals. They report that nosocomial transmission of MDR-TB bacilli among HIV-infected patients can occur. They caution that acid-fast-bacilli isolation procedures must be strictly enforced in hospitals. Additional data (Small et al. 1992) indicate that multi-drug resistance in HIV-infected people can result from re-infection with resistant strains of M. tuberculosis. This re-infection can occur during or after therapy for drug-sensitive tuberculosis. Inadequate treatment is the primary cause of the development of MDR-TB (Mahmoudi and Iseman, 1993). Multiple levels of resistance are especially likely to accrete when single drugs are added to a failing regimen. When initiating treatment in patients with confirmed MDR-TB, both the treatment history and the in vitro susceptibilities of the patient's strain should be evaluated (Iseman, 1993). The patient should be hospitalized, and the selected regimen should include between four and seven drugs. Drugs with potential utility in a re-treatment regimen include pyrazinamide, ethambutol, streptomycin, ofloxacin, ciprofloxacin, ethionamide, cycloserine, capreomycin and PAS. In cases where chemotherapy is unsuccesful, adjunctive treatment with resectional surgery may be considered. A clinical trial (ACTG 238/CPCRA 026) is under way to identify risk factors for the development of MDR-TB, and to evaluate the efficacy of multiple-drug regimens including levofloxacin. Streptomycin is available through Pfizer Pharmaceuticals for treatment of MDR-TB; telephone (800) 254-4445. PAS is available through the CDC; telephone (404) 639-8123. PROPHYLAXIS: The CDC has recommended that HIV-positive patients with latent M. tuberculosis infection (as determined by a tuberculin skin test reaction greater than 5mm, or prior history of positive skin test not followed by treatment) receive preventive isoniazid therapy. Isoniazid prophylaxis may also be indicated for some anergic HIV-positive patients at high-risk for TB (such as those from areas with a high incidence of TB). A retrospective chart review (Moreno et al.) illustrated both the high risk of re-activation of latent infection and the rapid progression of newly acquired infection in HIV-infected people. The study population included 374 HIV-infected people in Spain. The risk for active tuberculosis in patients not receiving isoniazid prophylaxis was 10.4 cases/100 person-years in patients with a positive PPD; 12.4 cases/100 person-years in anergic patients, and 5.4/ cases/100 person-years in patients with a negative PPD. Further, Markowitz et al. have shown that the prevalence of PPD reactivity decreases and the prevalence of anergy increases as CD4 counts decline in HIV-infected people. The investigators concluded that since responses to delayed-type hypersensitivity tests depend on immune status, such tests should be conducted early in the course of disease. Because of recent nosocomial outbreaks of MDR-TB and the lack of data on effective prophylaxis for contacts to MDR-TB cases, BCG vaccination has been considered. BCG vaccine is used extensively outside the U.S. for the prevention of TB. It is generally given at birth. A recent meta-analysis (Colditz et al.) suggested that the average effectiveness may be about 50% (although the efficacy reported in individual studies ranged from less than 0% to 80% protective efficacy). However, disseminated disease from BCG vaccine has occurred in HIV-infected persons, and it is contra- indicated in seropositive adults. Two prophylaxis studies are underway through NIAID's Community Programs for Clinical Research on AIDS and the ACTG. One study (CPCRA 004/ACTG 177) compares standard isoniazid for one year to a short course (two months) of pyrazinamide and rifampin in HIV-positive people with confirmed latent TB infection. Another study (CPCRA 005) compares a six month course of isoniazid to placebo in anergic HIV-positive patients suspected of carrying TB. One study (Halsey et al.) has found that isoniazid prophylaxis decreases the incidence of tuberculosis in HIV-infected asymptomatic patients. 784 HIV-infected people in Haiti were randomized to receive a six-month course of isoniazid or a combination of rifampin and pyrazinamide. The risk of TB during the first `0 months after randomization was 3.5% for the rifampin/ pyrazinamide group and 0.8% for the isoniazid group (P=.01). No significant differences in the rates of TB were observed 10 months after treatment had stopped. No TB was detected in either group during the first three months after randomization. The optimal duration of prophylaxis has not been determined. An effective prophylaxis regimen for people exposed to MDR-TB has not been established. One report (Horn et al.) described the use of ofloxacin 800 mg/day with pyrazinamide 1500 mg/day in 16 health-care workers exposed to MDR-TB. The health-care workers were not HIV-infected. 14/16 discontinued prophylaxis before the completion of six months of therapy because of side effects (arthralgia, GI distress, and others). REFERENCES: Berning SE et al. Malabsorption of antituberculous medications by a patient with AIDS. NEJM 327:1817-8, 1992. Berenguer J et al. Tuberculous meningitis in patients infected with the human immunodeficiency virus. NEJM 326:668-72, 1992. Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance. Recommendations of the advisory council for the elimination of tuberculosis. MMWR 42:RR-7, 1-8, 1993. Colditz GA et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 271:698-702, 1994. Daley CI et al. An outbreak of tuberculosis with accelerated progression among persons infected with HIV. NEJM 326: 231-5, 1992. Edlin BR et al. An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome. NEJM 326: 1514-21, 1992. Fischl MA et al. An outbreak of tuberculosis caused by multiple-drug resistant tubercle bacilli among patients with HIV infection. Ann Int Med 117: 177-83, 1992. Gordon S et al. Impaired absorption of oral regimen in treatment of disseminated M. avium complex. 32nd ICAAC, abstract #896, 1992. Halsey NA et al. Twice weekly INH for TB prophylaxis. Abstract #PB0681, X Intl Conf AIDS, Yokohama, 1994. Holt E et al. Efficacy of supervised, intermittent, short course therapy of tuberculosis in HIV infection. Abstract WS-B09-4, IX Intl Conf AIDS, 1993. Horn DL et al. Limited tolerance of ofloxacin and pyrazinamide prophylaxis against tuberculosis (correspondence). NEJM 330:1241, 1994. Iseman MD. Treatment of multidrug-resistant tuberculosis. NEJM 329:784-91, 1993. Jacobs WR et al. Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages. Science 260:819-22, 1993. Jones B et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 148:1292-7, 1993. Mahmoudi A and Iseman D. Pitfalls in the care of patients with tuberculosis; Common errors and their association with the acquisition of drug resistance. JAMA 270: 65-8, 1993. Markowitz N et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Ann Int Med 119:185-93, 1993. Moreno S et al. Risk for developing tuberculosis among anergic patients infected with HIV. Ann Int Med 119:194-8, 1993. Peloquin CA et al. Malabsorption of antimycobacterial medications. NEJM 329:1122-3, 1993. Small PM et al. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. NEJM 328:1137-44, 1993. OTHER REPORTS: Banerjee A et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227-30, 1994. Barnes PF et al. Tuberculosis in patients with HIV infection. NEJM 324: 1644-50, 1991. Davidson PT and Le HQ. Drug treatment of tuberculosis - 1992. Drugs 43(5): 651-72, 1992. Driver CR et al. Transmission of Mycobacterium tuberculosis associated with air travel. JAMA 272:1031-1035, 1994. Goble M et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. NEJM 328: 527-32, 1993. Copyright (c) 1993 - American Foundation for AIDS Research (AmFAR) - All Rights Reserved. Permission to reproduce for non-profit use granted with the condition that the source and date of the information be given, and that AmFAR be notified. Eric Fretz, Treatment Information Services, AmFAR. DISTRIBUTED BY GENA/aegis (714.248.2836 * 8N1/Full Duplex * v.34); taking you to the edge of the electronic AIDS-information frontier and beyond. GLOW-IN-THE-DARK ASSAY ILLUMINATES TB DIAGNOSIS With help from the firefly, investigators supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the World Health Organization (WHO) have developed an experimental technique that holds promise for speeding the diagnosis of tuberculosis (TB) and rapidly determining which drugs can be used to kill the TB strain a patient is carrying. The technique may also offer researchers an efficient method to screen large numbers of potential anti-TB compounds, a crucial concern as scientists work to develop effective new drugs against strains of the TB bacterium resistant to the current drugs. The new approach uses luciferase, an enzyme that is part of the "glow-in-the-dark" system in the tail of fireflies, to produce light in living TB bacteria. Using the technique, the investigators have detected the presence of TB bacteria in one to two hours and determined within 48 hours which drugs can kill a particular strain of the TB bacteria. As reported in the May 7 Science and at the second annual meeting of the NIAID International Centers for Tropical Disease Research in April, the study investigators, led by William R. Jacobs, M.D., of the Howard Hughes Medical Institute at the Albert Einstein College of Medicine, used genetic engineering to insert the firefly luciferase gene into the genetic material of a virus specific to the TB organism. When this genetically altered virus infects the TB bacterium, the viral DNA with the luciferase gene is integrated into the bacterium's genes. The TB organism now can produce luciferase. Luciferase reacts with another substance, luciferin, to change chemical energy in cells into light. Current TB diagnostic tests rely on cell cultures and can take weeks because the TB bacterium, Mycobacterium tuberculosis, grows slowly, multiplying only once every 24 hours. By comparison, other bacteria such as those that cause strep throat multiply every 20 minutes, rapidly forming colonies that are detected easily. While waiting for the results of TB cultures, physicians are forced to make treatment decisions with limited information. Patients may receive drugs that are not effective, while possibly transmitting the disease to others. With the new procedure, known as the luciferase phage assay, the genetically engineered virus and luciferin may be added to specimens suspected of containing TB bacteria. The luciferin diffuses easily into the cells and if TB bacteria are present, they are infected and make luciferase. Light is produced and can he measured by a light-sensitive instrument known as a luminometer. To determine the drug susceptibility of the TB strain a patient is carrying, various anti-TB drugs are added to TB cultures along with the altered virus and luciferin. If light is seen, the investigators know that the antibiotic is ineffective, because the living bacterium continues to produce luciferase and, consequently, light. However, if the TB bacteria are treated with an effective antibiotic, they will be killed and no light will be emitted. "This is a quick and sensitive method for detecting drug-resistant TB strains, and it could potentially be automated to process large numbers of samples in a short time," says Dr. Jacobs. "Refinement of the luciferase phage diagnostic system for use in the clinical setting is currently under way. It is anticipated that this assay also will be used in the near future to efficiently screen compounds for anti-TB activity." Dr. Jacobs' co-authors include Rupa Udani, Gabriel Sosne and Barry R. Bloom, Ph.D., all of the Howard Hughes Medical Institute/Albert Einstein College of Medicine; John Chan, M.D. and Gary Kalkut, M.D., of Albert Einstein; Raul Barletta, Ph.D., of the University of Nebraska; Tobias Kieser, Ph.D., of the John Innes Institute and AFRC Institute of Plant Science Research (U.K.); and Gary Sarkis and Graham F. Hatfull, Ph.D., of the University of Pittsburgh. (Press Release. National Institutes of Health, National Institute of Allergy and Infectious Diseases, May 6, 1993.) ====================== GMHC Treatment Issues Fact Sheet ====================== Patient Education Tuberculosis (TB) What is tuberculosis? Tuberculosis (TB) is a disease caused by a bacterium that is spread through the air usually when a person who has the disease coughs or sneezes. Anyone can become infected with TB bacteria, but people with HIV/AIDS are at greater risk of getting sick with TB disease. Although TB can occur any place in the body, only TB disease in the lungs (pulmonary TB) or throat is contagious. TB can occur at any t-cell range above or below 200 t-cells. What is the difference between TB infection and TB disease? TB infection (latent TB) means that TB bacteria have become active in your body and will make you sick. Only people with active TB disease can spread TB to others. TB disease can be prevented or cured, but if left untreated, it can be fatal. What are the signs and symptoms of TB disease? General symptoms of TB disease in the lungs or throat include fever, night sweats, weight loss, and fatigue. Pulmonary TB causes a persistent cough and sometimes bloody sputum (phlegm). TB disease can occur with other infections, especially Pneumocystis carinii pneumonia (PCP) and Mycobacterium avium complex (MAC). How can a doctor tell if I have TB? To diagnose TB infection, your healthcare provider will give you a special skin test, called a PPD, which causes a bump to appear within several days if you are infected. A positive test means you have TB infection. To determine if you have active TB disease, a chest x-ray and sputum culture need to be done. If you have HIV/kADIS the PPD test might not work. Can TB be prevented? Isoniazid, also called INH, is an antibiotic pill approved for prevention of TB disease. It is taken for at least one year. People with both HIV/AIDS and TB infection have a 10% risk per year of developing active TB disease. Your doctor should monitor you monthly for side effects of INH. If you are infected and cannot take medicine to prevent TB disease, it is very important to have regular check-ups and contact your doctor as soon as you start having signs of active TB disease. Remember, always cough or sneeze into tissues and ask others to do the same. Can TB be treated? TB disease can be treated and cured with medication. TB treatment starts with at least four drugs, but the number of drugs may be reduced after two months. People with HIV/AIDS have to take the drugs for a longer time than other people. It is important to take all your medication until the doctor says that the TB has been cured. Skipping medication or stopping because you feel better might lead your TB to become contagious again; your TB might become harder to treat and you might get sicker. ***************************************************************** Some drugs commonly used to treat TB include: ISONAZID (INH) Side effects: liver problems, pain or tingling in your hands and feet (neuropathy), fever, rash Drug tips: take with food to reduce stomach problems, take vitamin B6 to reduce neuropathy, do not drink alcohol (increases liver problems), do not use aluminum-containing antacids or laxatives (reduces INH absorption) RIFAMPIN (RIFADIN) Side effects: liver problems, fever, flu-like symptoms, can turn your body fluids orange (urine, feces, semen) and permanently stain soft contact lenses; patients on methadone may need up to 50% increase to avoid withdrawal symptoms Drug tips: do not drink alcohol, do not take with food, skipping medication may cause flu-like symptoms ETHAMBUTOL (MYAMBUTOL) Side effects: nausea, vomiting, eye problems, skin rashes PYRAZINAMIDE (PZA) Side effects: nausea, vmiting, rashes, liver problems, jont aches and pains Drug tips: drink plenty of fluids daily STREPTOMYCIN (INJECTED) Side effects: kidney problems, hearing problems, blood problems Drug tips: report any fever, nausea, vomiting, rash, allergic reaction, dizziness, hearing loss or difficulty breathing PARA-AMINO-SALICYLIC ACID (PAS) Side effects: severe allergic reaction, nausea, liver problems, vitamin B12 deficiency, blood problems Drug tips: take with food to reduce stomach problems, report rash, fever, sore throat, unusual bleeding or bruising =============== WHAT IS MDR-TB? =============== MDR-TB (Multiple Drug Resistant Tuberculosis) is TB that is resistant to at least two of the standard drugs used to treat TB (INH & Rifampin). Your TB can become resistant if you are not treated long enough, do not receive the right drugs or if you take your medication improperly. You can also become infected with MDR- TB directly. Since MDR-TB frequently causes death within a few weeks in people with HIV/AIDS, preventive treatment of suspected MDR infections is highly recommended. Treatment of MDR-TB disease requires the use of five or six drugs that vary according to the drug resistance pattern in your geographical area. ============================================================== BETA News Briefs: Studies of Rifabutin to Prevent Tuberculosis Ronald Baker, PhD ============================================================== [BETA (Bulletin of Experimental Treatments for AIDS) No. 26, September 1995; published by San Francisco AIDS Foundation, BETA Subscription Services, Infocom Group, 1250 45th Street, Suite 200, Emeryville, CA 94608-2924.] Rifabutin (Mycobutin) will be studied in a large international trial (2,000 participants) for its ability to prevent tuberculosis (TB) disease among HIV positive individuals who are also infected with Mycobacterium tuberculosis (MTb), but who do not have active TB. Infection with MTb is determined by a positive reaction to the PPD (purified protein derivative ), a skin test for TB. Three months of rifabutin therapy will be compared to 12 months treatment with the antibiotic isoniazid, the standard preventive therapy for TB. A second study will test the effectiveness of rifabutin in preventing TB among injection drug users who are anergic. Anergic individuals do not respond to standard skin tests (e.g., the PPD skin test for TB), because they are immunosuppressed. As HIV disease progresses, latent TB infection may reactivate in HIV positive individuals to cause active disease. Rifabutin (Mycobutin) is already FDA-approved for the prevention of Mycobacterium avium complex (MAC) and has also been used as part of combination regimens to treat active TB. The drug is manufactured by Pharmacia, Inc., a subsidiary of Pharmacia AB in Sweden, one of the 20 largest pharmaceutical companies in the world. DISTRIBUTED FOR GENA by AEGIS/San Juan Capistrano - 714.248.2836: Copyright (c) 1994 - Bulletin of Experimental Treatments for AIDS (BETA), a quarterly publication of the San Francisco AIDS Foundation (SFAF). Reproduced with permission. Reproduction of this article (other than one copy for personal reference) requires written consent from the SFAF. For subscription information contact the BETA Subscription Office at 1.800.959.1059 or 1.510.549.4300, or via the internet at beta@sfsuvax1.sfsu.edu. ================================================================ Abstracts from the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 17-20 September 1995 ================================================================ (I210) Tuberculosis (TB) in European HIV Patients (Pts): Efficacy of Three vs. Four Drugs. Jose M. Gatell, Stephane De Wit, Juan Gonzalez-Lahoz, Nathan Clumeck and ENTA05 Tuberculosis Study Group. Barcelona and Madrid; Spain. Brussels. Belgium. 598 HIV pts with suspected TB from Europe were randomized to a daily three (3D) or four drugs (4D) regimen (I plus R 9 mo. plus Z 2 mo. with or without E 2 mo.). Of the 463 cases with confirmed TB, 226 received 4D and 237 to 3D. 67% were drug addicts, 47% had <100 CD4's per milliliter and 46% had only pulmonary TB. Both groups had similar mean age, percentage of drug addicts, mean CD4+ count and localization of TB. The overall mortality was 22% *in 4D group) vs. 18% (in 3D group), discontinuation due to toxicity of at least one of the study drugs 12% vs. 10% and the loss to follow-up 35% vs. 31%. Failure rates, including mortality attributable to TB, was 12 percent and 8 percent in the 4D and 3D groups respectively. The relapse rate was 3.1 per 100 Pts-years among a subgroup of 104 pts who completed the treatment and could be followed for a median of 19 months. Resistance rates to at least one agent or to more than one was 5% and 4% respectively among the 100 strains tested at baseline. In conclusion, adding a fourth drug does not seem to be justified and DOT should be considered. (I211) Relapse in TB/HIV Patients During Long-Term Follow-up Christopher Lahart, MD, Katharine Breaux, PA-C, Jan Fisser, PhD, Ruby Nixon, RN, Houston Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas 77030. Since dual TB/HIV infection was first recognized in the mid 1980's, tuberculosis has been felt to be curable in patients with HIV. Traditional antituberculosis regimens appear equally effective in both HIV positive and negative patients with failures in both generally attributable to non-compliance. There is little evidence of expanded times to negative culture conversion or increased drug toxicity despite advanced immunosuppression and concurrent therapies for other HIV-related opportunistic infections. Though some data are available regarding relapse, there is little information about long-term follow-up. From 7/1/86 through 10/1/94, 135 HIV-infected patients diagnosed with TB by culture, radiographs, and clinical presentation were followed prospectively. All patients received standard therapy consisting of at least 2 months of INH/RIF/PZA {EMB added for extrapulmonary disease (29%)} followed by at least 4 months of INH/RIF. Regimens were individualized for patients with drug resistance (10%). Relapse was defined as a new bacteriologic conversion after resolution of clinical symptoms and serial negative cultures. HIV risk factor, CD4 count within 3 months of TB diagnosis, drug resistance and compliance were examined as potential predictors of relapse. Median length of follow-up was 19 months (range 1 to 82 months). Nine (6.7%) patients met the criterion for relapse, all were noncompliant. Median time to relapse was 18 months (range 11 to 61 months). Risk factor, CD4 count at TB dx, and drug resistance were not significantly different between those who did or did not relapse. No molecular information to help differentiate between relapse and reinfection is available at time of abstract submission. Standard anti-TB regimens appear effective over a median follow-up time of 19 months. Relapse can be minimized by assuring compliance. (I212) Tuberculosis After Isoniazid Chemoprophylaxis in HIV- Infected Patients: A Warning For Isoniazid Resistance. S. Moreno, P. Miralles, MD. Diaz, J. Baraia-Etxaburu, J. Cosin, JCL Bernaldo De Quiros, E. Bouza. Hospital General Universitiario "Gregorio Maranon." Madrid, Spain. Objective: To evaluate the long-term protection conferred by isoniazid against tuberculosis in patients co-infected with HIV and M. tuberculosis. Patients and Methods: A group of 27 HIV-infected patients who were PPD-positive and who received isoniazid (9-12 months) were followed for development of clinically and/or microbiologically documented tuberculosis. Patients were followed until development of tuberculosis, death, or the end of study (December, 1994). Results: Most patients (85%) were intravenous drug users; median CD4 count was 684/mm3. Seventeen patients (63%) completed the study, with a median follow-up of 58.6 months; the 10 patients who were lost had a median follow-up of 19 months. Tuberculosis developed in 3 patients (at months 21, 30, and 33 after completion of chemoprophylaxis), all of them proved by culture. Two of the isolates were resistant to isoniazid. Estimated incidence of tuberculosis in the total group was 3.19 per 100 patient-years, and 1.06 per 100 patient-years if isoniazid-resistant strains are excluded. When only patients who completed follow-up are considered, incidence rates were similar (3.61 and 1.2 per 100 patient-years, respectively). Conclusion: Tuberculosis can occur well after completion of adequate isoniazid prophylaxis in HIV-infected patients. If this happens, the presence of isoniazid-resistant strains should be considered. (J15) Mortality With Tuberculosis, Chronic Renal Failure, and AIDS, 1989-1992. J. Tokars, Centers for Disease Control and Prevention (CDC), Atlanta, GA. Infectious diseases are common in patients with chronic renal failure (CRF). Studies have shown a high risk of tuberculosis (TB) among CRF patients; however, most such studies were performed at single dialysis centers in the 1970s. To obtain a broader and more current perspective on the association between TB, CRF, and AIDS, the U.S. National Center for Health Statistics multiple-cause mortality tapes were studied. Deaths listed on the tapes were coded as "death with TB' if the underlying cause of death, or any of up to 20 additional diagnoses listed, indicated TB; a similar procedure was used to code for death with CRF and/or AIDS. Ages greater than or equal to 25 were studied. During 1987-1992, of 87,934 deaths with CRF, 223 (0.25%) also listed TB; of 7,864,149 deaths without CRF, 15,641 (0.20%) listed TB (relative risk = 1.3, p<0.001). Among persons sying with CRF, the percentage also dying with TB was 4.7% (34/728) for those with AIDS, 0.22% (189/87,206) for those without AIDS; 0.54% (23/4,296) for Hispanics, 0.12% 80/64,844) for non-Hispanic whites, 0.57% (98/17,110) for non- Hispanic blacks, 1.3% (22/1,684) for Asian, American Indian, and others; 1.5% (54/3,733) for ages 25-44, 0.39% (55/14,034) for ages 45-64, and 0.16% (114/70,167) for ages less than or equal to 65. These data represent proportional mortality rather than cases of disease, and must be interpreted with caution; however, few other national databases have information on TB, CRF, and AIDS. There is at most a modest association between death with CRF and TB. Among persons dying with CRF, the percentage dying with TB is higher among those with AIDS, nonwhites, and younger age groups. (K120) Clinical Features of Tuberculosis (TB) Diseases in HIV- Infected Patients. A. Gori, S. Antinori, F. Franzetti, F. Mainini, A. D'Arminio Monforte, L. Catozzi, G. Marchetti, G.P. Nardi, R. Esposito and M. Moroni. Clinic of Infectious Diseases, University of Milan, Department of Microbiology, "L. Sacco" Hospital, Milan, Italy. Objectives: To describe the clinical and X-ray features of TB in patients with HIV infection, to evaluate the drug susceptibility of M. tuberculosis strains and to evaluate the survival pattern from the time of TB diagnosis. Methods: This was a retrospective study of all cases of TB microbiologically diagnosed at the clinic of Infectious Diseases of the University of Milan from January, 1988 to October, 1993. Results: We evaluated 105 patients (pts) with TB. Pulmonary TB was diagnosed in 43% of pts, extrapulmonary localization was present in 22% of pts, while both pulmonary and extrapulmonary TB were found in 35% of pts. In 47% of pts, TB was diagnosed before other AIDS-defining diseases; in the other pts TB occurred after a median of 5 months from the diagnosis of AIDS. M. tuberculosis was isolated from the blood in the 27.5% of pts but to a significantly higher extent in pts with AIDS than those without AIDS (p<0.05). The median CD4+ cell count at the time of TB diagnosis was 33/mL. Multidrug-resistant strains of M. tuberculosis were isolated in 19.3% of pts. X-ray examination indicated a typical TB disease in 54% of the cases with no significant correlation with the level of immunodeficiency. Multivariate analysis (Cox model) showed that CD4+>100/mL at the time of TB diagnosis was the only parameter that correlated significantly with longer survival. Conclusions: We confirm that a high frequency of extrapulmonary involvement of TB is observed in patients with AIDS. The emergence of multidrug-resistant strains needs a careful microbiological monitoring. Survival is statistically dependent only on the Cd4+ level at the time of TB diagnosis. (K121) Characteristics of Patients (Pts) Enrolled in a Multicenter Study for the Treatment (Rx) of Tuberculosis (TB) in HIV-Infected (HIV+) Pts. W. El-Sadr, D.C. Perlman, E. Nelson, J. Matts, K. Chirgwin, E. Telzak, M. Olibrice, N. Salomon for Terry Beirn Community Program for Clinical Research on AIDS (CPCRA) and AIDS Clinical Trials Group (ACTG), NIAID. We report on baseline (BL) characteristics of pts with suspected pulmonary Tb and HIV enrolled to date in the first multicenter Tb Rx study in the US among HIV+ pts. In the induction phase (8 weeks), pts are assigned 4 drugs (INH, RIF, ETH, PZA) in sensitive (sens) areas of US and randomized in resistant (rst) areas (>10% INH resistance) to the 4 drugs or levofloxacin as the fifth drug. The continuation phase compares 6 to 9 months Rx in pansusceptible pts. Pts with suspected or confirmed multidrug resistant Tb are excluded. A total of 187 pts (54%black, 30.5%,latino, 34.2%IDU, 22.6%women) were enrolled in the IP from 12 cities, 145 from rst areas and 42 from sens areas. Of pts with BL cultures available, 107 of 161 (66%) had (+)cultures. Sputum smears were (+) in 66.4% of pts with (+)cultures. Of 101 pts with +ve cultures, 53(52.5%) had CD4 less than or equal to 100 and 47.5% had CD4>100. Among the 101 with (+) cultures versus -ve cultures, 91.6% versus 77.8% (p=.007) had abnormal CXrays, 25.5% versus 11.9% had abnormal lymph nodes (LN) on CXrays (p=0.057), 41.1% versus 24.1% had temp>100 (p=0.03). Pansusceptible (pansus) Tb was isolated from 84 of 93 (90.3%) pts. More pts with rst rather than pansus Tb had a temp >100 (p=0.05) with no other difference in clinical, CXray findings or % (+) smears. TB occurred among pts with wide spectrum of CD4 counts. Among pts with suspected Tb and HIV, 2/3 had (+) cultures. Of those, 1/3 had (-) smears. Pts with (+) cultures were more likely to have abnormal CXrays especially LN and higher temp. No clinical, radiologic or lab findings were predictive of resistant Tb. (LM32) Evaluation of the Pharmacokinetics and Safety of Single and Multiple High Dose Regimens of Levofloxacin in HIV Seropositive Subjects. KM Spooner, BF Baird, RT Davey, CL Fowler, M Dewaters, F Wong, A Chow, J Falloon, MA Polis, JA Kovacs, HC Lane, H Masur, RE Walker, NIH, Bethesda, MD, RW Johnson Pharmaceutical Research Institute, Raritan, NJ. Objectives: To evaluate the pharmacokinetics and tolerance of high dose regimens of levofloxacin in HIV seropositive subjects. Background: Patients with HIV infection are highly susceptible to tuberculosis, and in recent years strains of M. tuberculosis (M.Tb) resistant to standard drugs have become more common. Levofloxacin is the l-isomer of the quinolone ofloxacin with significant activity against M.Tb. Methods: 31 HIV infected subjects without M.Tb disease were enrolled in this randomized, double-blind, placebo controlled, multiple dose study. Subjects were stratified by CD4 count (less than 250 vs. greater than or equal to 250) and randomized to 1 of 3 treatment groups. Subjects received oral medication daily from days 1 to 14 and three times weekly (TIW) from days 15 to 28. Group A received levofloxacin 750 mg throughout, Group B received levofloxacin 750 mg days 1-14, then 1000 mg days 15-28, and Group C received placebo. Results: Five subjects did not complete the study due to: severe pruritus and fever (n=1); venous access (n=2); patient preference (n=2). Four of these 5 received levofloxacin; one who withdrew for personal reasons received placebo. The most common side effect was mild nausea: reported in 9/11 in Group A; 5/12 in Group B; and 2/7 in Group C. Other reported symptoms included diarrhea and pruritus. No laboratory abnormalities were attributable to the drug. Preliminary analysis demonstrates a mean Cmax of 7.82 at day 1 and 11.1 at day 14 for 750 mg QD; 10.3 for 750 mg QD TIW; 11.2 for 1 gm TIW. Serum half life (T1/2) ranged from 6.6 to 8.4 hrs for 750 mg and 7.3 to 7.4 hrs for 1 gm. Conclusions: At doses of levofloxacin used in this study, mild nausea was the most common adverse event identified. Based on this, and our data demonstrating that serum concentrations above the MIC(90) of M.Tb can be attained with intermittent high dose regimens, it is therefore appropriate to assess the safety and efficacy of levofloxacin as part of an anti-tuberculosis regimen in this patient population. Editor's Note More information about tuberculosis is included in the AIDS Information Newsletter series, Tuberculosis and HIV Infection. This nineteen part series was transmitted between August 27, 1993 and May 6, 1994 to all VA medical centers. The series (as well as other newsletter series) is available on the internet. Internet access is discussed below. INTERNET Access - Gopher The AIDS Information Newsletter is mailed directly to the National Institute of Allergy and Infectious Diseases gopher site (gopher.niaid.nih.gov). Menu path is: 2. AIDS Related Information; 11. VA AIDS Information Newsletter. The Safer Sex: Information for Counselors series (AIDS News Service) is also located here. Menu path is: 2. AIDS Related Information; 12. U.S. Community AIDS Resources; 9. Patient Teaching. INTERNET Access - World Wide Web WWW URLs for the newsletter and the Safer Sex series via the National Institute of Allergy and Infectious Diseases are: AIDS Information Newsletter: gopher://gopher.niaid.nih.gov/11/aids/vaain AIDS News Service (Safer Sex Series only): gopher://gopher.niaid.nih.gov//11/aids/comm/teach The newsletter and the Safer Sex: Information for Counselors series are also located on John Troyer's Safer Sex Page (http://www.cmpharm.ucsf.edu/~troyer/safesex.html). The URL for the AIDS Information Newsletter on this Page is: http://www.cmpharm.ucsf.edu/~troyer/safesex/vanews/ The URL for the Safer Sex series is: http://www.cmpharm.ucsf.edu/~troyer/safesex/vanews/vanewsss.html