AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 November 17, 1995 Opportunistic Infections (Part XIII) Histoplasmosis [Oportunistic Infections and Related Disorders. AmFAR's AIDS/HIV Treatment Directory, Vol. 7, No. 4 (Jan 1995).] PATHOGEN: Histoplasma capsulatum, a fungus endemic to the south-central U.S. and South America, and found in soil contaminated by bird droppings or other organic material. After inhalation, the spores germinate into the yeast form. SITES OF INFECTION: Wide-spread dissemination occurs in most patients, most frequently in the lungs and less frequently in the skin and G.I. system. SYMPTOMS: Fever, weight loss, nodular or ulcerative skin lesions, respiratory complaints, anemia, and enlargement of the liver, spleen, and lymph nodes. Histoplasmosis usually occurs in AIDS patients with CD4 cell counts below 100/mm3. DIAGNOSIS: By blood or bone marrow culture, biopsy, H. capsulatum variety capsulatum polysaccharide antigen detection in urine or serum. TREATMENT RESULTS: Amphotericin B and itraconazole are approved for the treatment of histoplasmosis. Long-term maintenance therapy is required to prevent relapse of disseminated histoplasmosis following initial induction treatment in patients with AIDS. Due to the absorption variability of itraconazole it is recommended that blood levels be monitored 2-4 hours after dosing during the second week of treatment and every 3 months thereafter. Ideally, itraconazole blood levels of 2 mcg/ml should be achieved for induction and 1 mcg/ml for maintenance. Wheat et al. enrolled 59 patients in a study (ACTG 120) of open-label itraconazole for the treatment and prevention of relapse of acute histoplasmosis. All subjects received 300 mg PO twice daily for 3 days followed by a 12 week course (200 mg twice daily). Fifty of 59 (85%) patients responded to treatment (clearance of fungemia) and were continued on itraconazole maintenance treatment (200 to 400 mg PO daily) for at least one year. Of the 9 non-responders, six failed treatment, two experienced toxicity, one was lost to follow-up. An interim analysis of ACTG 174, a study of fluconazole for the treatment and maintenance of histoplasmosis has shown that response rate is 70-85%. Of 37 patients evaluated in the maintenance phase, 11/37 relapsed (30%). The study was closed by the interim monitoring team when they found a difference in failure rate of patients on itraconazole in ACTG 120 (5%) compared to fluconazole treated subjects in ACTG 174 (33%). MAINTENANCE/PROPHYLAXIS: Itraconazole is the maintenance treatment of choice for histoplasmosis (see treatment results of ACTG 174 above). Forty-two AIDS patients with disseminated histoplasmosis were treated with open-label itraconazole for the prevention of relapse for acute histoplasmosis (Wheat et al.). All subjects initially received induction therapy with amphotericin B followed by itraconazole 200 mg PO twice daily. The median duration of follow-up of 109 weeks (range, 4 to 134 weeks), the median survival time was 98 weeks (range, 4 to >134 weeks). 39/42 patients responded to treatment (successful suppression of histoplasmosis). One patient withdrew from the study due to toxicity (hypokalemia). Histoplasma blood and urine antigen levels decreased in all patients except one. Fluconazole is more effective than clotrimazole in the prevention of invasive and serious systemic fungal infections (preliminary data from Powderly, Bozzette and co-workers, ACTG 981). 428 patients with CD4 counts <200/mm3 with no history of systemic fungal infections were randomized to receive fluconazole 200 mg/day or clotrimazole 10 mg five times daily. After a mean follow-up of 35 months, 11 fluconazole recipients and 38 clotrimazole recipients developed serious fungal infections (including cryptococcosis, histoplasmosis, coccidioidomycosis, and aspergillosis)(P <.0001). Histoplasmosis represented 3/11 infections in fluconazole recipients vs. 5/38 in the clotrimazole recipients. No survival benefit to fluconazole was observed: 98 subjects on fluconazole died vs. 89 on clotrimazole (P = 0.26). Norris et al. found fluconazole 100-400 mg to be moderately effective and a reasonable choice in patients who were given induction therapy with amphotericin B and who could not take itraconazole because of drug interactions, malabsorption or side effects. McKinsey et al. concluded that long-term, biweekly maintenance therapy with amphotericin B (50 mg IV every two weeks) was well tolerated and effective in preventing relapse of histoplasmosis in HIV-infected subjects. A double-blind randomized study (MSG 28) is under way to compare itraconazole (200 mg daily) with placebo for the prophylaxis of histoplasmosis in HIV positive people with CD4 counts below 150/mm3. REFERENCES: McKinsey DS et al. Histoplasmosis in patients with AIDS: efficacy of maintenance amphotericin B therapy. Amer Jrnl Med 92: 225-227, 1992. McKinsey DS et al. Histoplasmosis in AIDS: Incidence and risk factors. Abstract #PB0604, Intl Conf AIDS, Yokohama, 1994. Norris et al. Prevention of relapse of histoplasmosis with fluconazole in patients with the acquired immunodeficiency syndrome. Amer Jrnl Med 96: June, 1994. Wheat et al. Itraconazole is effective treatment for histoplasmosis in AIDS: prospective multicenter non-compliance trial. 32nd ICAAC, abstract 1206: 312, 1992. Wheat et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Int Med 118(8): 610-6, 1993. OTHER REPORTS: Smith D et al. The pharmacokinetics of oral itraconazole in AIDS patients. VII Intl Conf AIDS, Florence. Vol 2: 225(W.B.2174), 1991. 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. =================================================== INFECTION FIGHTERS: Itraconazole for histoplasmosis by Sean Hosein =================================================== [Treatment Update 61 - Volume 7, No. 7 - July 1995; Community AIDS Treatment Information Exchange 420 - 517 College Street, Toronto, Ontario, Canada M6G 4A2 * (416) 944-1916 - (416) 928-2185 BACKGROUND Another fungus (H. capsulatum) can cause life- threatening complications called histoplasmosis) in people with AIDS. Usually this fungus causes disease "in the South central USA and South America." Although the yeast tends to attack the lungs first, it can spread to other parts of the body. Symptoms may include: + fever + skin lesions + lower than normal levels of red blood cells + weight loss + swollen liver/spleen/lymph node People with HIV/AIDS who also develop histoplasmosis tend to have less than 100 CD4+ cells. Technicians can test blood and urine samples for parts of the fungus or identify it with dyes and a microscope. Treatment is usually amphotericin B or itraconazole STUDY DETAILS Researchers reported data on 59 subjects (55 males, 4 females), all of whom were having their first bout of histoplasmosis. Subjects received itraconazole 300 mg twice daily (total daily dose of 600 mg) for the first 3 days and then 200 mg twice daily with meals for 3 months. No subject had severe histoplasmosis. Subjects were monitored for up to 14 weeks. RESULTS BENEFITS According to the researchers, 50 subjects improved when they received itraconazole. These subjects had increased energy/less fatigue, loss of fever and weight gain. For many subjects these improvements happened within the first month of the study. Levels of fungus in the blood and urine fell dramatically within 2 weeks of using itraconazole. By the 8th week of the study, most signs/symptoms had cleared in 90% of the responding subjects. DISEASE DESPITE ITRACONAZOLE Six subjects became worse despite receiving itraconazole, and 2 of those died. The remaining 4 "recovered after being switched to [AmB]." The doctors did not know why these subjects did not recover when they received itraconazole. TOXICITY Two subjects left the study because of side effects from the itraconazole including; fever, swollen liver, rash, nausea and vomiting. Once these subjects were given amphotericin B instead of itraconazole their side effects cleared. Although the results from this study suggest that itraconazole is promising treatment histoplasmosis, it may not be the best drug for serious cases of histoplasmosis. It may be interesting to see results of long term monitoring of subjects treated with itraconazole and those treated with amphotericin B. REFERENCES: 1. Wheat J. Hafner R. Korzun AH, et al. Itraconazole treatment of disseminated histoplasmosis in patients with the Acquired Immunodeficiency Syndrome. American Journal of Medicine 1995;98:336-342. Copyright (c) 1995 - CATIE. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. 714.248.2836 * 8N1/Full Duplex * v.34+ ================================================================ Abstracts from the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 17-20 September 1995 ================================================================ LM93 Clinical and Laboratory Characteristics of Patients with AIDS and Disseminated Histoplasmosis. Iram K. Zando, Robert L. Penn, and John W. King, LSUMC, Shreveport, LA Disseminated Histoplasmosis (DH) complicating AIDS is often difficult to diagnose as the symptoms of these combined infections are protean. We reviewed 44 admissions of 30 patients with AIDS and proven DH, who were treated between 1/91-12/94 at our University hospital which is located in a Histoplasma endemic area. Diagnostic criteria for DH were based on histology and positive cultures of blood, bone marrow or tissue. Patients with AIDS and DH most often presented with fever and dehydration, and 17/44 were receiving antifungal therapy on admission (7 on Fluconazole, 8 on Itraconazole, and 2 on Ketoconazole). All patients were men with CD4 counts less than 200 per milliliter (0-170/mm3). Symptoms included: fever (37/44), cough (28/44), weight loss (22/44), vomiting (21/44), chills (20/44), and diarrhea (19/44). Mean peak temperature was 103.6 plus or minus 1.8 degrees F. Clinically, 13/44 had rash, 12/44 had abdominal tenderness and 13/44 had abnormal chest exam. Admission lab data (mean plus or minus SD) was: Hb 9.8 plus or minus 2.4 g/dL; platelets 114 plus or minus 82 k/mm3; WBC 2.7 plus or minus 1.9 k/mm3; granulocytes 71 plus or minus 18 per cent; bands 13 plus or minus 9%; lymphocytes 11 plus or minus 8%, monocytes 10 plus or minus 15%. Mean peak LDH was 6,640 plus or minus 5,849 U/L. Ferritin ranged from 975-118,740 ng/ml. Chest X-ray abnormalities were present in 19/34, but were non-specific. Mean time, in days (range) to positive cultures was; 28(10-101) for blood and 23 (2-68) for bone marrow. Bone marrow histology was abnormal in 13 of 19 patients and was diagnostic for H. capsulatum in 8 of these 19 patients. In 5/6 patients, Histoplasma antibodies were positive. In patients treated with Amphotericin B, defervescence occurred after infusion of 50 plus or minus 27 mg delivered over 4 plus or minus 2 days. Defervescence and rapid decline of LDH were the earliest predictors for clinical improvement. We emphasize the constellation of clinical and laboratory findings of fever greater than or equal to 103%F, abdominal symptoms, pancytopenia, markedly elevated ferritin and LDH as characterizing DH in AID patients. I200 Itraconazole Maintenance Treatment for Histoplasmosis in AIDS: Prospective Multi-Center Trial. F. Hecht, A. Korzun, J. Wheat, R. Hafner, San Francisco General Hospital, San Francisco CA, Harvard School of Public Health, Boston MA, Indiana University School of Medicine and Department of Veterans Affairs Hospital, Indianapolis IN; and NIH, Bethesda MD; and NIH ACTG. For disseminated histoplasmosis in patients with AIDS, itraconazole (itra) 200 mg twice daily was effective as maintenance therapy in patients who responded to amphotericin B induction therapy (ACTG 084, 5% 1-year relapse rate), and as induction therapy of non-severe cases (ACTG 120, 85% response rate). Patients responding to itra induction therapy in ACTG 120 continued it as maintenance therapy to prevent relapse. The maintenance dose was reduced to 200 mg daily if the plasma concentrations on the bid dose was greater than or equal to 4 mg/ml. of 46 patients enrolled in the maintenance phase, 42 (91%) reduced the dose to 200 mg daily. After a median follow-up of 87 weeks, only 1 patient relapsed (2.2% 1-year relapse rate), and that patient was non- compliant with treatment. He promptly responded to itra reinduction treatment and was maintained successfully on the once daily dosage during 9 months of follow-up. Itra was well tolerated, with only 4 patients (8.7%) withdrawn for adverse events (rash in 1 and abnormal hepatic enzymes in 3). In conclusion itra is save and effective maintenance treatment in patients with non- severe histoplasmosis who responded to itra induction treatment. A dosage of 200 mg daily is adequate in most patients, substantially reducing the cost of therapy. I99 Disseminated Histoplasmosis (DH) in AID Cases in Argentina. Rey Kelly G, Perez H, Guelfand L, Kaufman S, Cahn P. Infectologia- Microbiologia, Htal Fernandez, Buenos Aires-Argentina. Objective: To describe 32 AIDS-associated DH treated in Buenos Aires. Methods: We studied 32 AIDS patients (pts) with DH from June 1989 to December 1994, 5 additional cases were excluded because of lost follow-up. Diagnosis of DH was confirmed by: Blood cultures by lysis-centrifugation in 27, bronchial washing in 7, skin scarification or biopsy in 21 cases. Patients were treated with amphotericin-B (AMB) 1000 to 1500 mg. or itraconazole (I) 400- 800 mg/day during 6 weeks. Pts were assigned to AMB if the treating physician classified the pt as severely ill or at risk for death. Survival was censored at February 1995. Itraconazole (200 mg/day) was used as maintenance therapy. Results: Clinical presentation of DH was: Fever>38C>3 weeks in 21 pts, enlarged liver and spleen in 7, anemia and leukopenia in 12, skin and mucosal lesions in 21, lung infiltrates in 11. In 24 cases, DH was the first opportunistic infection (OI) diagnosed. In 4 cases, DH was diagnosed simultaneously with other OI. AMB was used as initial therapy in 16 cases, I in the other 16. Four cases were shifted from I to AMB, 1 because of liver toxicity, and 3 because of disease progression. No patient died during the acute stage of DH. Mean survival was of 13.5 months (2-36). Three cases relapsed and died at 6, 7 and 9 months respectively (mean:7,3). Ten patients died because of other OI, with a mean survival of 12.1 (2-27). Mean survival of patients alive at February 1995 was 15.3 months (4-36). Conclusions: DH is in our series frequently the first OI diagnosed, and presents as a systemic disease. Therapy with AMB or I, followed by maintenance therapy with I resulted in complete remission in all but 3 pts, who improved when shifted to AMB. AMB and I showed as effective treatments for DH. Editor's Note A print copy of the abstracts from the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy held in San Francisco, September 17-22, 1995 can be obtained from: ASM Press, P.O. Box 605, Herndon, Virginia 22070. Voice: 800-546-2416. The cost is $25.00 plus $3.50 shipping and handling. A copy of the program is available for $10.00 plus S&H.