AEGiS-11IAC: Comparison of two doses of clarithromycin in a randomized trial of four 3-drug regimens for treatment of disseminated Mycobacterium avium complex disease in AIDS: excess mortality associated with high-dose clarithromycin.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Comparison of two doses of clarithromycin in a randomized trial of four 3-drug regimens for treatment of disseminated Mycobacterium avium complex disease in AIDS: excess mortality associated with high-dose clarithromycin.

Int Conf AIDS 1996 Jul 7-12; 11:27 (abstract no. LB.B.6025)
Cohen DL, Fisher E, Franchino B, Hodges J, Chestnut J, Child C, Gilbert C, El-Sadr W, Hafner R, Ropka M, Heifets L, Clotfelter J, Munroe D, Caldwell R, Canady K, Horsburgh C; Denver CPCRA, Denver, CO. Fax: (303) 436-7211. E-mail: cohnd@essex.uchsc.edu.

OBJECTIVE: To compare the safety and efficacy of four regimens in treatment (Rx) of disseminated Mycobacterium avium complex disease (DMAC) in patients (pts) with AIDS.

METHODS: From 3/95 to 2/96, patients with AIDS and DMAC or presumptive DMAC were randomized to receive one of four 3-drug regimens in a factorial design; clarithromycin (CLA) 500 mg bid (C-500) or 1000 mg bid (C-1000); plus ethambutol 800-1200 mg qd; plus rifabutin (RBT) 300 mg qd or clofazimine (CLO) 100 mg qd. Pts were monitored for survival, clinical and microbiologic responses, toxicity, emergence of drug resistance, reports of well being, and adherence to study of drugs. After interim analysis in 2/96, the Data Safety Monitoring Board recommended discontinuation of the CLA dose comparison and all pts on C-1000 were dose-reduced to C-500. The study will continue follow-up until 8/96, when comparisons of the RBT and CLO arms and other analyses will be completed.

RESULTS: 85 pts were enrolled; 45 pts were randomized to receive C-500 and 40 pts C-1000. Baseline characteristics were similar for demographics, clinical findings, antiretroviral use, PCP prophylaxis and entry CD4 cells. Levels of mycobacteremia in mean log cfu/ml were 1.59 and 1.26 and number of CLA-resistant isolates (MIC greater than or equal to 32 ug/ml) were 2 and 4, for C-500 and C-1000, respectively. After mean follow-up of 4.4 months(C-500) and 4.7 months (C-1000), there were 10 deaths (22%,70/100 pt-yrs) for C-500 vs 17 deaths (43%, 159/100 pt-yrs.) for C-1000 (relative risk = 2.43, 95% CI 1.11-5.34, p=0.02). There were no differences in adverse events (AE), study drug discontinuations or self-reports of adherence. After 2 months, clinical improvement, as measured by decreases in fever and night sweats, were similar, and microbiologic responses (75% of pts had negative blood cultures) were the same in each group.

CONCLUSIONS: When used in a 3-drug regimen of Rx of DMAC, C-1000 was associated with excess mortality compared with C-500. There were no differences in demographics, clinical or microbiologic characteristics. AE, or adherence to Rx to explain the differences in survival. The reason(s) for excess mortality with C-1000 is unknown. In multidrug regimens for Rx of DMAC, CLA should be administered at a maximum dose of 500 mg bid.

Keywords: AEGIS, Mycobacterium avium Complex, Clarithromycin, Mycobacterium avium-intracellulare Infection, Acquired Immunodeficiency Syndrome, Rifabutin, Ethambutol, Clofazimine, Antibiotics, Macrolide, Antibiotics, Antitubercular, Pharmaceutical Preparations, Antibiotics, Combined, Mycobacterium Infections, Anti-HIV Agents, Human, therapy, mortality, drug therapy, ICA11

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