Molloy, SF; Kanyama, C; Heyderman, RS; Loyse, A; Kouanfack, C; Chanda, D; Mfinanga, S; ... Harrison, TS; + view all Molloy, SF; Kanyama, C; Heyderman, RS; Loyse, A; Kouanfack, C; Chanda, D; Mfinanga, S; Temfack, E; Lakhi, S; Lesikari, S; Chan, AK; Stone, N; Kalata, N; Karunaharan, N; Gaskell, K; Peirse, M; Ellis, J; Chawinga, C; Lontsi, S; Ndong, J-G; Bright, P; Lupiya, D; Chen, T; Bradley, J; Adams, J; Van der Horst, C; van Oosterhout, JJ; Sini, V; Mapoure, YN; Mwaba, P; Bicanic, T; Lalloo, DG; Wang, D; Hosseinipour, MC; Lortholary, O; Jaffar, S; Harrison, TS; - view fewer (2018) Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa. The New England Journal of Medicine , 378 (11) pp. 1004-1017. 10.1056/NEJMoa1710922.

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Abstract

BACKGROUND: Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)–related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODS: We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTS: A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. CONCLUSIONS: One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509.)

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