Molloy, Síle F; Kanyama, Cecilia; Heyderman, Robert S; Loyse, Angela; Kouanfack, Charles; Chanda, Duncan; Mfinanga, Sayoki; Temfack, Elvis; Lakhi, Shabir; Lesikari, Sokoine; +28 more... Chan, Adrienne K; Stone, Neil; Kalata, Newton; Karunaharan, Natasha; Gaskell, Kate; Peirse, Mary; Ellis, Jayne; Chawinga, Chimwemwe; Lontsi, Sandrine; Ndong, Jean-Gilbert; Bright, Philip; Lupiya, Duncan; Chen, Tao; Bradley, John; Adams, Jack; van der Horst, Charles; van Oosterhout, Joep J; Sini, Victor; Mapoure, Yacouba N; Mwaba, Peter; Bicanic, Tihana; Lalloo, David G; Wang, Duolao; Hosseinipour, Mina C; Lortholary, Olivier; Jaffar, Shabbar; Harrison, Thomas S; ACTA Trial Study Team; (2018) Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa. The New England journal of medicine, 378 (11). pp. 1004-1017. ISSN 0028-4793 DOI: https://doi.org/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 .).
Item Type | Article |
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Faculty and Department |
Faculty of Infectious and Tropical Diseases > Dept of Clinical Research Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology |
PubMed ID | 29539274 |
ISI | 427399000006 |
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