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Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

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Molloy, Síle F., Kanyama, Cecilia, Heyderman, Robert, Loyse, Angela, Kouanfack, Charles, Chanda, Duncan, Mfinanga, Sayoki, Temfack, Elvis, Lakhi, Shabir, Lesikari, Sokoine, 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 ORCID: https://orcid.org/0000-0002-5489-6450, Bradley, John, Adams, Jack, van der Horst, Charles, van Oosterhout, Joep J., Sini, Victor, Mapoure, Yacouba N., Mwaba, Peter, Bicanic, Tihana, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, Wang, Duolao ORCID: https://orcid.org/0000-0003-2788-2464, Hosseinipour, Mina C., Lortholary, Olivier, Jaffar, Shabbar and Harrison, Thomas S. (2018) 'Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa'. New England Journal of Medicine, Vol 378, Issue 11, pp. 1004-1017.

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Abstract

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
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 252 Antifungal agents. Antifungal antibiotics
QW Microbiology and Immunology > Fungi. Pathogenic Fungi. > QW 180 Pathogenic Fungi
WA Public Health > WA 30 Socioeconomic factors in public health (General)
WL Nervous System > WL 200 Meninges. Blood-brain barrier
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Clinical Sciences & International Health > International Public Health Department
Digital Object Identifer (DOI): https://doi.org/10.1056/nejmoa1710922
SWORD Depositor: JISC Pubrouter
Depositing User: Stacy Murtagh
Date Deposited: 20 Mar 2018 14:29
Last Modified: 06 Dec 2018 11:25
URI: http://archive.lstmed.ac.uk/id/eprint/8382

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