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N Engl J Med. 2018 Mar 15;378(11):1004-1017. doi: 10.1056/NEJMoa1710922.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa.

Author information

1
From the Centre for Global Health, Institute for Infection and Immunity, St. George's University of London (S.F.M., A.L., N.S., N. Karunaharan, J.A., T.B., T.S.H.), University College London (R.S.H.), and the MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine (J.B.), London, and Liverpool School of Tropical Medicine, Liverpool (T.C., D.G.L., D.W., S.J.) - all in the United Kingdom; the University of North Carolina Project-Malawi, Kamuzu Central Hospital, Lilongwe (C. Kanyama, C.C., C.H., M.C.H.), Malawi-Liverpool-Wellcome Trust Clinical Research Programme (R.S.H., N. Kalata, K.G., M.P., J.E.) and the College of Medicine, University of Malawi (R.S.H., N. Kalata, K.G., M.P., J.E., J.J.O.), Blantyre, and Dignitas International, Zomba Central Hospital, Zomba (A.K.C., P.B., D.L., J.J.O.) - all in Malawi; University of Dschang, Dschang (C. Kouanfack), Hôpital Central Yaoundé/Site Agence Nationale de Recherche sur le Sida (ANRS) Cameroun, Yaoundé (C. Kouanfack, S. Lontsi, J.-G.N., V.S.), and Douala General Hospital (E.T., Y.N.M.) and University of Douala (Y.N.M.), Douala - all in Cameroon; the Institute for Medical Research and Training (D.C., N.S., N. Karunaharan, P.B.), University Teaching Hospital (D.C., S. Lakhi, N.S., N. Karunaharan, P.B.), and the Department of Internal Medicine and Directorate of Research and Postgraduate Studies, Lusaka Apex Medical University (P.M.), Lusaka, Zambia; the National Institute for Medical Research, Muhimbili Medical Research Centre, Dar Es Salaam, Tanzania (S.M., S. Lesikari); Institut Pasteur, Molecular Mycology Unit (E.T., O.L.), and Paris Descartes University, Necker Pasteur Center for Infectious Diseases and Tropical Medicine, IHU Imagine, Assistance Publique-Hôpitaux de Paris (O.L.), Paris; the Division of Infectious Diseases, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto (A.K.C.); and the University of North Carolina, Chapel Hill (C.H., M.C.H.).

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 .).

PMID:
29539274
DOI:
10.1056/NEJMoa1710922
[Indexed for MEDLINE]
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