• Joseph N Jarvis, David S Lawrence, David B Meya, Enock Kagimu, John Kasibante, Edward Mpoza, Morris K Rutakingirwa, Kenneth Ssebambulidde, Lillian Tugume, Joshua Rhein, David R Boulware, Henry C Mwandumba, Melanie Moyo, Henry Mzinganjira, Cecilia Kanyama, Mina C Hosseinipour, Chimwemwe Chawinga, Graeme Meintjes, Charlotte Schutz, Kyla Comins, Achita Singh, Conrad Muzoora, Samuel Jjunju, Edwin Nuwagira, Mosepele Mosepele, Tshepo Leeme, Keatlaretse Siamisang, Chiratidzo E Ndhlovu, Admire Hlupeni, Constantine Mutata, Erik van Widenfelt, Tao Chen, Duolao Wang, William Hope, Timothée Boyer-Chammard, Angela Loyse, Síle F Molloy, Nabila Youssouf, Olivier Lortholary, David G Lalloo, Shabbar Jaffar, Thomas S Harrison, and Ambition Study Group.
• From the Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (J.N.J., D.S.L., N.Y.), the Institute for Infection and Immunity, St. George's University London (A.L., S.F.M., T.S.H.), and the Clinical Academic Group in Infection and Immunity, St. George's University Hospitals NHS Foundation Trust (T.S.H.), London, Liverpool School of Tropical Medicine (H.C.M., E.W., D.W., D.G.L., S. Jaffar) and the Department of Public Health, Policy, and Systems, Institute of Population Health (T.C.), and the Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology (W.H.), University of Liverpool, Liverpool, and the Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter (T.S.H.) - all in the United Kingdom; the Botswana-Harvard AIDS Institute Partnership (J.N.J., D.S.L., M. Mosepele, T.L., K. Siamisang, N.Y.), the Departments of Internal Medicine (M. Mosepele) and Family Medicine and Public Health (K. Siamisang), University of Botswana, and the Department of Health Services Management, Ministry of Health and Wellness (K. Siamisang) - all in Gaborone, Botswana; the Infectious Diseases Institute, College of Health Sciences (D.B.M., E.K., J.K., E.M., M.K.R., K. Ssebambulidde, L.T., J.R., D.R.B., S. Jjunju, E.N.), and the Department of Medicine, School of Medicine (D.B.M.), Makerere University, Kampala, and Mbarara University of Science and Technology, Mbarara (C. Muzoora, E.N.) - both in Uganda; the University of Minnesota, Minneapolis (D.B.M., J.R., D.R.B.); the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (H.C.M., M. Moyo, H.M., D.G.L.) and the Department of Medicine, Kamuzu University of Health Sciences (H.C.M., M. Moyo), Blantyre, and the Lilongwe Medical Relief Fund Trust (University of North Carolina-Malawi Project), Lilongwe (C.K., M.C.H., C.C.) - all in Malawi; the Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill (M.C.H.); the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G.M., C.S., K.C., A.S.), and the Department of Medicine (G.M., C.S., K.C.), University of Cape Town, and the Department of Radiology, Groote Schuur Hospital (A.S.) - both in Cape Town, South Africa; the Internal Medicine Unit, Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare (C.E.N., A.H., C. Mutata); Institut Pasteur, National Center for Scientific Research, Molecular Mycology Unit and National Reference Center for Invasive Mycoses and Antifungals, Unités Mixtes de Recherche 2000, and Université de Paris, Necker Pasteur Center for Infectious Diseases and Tropical Medicine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Institut Hospitalo-Universitaire Imagine - both in Paris (T.B.-C., O.L.).
• N. Engl. J. Med. 2022 Mar 24; 386 (12): 110911201109-1120.

BackgroundCryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known.MethodsIn this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin.ResultsA total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%).ConclusionsSingle-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).Copyright © 2022 Massachusetts Medical Society.

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