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Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis. 2022
Joseph N Jarvis, and
David S Lawrence, and
David B Meya, and
Enock Kagimu, and
John Kasibante, and
Edward Mpoza, and
Morris K Rutakingirwa, and
Kenneth Ssebambulidde, and
Lillian Tugume, and
Joshua Rhein, and
David R Boulware, and
Henry C Mwandumba, and
Melanie Moyo, and
Henry Mzinganjira, and
Cecilia Kanyama, and
Mina C Hosseinipour, and
Chimwemwe Chawinga, and
Graeme Meintjes, and
Charlotte Schutz, and
Kyla Comins, and
Achita Singh, and
Conrad Muzoora, and
Samuel Jjunju, and
Edwin Nuwagira, and
Mosepele Mosepele, and
Tshepo Leeme, and
Keatlaretse Siamisang, and
Chiratidzo E Ndhlovu, and
Admire Hlupeni, and
Constantine Mutata, and
Erik van Widenfelt, and
Tao Chen, and
Duolao Wang, and
William Hope, and
Timothée Boyer-Chammard, and
Angela Loyse, and
Síle F Molloy, and
Nabila Youssouf, and
Olivier Lortholary, and
David G Lalloo, and
Shabbar Jaffar, and
Thomas S Harrison, and
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.).
Cryptococcal 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. In 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. A 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%). Single-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.).
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Constantine Mutata, and
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Timothée Boyer-Chammard, and
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