Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis
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
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.).