Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis

Joseph Jarvis (1, 2) , David Lawrence (3) , David Meya , Enock Kagimu , John Kasibante , Edward Mpoza , Morris Rutakingirwa , Kenneth Ssebambulidde , Lillian Tugume , Joshua Rhein , David Boulware , Henry Mwandumba , Melanie Moyo , Henry Mzinganjira , Cecilia Kanyama (4) , Mina Hosseinipour (4, 5) , Chimwemwe Chawinga , Graeme Meintjes (6) , Charlotte Schutz , Kyla Comins , Achita Singh , Conrad Muzoora , Samuel Jjunju , Edwin Nuwagira , Mosepele Mosepele , Tshepo Leeme , Keatlaretse Siamisang , Chiratidzo Ndhlovu , Admire Hlupeni , Constantine Mutata , Erik van Widenfelt , Tao Chen , Duolao Wang , William Hope , Timothée Boyer-Chammard (7, 8, 9) , Angela Loyse , Síle Molloy , Nabila Youssouf , Olivier Lortholary (7, 8, 9) , David Lalloo , Shabbar Jaffar , Thomas Harrison , Ambition Study Group

1 LSHTM - London School of Hygiene and Tropical Medicine
2 Bostwana Harvard AIDS Institute Partneship Gaborone
3 NCAR - National Center for Atmospheric Research [Boulder]
4 UNC Project - University of North Carolina Project-Malawi
5 UNC - University of North Carolina [Chapel Hill]
6 University of Cape Town
7 Mycologie moléculaire - Molecular Mycology
8 CNRMA - Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals
9 CHU Necker - Enfants Malades [AP-HP]

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: 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%). 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.)

Domains: Life Sciences [q-bio]; Microbiology and Parasitology; Mycology

Joseph Jarvis, David Lawrence, David Meya, Enock Kagimu, John Kasibante, et al.. Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis. New England Journal of Medicine, 2022, 386 (12), pp.1109-1120. ⟨10.1056/NEJMoa2111904⟩. ⟨pasteur-03696185⟩