Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

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:

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.).

• Authors: 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, Ambition Study Group
• Journal: The New England journal of medicine (N Engl J Med) Vol. 386 Issue 12 Pg. 1109-1120 (03 24 2022) ISSN: 1533-4406 [Electronic] United States
• PMID: 35320642 (Publication Type: Clinical Trial, Phase III, Equivalence Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Massachusetts Medical Society.

Chemical References

• Antifungal Agents
• liposomal amphotericin B
• Amphotericin B
• Fluconazole
• Flucytosine

Topics

• AIDS-Related Opportunistic Infections (drug therapy, mortality)
• Administration, Oral
• Africa South of the Sahara
• Amphotericin B (administration & dosage, adverse effects)
• Antifungal Agents (administration & dosage, adverse effects)
• Drug Administration Schedule
• Drug Therapy, Combination
• Fluconazole (administration & dosage, adverse effects)
• Flucytosine (administration & dosage, adverse effects)
• HIV Infections (complications)
• Meningitis, Cryptococcal (drug therapy, mortality)