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Single dose of liposomal amphotericin B as effective in treating HIV-associated cryptococcal meningitis as current standard of care
24 March 2022
An EDCTP-funded phase III trial of the AMBITION-cm research team confirms that an alternative formulation of amphotericin B, delivered in tiny lipid-based packages (liposomes), would be more suitable for resource-poor settings than the current treatment regimen. The results of the trial, which were published in the New England Journal of Medicine on 23 March, show that a single high-dose liposomal amphotericin B given with 14 days of flucytosine and fluconazoleis as good as the current recommended treatment regimen at reducing mortality at 10 weeks and has fewer side effects. These promising results strengthen hope that treatment of one of the most important causes of HIV-associated mortality in Africa can be transformed.
The AMBITION-cm trial is the largest HIV-associated cryptococcal meningitis treatment trial ever undertaken. An earlier phase II study already showed that a single high dose of liposomal amphotericin B (AmBisome®) given with 14 days of flucytosine and fluconazole is non-inferior to the current standard of care of seven days of amphotericin B plus seven days of flucytosine, followed by seven days of fluconazole, in the treatment of HIV-associated cryptococcal meningitis (CM).
Building on these promising findings, the phase III AMBITION-cm trial compared a one-week course of amphotericin B with single high-dose liposomal amphotericin B. The trial, which took place in five African countries, confirmed that a single-dose liposomal amphotericin B plus 14 days of flucytosine and fluconazole is as good as the current recommended treatment regimen at reducing mortality at 10 weeks, is easier to administer and better tolerated.
Despite its major burden in sub-Saharan Africa, cryptococcal meningitis remains under-studied and under-funded. Cryptococcal meningitis is an important cause of morbidity and mortality among people with advanced HIV disease and accounts for an estimated 15% of all AIDS-related deaths globally, of which three quarters occur in sub-Saharan Africa. In 2014, it is estimated that 223,100 cases of cryptococcal meningitis resulted in 181,000 deaths. The 2019 G-FINDER annual report highlighted the fact that the bulk of non-USA funding was routed through EDCTP, and accounted for 85% of global funding on clinical development.
The current recommended induction treatment consists of a one-week course of amphotericin B deoxycholate and flucytosine, followed by 1 week of fluconazole. This regimen is however not widely available in most African countries as access to both amphotericin B and flucytosine is limited. Even when registered, amphotericin B is rarely used in African settings because it has to be given intravenously over one week and can trigger severe toxic reactions so patients require specialist monitoring. The AMBITION-cm phase III trial aimed to improve this situation and follow-up funding from the US Centers for Disease Control and Prevention (CDC) has been allocated to help implement the study findings.
About the study
The study was conducted by the London School of Hygiene & Tropical Medicine, the Infectious Diseases Institute at Makerere University, Kampala, Uganda, the Malawi-Liverpool Wellcome Trust Clinical Research Unit, University of North Carolina Project in Malawi, University of North Carolina Project in Malawi, the University of Cape Town in South Africa, the Botswana-Harvard AIDS Institute Partnership, and the University of Zimbabwe, with European collaborators at St. George’s University of London, the Liverpool School of Tropical Medicine and University of Liverpool, and the Institut Pasteur in Paris.
The study was funded by EDCTP, the Swedish International Development Cooperation Agency, and the UK Department of Health and Social Care, the UK Foreign Commonwealth and Development Office, the UK Medical Research Council and Wellcome Trust, through the Joint Global Health Trials scheme.