A team of researchers from the University of Cape Town (UCT) participated in a research study to evaluate safer, shorter and more effective treatment for cryptococcal meningitis (CM) in under-resourced areas. The result of the research project, titled AMBIsome Therapy Induction OptimisatioN (AMBITION-cm), found a new treatment schedule that is at least as effective as current treatments, but better in terms of side effect profile.
Globally, there are roughly 230 000 cases of CM and 180 000 CM-related deaths each year, the majority of which occur in sub-Saharan Africa. Tackling the high mortality rate remains challenging. The current treatment for CM in sub-Saharan Africa is a seven- to 14-day course of amphotericin-B combined with oral antifungal tablets or oral fluconazole. The 10-week mortality with fluconazole treatment remains at approximately 60%, and standard treatment with amphotericin-B also has major drawbacks in terms of side effects.
Amphotericin-B is not widely available across Africa. It can cause kidney impairment and reduced blood counts. In addition, prolonged hospitalisation requires intensive nursing care and expensive laboratory monitoring which can be expensive for the healthcare system and the patient. Led by the research groups of Professor Joe Jarvis (at the London School of Hygiene and Tropical Medicine [LSHTM]) and Professor Tom Harrison (at St George’s, University of London [SGUL]), a global study was conducted to respond to the urgent need for a sustainable, cost-effective and easily administered treatment.
“Through this study we have established evidence for a shorter, less toxic but equally effective treatment method.”
The research groups had previously found that a single, high dose of AmBisome (a liposomal formulation of amphotericin B) was effective at clearing cryptococcus from around the brain. The AMBITION-cm study aimed to test the impact of this approach on deaths from CM in a large number of participants.
The trial recruited individuals from eight hospitals across seven cities in five countries in southern and eastern Africa. Adult patients with a first episode of HIV-associated CM were recruited and a total of 844 individuals were enrolled in the study. “Through this study we have established evidence for a shorter, less toxic but equally effective treatment method,” said Dr Charlotte Schutz of UCT’s Department of Medicine and the Centre for Infectious Diseases Research in Africa (CIDRI-Africa).
Partners in the study included UCT, Malawi-Liverpool-Wellcome Clinical Research Programme, the UNC Project in Lilongwe (Malawi), the Botswana Harvard AIDS Institute Partnership, the University of Zimbabwe, the Infectious Diseases Institute at Makerere University, the Liverpool School of Tropical Medicine, and Institut Pasteur.
The Ambition-CM South African team was composed of the national principal investigator, Professor Graeme Meintjes, and site principal investigator and sub-investigator, Dr Schutz, from UCT. The UCT team of sub-investigators included Dr Sumaya Sayed, Dr Kyla Comins, Dr Achita Singh, and Dr Lee-Ann Davids.
Collaborators from the Provincial Government of the Western Cape at Khayelitsha and Mitchells Plain Hospitals included Dr Thomas Crede, Dr Jonathan Naude, Dr Patryk Szymanski, Dr Deborah Maughan (Mitchells Plain), and Dr Ayanda Trevor Mnguni (Khayelitsha Hospital). Other team members included research nurse, Ida Manana Oliphant, and clinical research worker, Mkanyisela Kenneth Mpalali. Research nurse coordinator, Siphokazi Hlungulu, who was part of AMBITION-cm team for the duration of the trial, sadly passed away on 14 November 2021.
Largest trial to date
This was the largest cryptococcal meningitis trial conducted to date and demonstrated that single, high-dose AmBisome given with flucytosine and fluconazole was as good as the current World Health Organization eHeH(WHO) recommended standard of care in avoiding mortality. The AmBisome regimen effectively cleared cryptococcus from around the brain and was associated with a significant reduction in side events. “These results will be used to inform the WHO treatment guidelines,” said Dr Schutz. “It’s a very exciting trial to have been part of.”
“The next challenge is to ensure affordable access to liposomal amphotericin B and flucytosine for countries across Africa.”
“These findings provide the potential for a paradigm shift in the way cryptococcal meningitis is treated globally by reducing the number of intravenous doses of amphotericin from seven or 14 to one single infusion and thereby substantially reducing side effects without compromising efficacy. The next challenge is to ensure affordable access to liposomal amphotericin B and flucytosine for countries across Africa,” said Professor Meintjes.
The research project was supported by a grant through the European Developing Countries Clinical Trials Partnership, the Swedish International Development Cooperation Agency, and the Wellcome Trust / Medical Research Council (UK) / UKAID Joint Global Health Trials. This work was also funded by the National Institute for Health Research through a Global Health Research Professorship to Professor Jarvis using UK aid from the UK Government to support global health research.
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