Professor Tom Harrison is leading major international trials that are transforming the treatment of cryptococcal meningitis.
In resource-poor settings, cryptococcal meningitis, estimated to account for 180,000 deaths per year world-wide, is typically treated with fluconazole which, although only weakly effective, is safe and affordable. A more effective option, amphotericin B, is more expensive, must be given intravenously, and its toxicity requires close monitoring of patients. It is therefore rarely used in sub-Saharan Africa.
In a bid to identify more effective alternatives to fluconazole, Professor Harrison and colleagues ran a series of Phase II studies which identified clinical benefits associated with higher-dose fluconazole, shorter courses of amphotericin B, and the combination of fluconazole with flucytosine (an anticancer drug with fungicidal properties).
The success of these studies led to an MRC-funded Phase III Advancing Cryptococcal meningitis Treatment for Africa (ACTA) trial, which compared the high-dose fluconazole–flucytosine combination with amphotericin-B-based regimens, at sites in Malawi, Zambia, Tanzania and Cameroon. Unveiled in 2017, the results provided strong evidence of the efficacy of short-course amphotericin and the fluconazole–flucytosine combination, with mortality rates halved compared with current treatments. In March 2018, WHO updated their guidance to recommend the short course amphotericin plus flucytosine regimen and the oral combination regimen as the preferred and second line choices. The results are also driving world-wide access to flucytosine, a component of the both best performing regimens.
Meanwhile, further trials are exploring a potential new generation of treatments incorporating AmBisome, a less toxic liposome-based formulation of amphotericin B. Following a successful phase II trial run in collaboration with Professor Joe Jarvis, a €10M EDCTP-funded phase III trial, AMBITION, is evaluating single high-dose AmBisome–oral combinations in Botswana, Zambia, Malawi, South Africa and Uganda.
Publications
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Molloy SF, et al. Antifungal Combinations for treatment of Cryptococcal Meningitis in Africa. New Engl J Med 2018 378:1004-17 doi: 10.1056/NEJMoa1710922.
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ACTA: results presented at IAS 2017
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Jarvis JN, et al. Short Course High-dose Liposomal Amphotericin B for HIV-associated Cryptococcal Meningitis: A phase-II Randomized Controlled Trial. Clin Infect Dis. 2018 Jun 26. doi: 10.1093/cid/ciy515.
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AMBITION: results presented at CROI 2017