Access to flucytosine for the treatment of HIV-associated cryptococcal meningitis in Africa

Abstract

Cryptococcal meningitis, a major cause of meningitis in adults living with HIV infection, accounts for 15% of global HIV-associated mortality. 1 Rajasingham R Smith RM Park BJ et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis. 2017; 17: 873-881 Summary Full Text Full Text PDF PubMed Scopus (973) Google Scholar Treatment of cryptococcal meningitis involves three phases: induction, consolidation, and maintenance. The induction phase, which aims at reducing cerebral and meningeal fungal burden crucial for early survival, requires combination antifungal therapy and management of increased cerebrospinal fluid intracranial pressure. WHO in 2018 recommended at induction either 1-week amphotericin B deoxycholate plus flucytosine followed by high-dose fluconazole or 2-week oral fluconazole plus flucytosine. 2 WHOGuidelines for the diagnosis, prevention, and management of cryptococcal disease in HIV-infected adults, adolescents and children. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. https://www.who.int/publications/i/item/9789241550277Date: 2018 Date accessed: April 14, 2022 Google Scholar However, in the absence of flucytosine, fluconazole plus amphotericin B deoxycholate could be an alternative. The Advancing Cryptococcal Meningitis treatment for Africa trial on which these recommendations were based showed flucytosine to be a better drug at reducing mortality than is fluconazole in combination with amphotericin B deoxycholate. 3 Molloy SF Kanyama C Heyderman RS et al. Antifungal combinations for treatment of cryptococcal meningitis in Africa. N Engl J Med. 2018; 378: 1004-1017 Crossref PubMed Scopus (176) Google Scholar In a recent trial, a combination of single dose 10 mg/kg liposomal amphotericin B and 2-week flucytosine plus fluconazole showed non-inferiority and tolerance benefits to previously recommended induction therapy. 4 Jarvis JN Lawrence DS Meya DB et al. Single-dose liposomal amphotericin B treatment for cryptococcal meningitis. N Engl J Med. 2022; 386: 1109-1120 Crossref PubMed Scopus (9) Google Scholar These trials and some observational studies 5 Dromer F Mathoulin-Pelissier S Launay O Lortholary O French Cryptococcosis Study GDeterminants of disease presentation and outcome during cryptococcosis: the CryptoA/D study. PLoS Med. 2007; 4: e21 Crossref PubMed Scopus (280) Google Scholar provide data that confirm flucytosine as an important drug combination for inductive treatment of cryptococcal meningitis. However, access to this old, off patent drug is not guaranteed in Africa, South America, and Asia where the burden of cryptococcal meningitis is highest. 6 Loyse A Dromer F Day J Lortholary O Harrison TS Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J Antimicrob Chemother. 2013; 68: 2435-2444 Crossref PubMed Scopus (83) Google Scholar In South Africa, a region with a long-standing high burden of cryptococcal meningitis, flucytosine was only registered in December, 2021, by the South African Health Products Regulatory Authority (SAHPRA) despite the application being submitted 2 years previously by Viatris. 7 Application for WHO Model List of Essential Medicines: flucytosine (5FC). http://www.life-worldwide.org/assets/uploads/files/Flucytosine_63_CORE_AC.pdfDate: 2018 Date accessed: April 24, 2022 Google Scholar Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational studyIn-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. Full-Text PDF