Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study

Background Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines. Methods In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality. Findings From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38.7%) individuals received a flucytosine-containing regimen and 943 (61.3%) received another regimen. The median age was 36 years (IQR 32-43) and 906 (58.9%) participants were male and 633 (41.1%) were female. The crude in-hospital case-fatality ratio was 23.9% (95% CI 20.0-27.0; 143 of 596) in those treated with flucytosine-containing regimens and 37.2% (95% CI 34.0-40.0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1.95 [95% CI 1.53-2.48]; p<0.0001) and those who were antiretroviral treatment-experienced (aOR 1.30 [1.02-1.67]; p=0.033) were more likely to receive flucytosine. After adjusting for relevant confounders, flucytosine treatment was associated with a 53% reduction in mortality (aOR 0.47 [95% CI 0.35-0.64]; p<0.0001). Among survivors, the median length of hospital admission in the flucytosine group was 11 days (IQR 8-15) versus 17 days (13-21) in the comparison group (p=0.0010). Interpretation In-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. Copyright (c) 2022 Elsevier Ltd. All rights reserved.