Effectiveness of a national reflex laboratory cryptococcal antigen screening programme for people with advanced HIV disease in South Africa: A nationwide-sampled cohort study (CAST-NET)

Background:Cryptococcal antigen (CrAg) screening and pre-emptive treatment of antigenaemia can reduce mortality among people living with HIV.Setting:We evaluated the effectiveness of a national CrAg screening program in South Africa.Methods:We enrolled a retrospective cohort of adults aged ≥18 years with a CD4 count <100 cells/L and antigenaemia at 442 facilities in a stratified-random sample of 27 sub-districts, 2017-2019. We determined a composite outcome of incident cryptococcal meningitis or death through 6-months.Results:Overall, 99% (85,791/86,274) of eligible patients had CrAg testing in the study sub-districts; 5,124 (6.0%) tested CrAg-positive. Among 1,651 with imaged medical records and without concurrent meningitis, 76% (1,261/1,651) were outpatients. CrAg results were documented in records for 75% (1,245/1,651). Only 39% (649/1,651) had a meningitis symptom review documented at a median of 14 days (IQR, 5-44) from their CrAg blood draw. Fluconazole was dispensed for 50% (827/1,651) but only 32% (523/1,651) had an adequate daily dose of ≥800 mg dispensed. The proportion with meningitis or death within 6-months was 23% (382/1,651; 95%CI, 19%-27%). Hospitalised patients had a 2.29 higher adjusted odds of meningitis/death within 6-months versus outpatients (95% CI, 1.72-3.04; p<0.001).Conclusion:Nationwide reflex laboratory CrAg screening was successfully implemented. However, challenges existed for healthcare providers to act on positive CrAg results to exclude meningitis and dispense pre-emptive antifungal therapy. Our findings emphasise the critical need for improved linkage from reflex CrAg screening to clinical care, in both ambulatory and in-patient settings, to maintain the effectiveness of this intervention.