In HIV-infected adults/children with CD4<100 cells/ul starting ART in sub-Saharan Africa, the REALITY trial (ISRCTN43622374) showed that an enhanced prophylaxis (Px+) package (minimum cost $5.6) including 12 weeks’ fluconazole 100mg OD at ART initiation significantly reduced all-cause mortality, mortality from unknown causes and cryptococcus, and incidence of new cryptococcal disease vs cotrimoxazole alone (CTX). We assessed the impact of enrolment cryptococcal antigen (CRAG) status on these outcomes.
Stored enrolment plasma was tested using the IMMY CrAg lateral flow assay. Logistic regression with backwards elimination (p>0.1) identified independent predictors of baseline CRAG status, and proportional hazards models estimated the impact of Px+ vs CTX on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks by baseline CRAG.
1550(86%) adults from Kenya, Uganda and Zimbabwe (Malawi results pending) with median baseline CD4 36 cells/ul (IQR 16-63) and VL 275,700 c/ml, were randomized to CTX (n=771) vs Px+ (n=779). Excluding 23 (1.5%) with active cryptococcal disease at enrolment, 55(7.3%) vs 51(6.7%) were CRAG+ in CTX vs Px+ respectively. CRAG+ patients had lower CD4 (OR=0.90 per 10 cells/ul higher (95% CI 0.83-0.97) p=0.006) and were less often female (OR vs male=0.68 (0.45-1.02) p=0.06). Over 24 weeks on ART, there were 96 CTX vs 68 Px+ deaths. 6 of 7 CTX deaths and 2 of 3 Px+ deaths due to cryptococcal disease were CRAG+, whereas there was only 1 CRAG+ among 44 deaths from unknown causes in CTX vs 1 among 24 on Px+. Over 24 weeks, there were 12 CTX vs 6 Px+ new cryptococcal meningitis cases; 10 vs 5 respectively were baseline CRAG+. Px+ reduced new cryptococcal disease equally in CRAG+ (HR=0.50) and CRAG- (HR=0.49) (interaction p=0.99) (figure); similarly for all deaths (interaction p=0.93). Of 49 patients treated for cryptococcal disease post-enrolment, only 12(24%) were CRAG+ at enrolment.
∼7% patients were CRAG+ pre-ART, without overt cryptococcal disease. CRAG+ was rare among unknown deaths suggesting these were unlikely due to cryptococcus. The relative benefits of fluconazole-containing Px+ were similar among CRAG+ and CRAG- patients. These data support the use of this affordable fluconazole-containing enhanced Px+ bundle in this severely immunocompromized group, particularly where costs of tests are similar to costs of fluconazole ($2.6) or where availability is limited.