Early antiretroviral therapy not associated with higher cryptococcal meningitis mortality in people with HIV in high-income countries: an international collaborative cohort study

Background: Randomized trials (RCTs) from low- and middle-income settings suggested early initiation of antiretroviral therapy (ART) leads to higher mortality among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about impact of ART timing on mortality in similar people in high-income settings. Methods: Data on ART-naïve PWH diagnosed with CM from 1994-2012 from Europe/North America were pooled from the COHERE, NA-ACCORD and CNICS HIV cohort collaborations. Follow-up was considered from the date of CM diagnosis to earliest of the following: death, last follow-up or 6 months. We used marginal structural models to mimic an RCT comparing effects of early (within 14 days of CM) with late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders. Results: Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, median age was 38 years (interquartile range 33-44); CD4 count was 19 cells/mm3 (10-56); and HIV viral load was 5.3 log10 copies/mL (4.9-5.6). Most participants (157, 83%) were males and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants following early ART regimen and 20 deaths among those following late ART regimen. Crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% CI: 0.64, 2.56) and 1.40 (0.66, 2.95). Conclusions: We found little evidence that early ART was associated with higher mortality among PWH presenting with CM in high income settings, although confidence intervals were wide.