High Mortality Associated with Unmasking Cryptococcal Meningitis

Abstract

Introduction: Increased antiretroviral therapy (ART) availability in Africa has led to more patients developing cryptococcosis after ART initiation. Despite this changing epidemiology, data regarding cryptococcal meningitis (CM) in those already receiving ART are lacking. Preliminary analyses (2015; n=172) suggested poor outcomes of unmasking CM with recent ART initiation. We sought to confirm and further characterize this observation by comparing clinical presentation and outcomes in a large cohort of ART-naïve and ART-experienced adults. Methods: We prospectively enrolled 627 HIV-infected persons with CM in Uganda from August 2013 to May 2017. Participants were classified by ART status and the timing of ART initiation. Statistical comparisons were made with Kruskal-Wallis or Fisher’s Exact tests, with a primary endpoint of 2-week survival. Results: Overall, 48% (301/627) of participants were receiving ART at presentation, having initiated ART a median of 126 (IQR, 29-760) days prior to CM diagnosis. Compared with those not receiving ART, participants receiving ART had higher CD4 counts (median 30 (IQR, 10-79) vs 12 (IQR, 6-46) cells/μL; p=.02) and lower CSF fungal burdens (median 4.1 (IQR, 2.1-5.2) vs 5.0 (IQR, 4.0-5.6) log10 CFU/mL CSF; p<.001). Of those receiving ART, 50% (150/301) had initiated ART ≤ 4 months, and 16% (48/301) had initiated ART ≤ 14 days. Persons starting ART ≤ 4 months prior were more likely to present with CSF pleocytosis (47% vs 30%; p=.003) compared to those initiating ART > 4 months prior to diagnosis. Among persons receiving ART for > 4 months, 80% had HIV viral loads > 1000 copies/mL. Two-week mortality did not differ by overall ART status (27% vs 26%; p=.86). However, 50% (24/48) of those receiving ART for ≤ 14 days died within 2-weeks compared with 19% (19/102) of those receiving ART for 15-122 days and 23% (35/151) of those receiving ART for > 4 months (p<.001). Hazard ratio for mortality decreased as the duration from ART initiation to development of CM increased from 7 to 28 days. Conclusions: Cryptococcosis after ART initiation is common in Africa. Patients initiating ART who unmask cryptococcal meningitis are at a high risk of death. Immune recovery in the setting of CNS infection is detrimental, and management of this population requires further study. Implementing pre-ART cryptococcal antigen screening is urgently needed to prevent CM after ART initiation.