Abstract

BACKGROUND: Cryptococcal antigen (CrAg) screening and treatment with pre-emptive fluconazole reduces the incidence of clinically-evident cryptococcal meningitis in individuals with advanced HIV-disease. However, mortality remains higher in CrAg-positive than in CrAg-negative patients with similar CD4+ T-lymphocyte counts. METHODS: We conducted a cohort study to investigate causes of morbidity and mortality during six-months follow-up, among asymptomatic CrAg-positive and CrAg-negative (ratio of 1:2) HIV-infected patients with CD4 counts <100 cells/µL attending two hospitals in Johannesburg, South Africa. When possible, minimally-invasive autopsy (MIA) was performed on participants who died. RESULTS: Sixty-seven CrAg-positive and 134 CrAg-negative patients were enrolled. Antiretroviral therapy (ART) was started 36 days (interquartile range 26-45) and 17 days (IQR 7-32) following screening in CrAg-positive and CrAg-negative participants respectively (p<0.001). Death occurred in 17/67 (25%) CrAg-positive and 12/134 (9%) CrAg-negative participants (hazard ratio for death, adjusted for CD4 count 3.0, 95% CI 1.4-6.7, p=0.006). Cryptococcal disease was an immediate or contributing cause of death in 11/17 (65%) CrAg-positive participants. Post-mortem cryptococcal meningitis and pulmonary cryptococcosis were identified at MIA in all four CrAg-positive participants, three of whom had negative cerebrospinal fluid CrAg tests from lumbar punctures (LPs) at the time of CrAg screening. CONCLUSIONS: Cryptococcal disease remained an important cause of mortality among asymptomatic CrAg-positive participants despite LPs to identify and treat those with subclinical cryptococcal meningitis, and pre-emptive fluconazole for those without meningitis. Thorough investigation for cryptococcal disease, prompt ART initiation and more intensive antifungals may reduce mortality among asymptomatic CrAg-positive patients identified through screening.