Cryptococcal-related mortality despite fluconazole pre-emptive treatment in a cryptococcal antigen (CrAg) screen-and-treat programme

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.