Point-of-Care Cryptococcal Antigen Screening Predicts Cryptococcal Meningitis and Mortality Among People Living with HIV in a South African Township

Abstract

Background: Cryptococcal meningitis remains a leading cause of HIV-related mortality. Point-of-care tests for cryptococcal antigen (CrAg) may identify HIV-associated cryptococcal infections for administering anti-fungal preemptive treatment to prevent cryptococcal meningitis and death. Methods: We conducted a prospective study of adults presenting for HIV testing in Umlazi Township, South Africa. Among people living with HIV, we performed laboratory-based serum CrAg enzyme immunoassay (EIA) testing, and clinic-based testing of fingerprick capillary blood, venous whole blood, and urine with a rapid CrAg lateral flow assay (LFA) (Immy Diagnostics, Norman, USA). We followed participants for 12 months to assess cryptococcal meningitis and all-cause mortality using medical charts, hospital records, phone calls, and the national death registry. We used Cox proportional hazards to measure associations between baseline CrAg testing and progression to cryptococcal meningitis and/or death, controlling for age, sex, baseline CD4 count, and initiation of antiretroviral therapy. Findings: Among 2,379 HIV-infected adults, 1,370 (58%) were female; median CD4 count was 317 (IQR 173-491) cells/mm3. Overall, 50 (3.2%) participants were CrAg LFA positive by fingerprick capillary blood, 32 (2.0%) by venous whole blood, and 132 (8.4%) by urine. Among all participants after twelve months, 22 (0.9%) participants developed cryptococcal meningitis, 87 (3.7%) participants died, and 104 (4.4%) either developed cryptococcal meningitis or died. In unadjusted analyses, positive fingerprick and venous blood, but not urine, CrAg LFA results were associated with cryptococcal meningitis. In adjusted analyses, positive CrAg LFA results from fingerprick or venous blood had a 3.8 (95% CI 1.7-8.4) and 4.3 (95% CI 2.0-9.2) greater hazard of cryptococcal meningitis or death, with most events occurring within six months. Positive lab-based serum EIA had a 6.3 (95% CI 2.9-14.0) greater hazard of cryptococcal meningitis or death. Interpretation: Clinic-based CrAg LFA screening results strongly predict HIV-associated cryptococcal meningitis or death, and could provide a strategy for rapid anti-fungal prophylaxis or treatment initiation to improve HIV-associated outcomes. Funding: This work was supported by the Infectious Disease Society of America Education & Research Foundation and National Foundation for Infectious Diseases (PKD); Massachusetts General Hospital Executive Committee on Research (PKD); the Harvard University Center for AIDS Research [P30 AI060354] (PKD); and the National Institute of Allergy and Infectious Diseases [K23 AI108293] (PKD) and [R21AI110264] (IVB). Declaration of Interest: We declare that we have no competing interests. Ethical Approval: The study was approved by the University of Washington’s Institutional Review Board (IRB #49563) and the University of KwaZulu-Natal’s Medical Research Ethics Committee (Protocol #BF052/13). All study participants provided written informed consent.