Systematic Review and Meta-analysis of Individual Participant Data on the Association Between Cryptococcal Antigen Titer Levels and Clinical Outcomes in People Living with HIV

Abstract

Background: Cryptococcal meningitis is a common opportunistic infection among people living with HIV, particularly in those with advanced immunosuppression. Cryptococcal antigen (CrAg) titers are thought to correlate with disease severity, including increased mortality risk, yet evidence on predictive thresholds is limited and based on small studies.

Methods: This meta-analysis assessed individual participant data from studies examining CrAg titers and clinical outcomes in people living with HIV. Databases were searched up to March 2024 for studies reporting CrAg titers and clinical outcomes, including mortality. Corresponding authors were contacted to obtain data, and various statistical analyses were performed, including Cox regression and Kaplan-Meier survival analysis.

Results: Data from eight studies were received and analysed. CrAg-positive patients had a significantly higher risk of mortality compared to CrAg-negative patients, with mortality risk increasing with higher CrAg titers. Patients with titers ≥2560 had the highest mortality risk (hazard ratio 3.13), even after adjusting for CD4 count, age, and gender. The ROC analysis identified a CrAg titer threshold of ≥160 as predictive of increased mortality.

Conclusions: Higher CrAg titers are associated with increased mortality independent of CD4 count. A CrAg titer of ≥160 may serve as a critical threshold for identifying high-risk patients who may benefit from intensified clinical management.