Barriers to and strategies for diagnosis of cryptococcal meningitis in people living with HIV in low-income countries

Cryptococcal meningitis (CM) is the second leading cause of AIDS-related mortality where the burden of advanced HIV disease is concentrated. Advances in diagnostics and treatment, including cryptococcal antigen (CrAg) screening and short-course antifungal regimens, have improved clinical outcomes in trials, but replicating these same benefits in routine care has proven more difficult. This review outlines the biological rationale for CrAg screening and examines the major operational barriers to effective CM diagnosis in low-income countries. An exploratory literature review identified peer-reviewed articles published before May 2025. We assess challenges for CD4 testing, CrAg screening, lumbar puncture (LP) performance, and routine surveillance. Novel approaches, including risk stratification with semi-quantitative CrAg testing are also described. The impact of recent diagnostic and treatment advances for cryptococcal disease has been constrained by gaps in implementation. Closing the diagnostic gap requires strengthening decentralized CD4 testing; expanding reflex and point-of-care CrAg, including use of semi-quantitative CrAg assays to prioritize those at highest risk for urgent LP and/or enhanced antifungal treatment; strengthening healthcare provider training, referral systems, LP access and enhancing community engagement. Integration of these measures into national HIV programs alongside operational research, could reduce mortality for patients and costs for health systems.