Predictors of immunological non-response despite virological suppression in people living with HIV on antiretroviral therapy: A systematic review and meta-analysis

Immunological Nonresponse (INR) in people living with HIV (PLWH) is characterized by inadequate CD4 + T-cell recovery despite effective viral suppression through antiretroviral therapy (ART). This systematic review and meta-analysis identify key clinical, demographic, and molecular predictors of INR to optimize immune recovery strategies. A comprehensive literature search was conducted in accordance with PRISMA 2020 guidelines, yielding 59 eligible studies, with a total of 19,511 individuals with INR. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and pooled effect estimates were calculated as odds ratio (OR), mean difference (MD), or standardized mean difference (SMD). Significant predictors of INR included male sex [OR 1.33 (1.12–1.58)], older age [MD 2.61 (1.42–3.81)], intravenous drug use [OR 1.67 (1.15–2.42)], hepatitis B coinfection [OR 1.30 (1.08–1.57)], hepatitis C coinfection [OR 1.85 (1.50–2.28)], tuberculosis [OR 1.77 (1.41–2.21)], advanced HIV stage [OR 2.66 (2.34–3.02)], and lower baseline and nadir CD4 + counts [SMD −3.82 (−4.94-(−2.70)), SMD −1.69 (−2.69-(−0.68))], respectively. Additionally, 57 biomarkers were identified as potential predictors of INR, implicating several immunological pathways. These findings underscore the multifactorial nature of INR and the need for personalized approaches among ART-treated individuals.