Cognitive impairment in children and adolescents living with perinatal HIV disease in the ART era: a meta-analysis

Background Despite improved survival and overall health outcomes from modern antiretroviral therapy (ART), children and adolescents living with HIV are facing pervasive impairments in neurodevelopment including cognitive impairment, but there remains a lack of consensus on the cognitive domains that are affected in those children and adolescents. The objective of this meta-analysis was to evaluate the impact of perinatal HIV-infection on executive function, working memory, and speed of information processing in the ART era. Methods The PubMed database was searched for studies published between 1997 and 2024, plus additional search with the ScienceDirect, bioRxiv, and medRxiv databases. A meta-analysis was conducted on thirty-five studies published between 2012 and 2023 that encompassed a total of 4066 perinatally-infected HIV patients, 2349 HIV-exposed uninfected (HEU) controls, and 2466 HIV-unexposed, uninfected (HUU) controls. Performance scores on executive function, working memory, and processing speed were pooled using random-effects meta-analysis. Findings Compared to HEU and HUU controls, perinatally HIV-infected children and adolescents presented with significant impairments in processing speed (Hedges g = −0.64, p < 0.00001), working memory (Hedges g = −0.69, p < 0.00001), and to a lesser degree, executive function (Hedges g = −0.35, p = 0.02). Meta-regression analysis suggested that the effect estimate of processing speed impairment negatively correlated with Gross National Income (GNI) per capita of the study countries (CALHIV vs HUU, p = 0.0016; CALHIV vs HEU, p = 0.0019), even though HIV-infected cases were compared to sociodemographically matched HUU controls from the same countries. Sub-group meta-analyses with participants from high-income or low-/middle-income countries provided further evidence suggesting that the performance gap between HIV-infected cases and HUU/HEU controls may be larger in low-/middle-income countries than high-income countries. Interpretation In the ART era, cognitive impairment (especially reduced processing speed and working memory) persists in children and adolescents living with HIV. These impairments may be more pronounced among those children and adolescents living with HIV in low-income countries, suggesting that there may be global health inequities in treatment outcomes with perinatal HIV-infection. However, meta-analysis and meta-regression analysis have their limitations, which calls for future collaborative multi-country international studies to directly investigate this important topic. Nevertheless, there is an unmet need to assure equity in timely assessments and interventions to optimize neurocognitive development and outcomes among children and adolescents with perinatal HIV globally. Funding This research was supported in part by NIH R01MH108466, NIH R56NS124422, and NIH R01NS124422.