Folate deficiency, peripartum antiretroviral drug exposure and neurodevelopmental outcomes at 6 - 18 years old in HIV affected and control children

This comparative study investigates the association between perinatal HIV status and long-term executive function (EF) during school-age and adolescence among children in a high HIV prevalence setting in Uganda. The study classified children into three perinatal HIV status groups determined by 18 months via DNA polymerase chain reaction and confirmed at cognitive assessment between ages 6 and 18 using rapid diagnostic testing: perinatally HIV-infected (PHIV), perinatally HIV-exposed uninfected (PHEU), and perinatally HIV-unexposed (PHU). The primary outcome was executive function measured using the Behavior Rating Inventory of Executive Function (BRIEF), summarized across eight subscales into the Global Executive Composite (GEC). EF was assessed via caregiver proxy-report for all children and via child self-report for those aged 11 years or older.

Analyses included descriptive statistics and standardized scoring by age and sex, with EF deficits warranting clinical vigilance defined as scores ≥ mean + 1.5 standard deviations. Proxy-reported EF measures were available for 166 children and self-reported measures for 82 children aged 11 and older. The study found a graded relationship between perinatal HIV status and mean GEC scores: highest deficits were observed in PHIV children (mean GEC = 121.9, SD = 29.9), intermediate deficits in PHEU children (mean = 107.5, SD = 26.8), and lowest deficits in PHU children (mean = 103.4, SD = 20.7), with a significant trend (P-trend < 0.01). The prevalence of GEC scores in the range warranting clinical vigilance was 15.8% in PHIV, 9.3% in PHEU, and 0% in PHU children (P-trend = 0.01). Nineteen percent (n = 32) of children had deficits requiring clinical vigilance in two or more proxy-reported EF subscales. Among these multisubscale deficits, occurrence differed by group: 35.1% in PHIV, 13.0% in PHEU, and 9.3% in PHU (P-trend = 0.001).

Multivariable linear regression analyses, adjusted for caregiver and child sociodemographic and health factors, found significantly higher GEC deficits for PHIV compared with PHU and PHEU children regardless of respondent. Proxy-reported EF did not differ significantly between PHEU and PHU groups; however, child self-reported GEC scores were elevated for PHEU children aged 11 years or older, with an increase of 12.8 units (95% CI: 5.4–25.5) compared with PHU, suggesting potential emerging or perceived EF difficulties among older PHEU youth.

These findings indicate that perinatal HIV infection is associated with persistent executive function deficits into school age and adolescence. The results also raise concern that some HIV-exposed uninfected children, particularly in later childhood or early adolescence, may experience elevated self-perceived executive function difficulties compared with unexposed peers. The authors emphasize the potential value of cognitive remediation interventions that target executive function as a strategy to improve long-term functional outcomes and survival in HIV-affected children in sub-Saharan Africa. They also highlight the need for future studies to clarify the relationship between perinatal HIV exposure without infection and later executive function, particularly during the transition to adolescence.