Structural brain differences in school-aged children who are HIV-exposed uninfected.

Abstract

Background: Antiretroviral therapy (ART) has dramatically reduced perinatal HIV transmission, leading to a growing population of children who are HIV-exposed but uninfected (CHEU). While the neuroanatomic developmental impacts of in utero HIV and ART exposure have been studied in young children, long-term effects on school-aged children are poorly understood, prompting this investigation.

Methods: Fifty-eight CHEU and 38 children who are HIV-unexposed, uninfected (CHUU), 6-12 years old, were recruited through hospitals and community groups in Ontario, Canada. From T1-weighted magnetic resonance images, volume, cortical thickness, and gray-/white-matter tissue volume were extracted. Multiple linear regression models controlling for sex, age, household income, and total brain volume were fit to assess differences by in utero HIV exposure, with additional sex-stratified analyses to uncover sex-specific effects.

Results: Compared with CHUU, CHEU showed total brain volumes that were significantly smaller by 49.7cm³ (95% CI [- 95.66, - 3.67]) and cortices thinner by 0.08 mm (95% CI [- 0.13, - 0.02]). In male CHEU, three regions displayed volumetric age-exposure interactions: the bilateral pars opercularis at 0.36 cm³/year (95% CI [0.10, 0.62]), left rolandic operculum at 0.22 cm³/year (95% CI [0.04, 0.39]) and left precentral gyrus at 0.71 cm³/year (95% CI [0.22, 1.21]), suggesting delayed maturation in those regions. Bilateral frontal lobe cortical thickness was reduced by 0.07 mm in CHEU (95% CI [- 0.14, - 0.006]), most pronounced in the left orbital middle frontal gyrus with a reduction of 0.20 mm among male CHEU (95% CI [- 0.32, - 0.07]). An age-exposure interaction of 0.06 cm³/year in bilateral amygdala volume (95% CI [- 0.11, - 0.01]) suggested reduced growth or altered developmental trajectory among CHEU, whereas male CHEU showed bilateral hippocampal volumes diminished by 0.21 cm³ (95% CI [- 0.40, - 0.01]).

Conclusions: These findings suggest that in utero HIV and ART exposure have broad neuroanatomic developmental impacts, particularly in boys, with significant differences in brain regions critical for motor function, expressive language, memory, and emotion. These structural differences align with previously reported motor and language deficits and highlight the importance of early intervention and tailored support strategies for CHEU.