Similar cortical morphometry trajectories from 5 to 9 years in children with perinatal HIV who started treatment before age 2 years and uninfected controls

Abstract

Background: Life-long early ART (started before age 2 years), often with periods of treatment interruption, is now the standard of care in pediatric HIV infection. Although cross-sectional studies have investigated HIV-related differences in cortical morphology in the setting of early ART and ART interruption, the long-term impact on cortical developmental trajectories is unclear. This study compares the longitudinal trajectories of cortical thickness and folding (gyrification) from age 5 to 9 years in a subset of children perinatally infected with HIV (CPHIV) from the Children with HIV Early antiRetroviral therapy (CHER) trial to age-matched children without HIV infection.

Methods: 75 CHER participants in follow-up care at FAMCRU (Family Centre for Research with Ubuntu), as well as 66 age-matched controls, received magnetic resonance imaging (MRI) on a 3 T Siemens Allegra at ages 5, 7 and/or 9 years. MR images were processed, and cortical surfaces reconstructed using the FreeSurfer longitudinal processing stream. Vertex-wise linear mixed effects (LME) analyses were performed across the whole brain to compare the means and linear rates of change of cortical thickness and gyrification from 5 to 9 years between CPHIV and controls, as well as to examine effects of ART interruption.

Results: Children without HIV demonstrated generalized cortical thinning from 5 to 9 years, with the rate of thinning varying by region, as well as regional age-related gyrification increases. Overall, the means and developmental trajectories of cortical thickness and gyrification were similar in CPHIV. However, at an uncorrected p < 0.005, 6 regions were identified where the cortex of CPHIV was thicker than in uninfected children, namely bilateral insula, left supramarginal, lateral orbitofrontal and superior temporal, and right medial superior frontal regions. Planned ART interruption did not affect development of cortical morphometry.

Conclusions: Although our results suggest that normal development of cortical morphometry between the ages of 5 and 9 years is preserved in CPHIV who started ART early, these findings require further confirmation with longitudinal follow-up through the vulnerable adolescent period.

Keywords: CHER; Children with HIV; Cortical thickness; FreeSurfer; Gyrification; Longitudinal; Vertex-wise.

Fig. 1

Colour map of regression coefficients showing rate of change from age 5 to 9 years of (left) cortical thickness and (right) local gyrification indices in HIV-uninfected (HIV-) children controlling for sex. Positive regression coefficients (red/yellow) indicate increases with age, while negative coefficients (cyan/blue) indicate decreases with age. The colour bar scale in each figure applies to both lateral (top) and medial (bottom) views. (N = 66 HIV- controls)

Fig. 2

Colour map of the vertex-wise regression coefficients of the effect on cortical thickness of A, B HIV status [β₃ in Eq. (2)] and C age by HIV status interactions [β₄ in Eq. (2)], respectively. In A and B, positive regression coefficients (red/yellow) indicate thicker cortex in CPHIV compared to uninfected controls and negative coefficients (cyan/blue) thinner cortex. In C, positive regression coefficients (red/yellow) indicate a greater rate of change of cortical thickness from age 5 to 9 years in CPHIV than uninfected controls, and negative coefficients (cyan/blue) indicate a slower rate of change. The colour bar scale in each figure indicates the effect size (Cohen’s d). While the scales in A and C extend to effect sizes required for significance at FDR-corrected p-values, the scale in B has been right censored to highlight clusters showing group differences that survive at uncorrected p < 0.005. For HIV status, effect sizes ≥ 0.06 and ≥ 0.29 are significant at uncorrected and FDR corrected p = 0.05, respectively. For age by HIV status interactions, effect sizes ≥ 0.09 and ≥ 0.31 are significant at uncorrected and FDR corrected p = 0.05, respectively. (N = 141: PHIV = 75, HIV − = 66)

Fig. 3

Developmental trajectories of cortical thickness from age 5 to 9 years in regions where the cortex of children with PHIV was thicker than in uninfected controls at an uncorrected p < 0.005. The shadows represent the 95% confidence interval (CI). (N = 141: PHIV = 75, HIV − = 66)

Fig. 4

Colour map of the vertex-wise regression coefficients of the effect on local gyrification indices of A HIV status (β₃ in Eq. (2)) and B HIV status by age interactions (β₄ in Eq. (2)), respectively. In A, positive regression coefficients (red/yellow) indicate greater gyrification in CPHIV compared to uninfected controls and negative coefficients (cyan/blue) less gyrification. In B, positive regression coefficients (red/yellow) indicate a greater rate of change from age 5 to 9 years in CPHIV than uninfected controls, and negative coefficients (cyan/blue) indicate a slower rate of change. The colour bar scale in each figure indicates the effect size (Cohen’s d). For HIV status and status by age interactions, respectively, effect sizes ≥ 0.30 and ≥ 3.77 are required for significance at an FDR corrected p = 0.05. (N = 141: PHIV = 75, HIV- = 66)