Early Antiretroviral Therapy in HIV-Infected Children Is Associated with Diffuse White Matter Structural Abnormality and Corpus Callosum Sparing

Abstract

Background, purpose Fractional anisotropy in the frontal white matter, corpus callosum and internal capsule are abnormal in HIV+ adults. We describe the distribution, nature of white matter abnormalities in a cohort of children who started ART within the first year of life - and benefit of early treatment using DTI measures (fractional anisotropy, mean, axial and radial diffusion). Materials, methods DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons were performed to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children. Associations of DTI parameters with timing of ART initiation were examined. Results 39 HIV+ children (15 male, mean age 5.4 years) and 13 controls (5 male, mean age 5.7 years) were imaged. 2 Clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group with symmetrical distribution predominantly due to increased radial diffusion, suggestive of decreased myelination. Corticospinal tracts rather than the corpus callosum were predominantly involved. Children on early interrupted ART had lower fractional anisotropy compared to those receiving continuous treatment. Conclusion HIV+ children at 5 years have white matter abnormalities measured by fractional anisotropy, despite early ART, suggesting that early ART does not fully protect the white matter either from peripartum or in utero infection. In contrast to adults, the corticospinal tracts are predominantly involved rather than the corpus callosum, possibly due to early ART. Continuous early ART can limit white matter damage.

White Matter Abnormalities in Children with HIV Infection and Exposure

“…Importantly, compared to Ackermann's study (Ackermann et al, 2016 ), the present study has an increased sample size and a group of HIV exposed, uninfected (HEU) children. While HEU children tend to be healthier than HIV+ children, studies find increased rates of infections and developmental delays compared to their HIV unexposed uninfected (HU) peers.…”

“…These children initiated ART before 18 months of age and have been followed since enrollment under 12 weeks of age. We have previously reported lower FA in corticospinal tract and MD increases in inferior/superior longitudinal fasciculi (ILF/SLF), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus (UF) in these children compared to uninfected controls at age 5 years (Ackermann et al, 2016 ), indicating that early ART may not fully protect WM development. Follow-up studies of infected children are particularly important for monitoring brain maturation in the presence of both HIV infection and ART, and the results can be used to identify critical time points for intervention.…”

Brain Magnetic Resonance Imaging Findings Associated With Cognitive Impairment in Children and Adolescents With Human Immunodeficiency Virus in Zambia

“…Frequently reported findings include decreased gray and white matter volumes, white matter hyperintensities, and diffusion tensor imaging abnormalities. 3,7,[12][13][14][15] Regional differences in brain volumes have been identified in the frontal and temporal lobes and basal ganglia, although findings have been inconsistent across studies. 7,8,12 Evidence of increased risk of cerebrovascular disease in children with HIV infection is also documented, with vasculopathy, opportunistic vasculitis, cardioembolism, and coagulopathy associated with HIV infection.…”

Recovery of HIV encephalopathy in perinatally infected children on antiretroviral therapy

“…Of 133 surviving participants who initiated ART at a median age of 9 weeks and who were followed until a median age of 6 years, 20 (12%) developed HIVE at a median age 31 months (interquartile range [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. In these, the first neurological deterioration was noticed at a median age of 19 months, when 16 were on ART and nine had undetectable HIV viral load for a median of 12 months.…”