Effects of HIV and different anti-retroviral therapy (ART) regimes on brain structure in HIV infected children at age 7

Includes bibliographical referencesBy 2013, more than 300, 000 children were living with HIV-infection in South Africa. The World Health Organization (WHO) recommended early aggressive antiretroviral therapy (ART) initiation to manage HIV in children, based on studies that reported this protocol as effective in reducing mortality and HIV progression. Early ART initiation in HIV-infected children generated new concern about the long-term effects on neurodevelopment. There is still much to understand about the outcome of HIV and early ART on children's brain structure and neurocognitive skills. This study therefore investigated the effects of HIV and early ART on brain morphometry in 7-year old children using magnetic resonance imaging (MRI). Participants were 99 Xhosa children (56 HIV-infected children 43 uninfected controls, 50 boys, mean age = 7.21 ± 0.14 years) from the neuroimaging follow-on study of the Children with HIV Early Antiretroviral (CHER) trial. T1-weighted structural MRI data were acquired on a 3T Allegra (Siemens, Erlangen, Germany) within 6 months of their 7th birthday. In the CHER trial, HIV-infected infants were randomized at 7 weeks of age into three arms, two of which received immediate ART for either 40 or96 weeks. The third arm received ART when clinically or immunologically indicated by WHO 2006criteria. At age 7 years, all children were stable on ART. Scans were performed in accordance with protocols approved by the human research ethics committees of Stellenbosch and Cape Town Universities; all parents provided written informed consent and children provided oral assent. MRI scans were analysed with FreeSurfer's automated processing stream (http://freesurfer.net/) to generate measures of cortical thickness, local gyrification index (LGI), and regional (corpus callosum, bilateral caudate, hippocampus, putamen, thalamus, and lateral ventricle) and global brain volumes. Vertex-wise and region of interest (ROI) comparisons were performed between and within HIV infected and uninfected children. Relationships between morphometric and clinical data were investigated. Our results showed no significant difference in cortical thickness between HIV-infected and uninfected children. Uninfected children had greater gyrification than HIV-infected children in a left medial parietal region while HIV-infected children had smaller volumes of the bilateral putamen (p=0.001)and right hippocampus (p=0.01), and smaller total white (p=0.001) and gray (p=0.02) matter volumes. There was no effect of duration of ART in HIV-infected children except in the left hippocampus where longer (96 weeks) duration was associated with greater volume. There was no significant relationship between cortical thickness at age 7 and immunological status at enrollment, but regional (caudal middle frontal, pars orbitalis, lateral occipital and superior parietal regions) gyrification showed a relationship with immune system parameters (CD4 count, CD4percentage and CD4/CD8 ratio) respectively. A healthier immune system at enrollment - CD4percentage and CD4/CD8 ratio - was associated with reduced volume in the caudate nucleus, while longer cumulative duration on ART was associated with increased volume of the bilateral thalamus at age 7. There was no difference in brain volume or cortical thickness measures between HIV-exposed but uninfected (HEU) children and HIV-unexposed uninfected (HUU), but HEU children had greater gyrification in the left precuneus region which may be abnormal due to HIV/ART exposure in utero. In conclusion, LGI and subcortical volumes were affected in HIV-infected children but their cortical thickness was not affected. This may likely have effects on neurodevelopmental skills and cortical folding development