Neural correlates of in utero HIV and ART exposure: early childhood follow-up of a prospectively recruited cohort

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Project Summary Programs to prevent vertical transmission of HIV have been extremely effective. As a result, there is an increasing population of HIV-exposed and uninfected children (CHEU). Currently, at least one in every five children (approximately 4.1 million children) in South Africa is HEU. These children face higher risks even though they are not infected, exhibiting reduced growth, neurodevelopmental delays and increased risk of severe infections and even death before age two years. In 2017, we started recruiting a cohort of pregnant women living with HIV who had either commenced triple-regimen ART prior to conception or during pregnancy immediately upon testing positive for HIV infection, along with uninfected women. We thus established a cohort of infants in three study arms viz. unexposed, exposed with ART throughout fetal development, and exposed with ART started later in pregnancy. In R01 HD085813, we imaged the children at 39-45 weeks equivalent gestational age with MRI to assess brain development, and we performed cognitive and clinical assessments at regular intervals. We observed structural, functional and metabolic differences in deep gray and white matter in CHEU, and poorer cognitive performance at 10 and 20 months. In R01 HD093578, we additionally studied the relationship between neuroimaging in infancy and between one and two years of age, and microbiome markers of infant development, including infant nutrition and breastmilk, to establish the relationship between gut microbial diversity, milk oligosaccharide composition and the brain. This study is ongoing. There is an urgent need to understand how and why children exposed to HIV are not thriving as well as their unexposed peers. Early life factors around birth may have consequences throughout life. In this study we will follow this well-characterized cohort established before birth to examine the effects of pre- and perinatal HIV/ART exposure on neurodevelopment around ages 6 and 8 years, using multimodality neuroimaging (morphometry, spectroscopy and connectivity) and clinical and cognitive assessments. This period is important as the children start school at 7 years. We expect to enroll 150 children from the original infant cohort. Our data will enable a longitudinal assessment of HIV/ART exposure on neurodevelopmental out-comes, and potential moderation by environmental factors, infant nutrition and maternal well-being and health. We will continue to sustain the capacity for pediatric neuroimaging and cognitive assessment built up over more than a decade of NIH-supported collaboration between Drs. Meintjes (University of Cape Town), Laughton (Stellenbosch University) and van der Kouwe (Massachusetts General Hospital). We will build new capacity for brain imaging in resource-limited settings by imaging our cohort with a low-field mobile MRI scanner alongside the high-field scanner. With these comparative images we will develop longitudinal morphometric analysis tools to discriminate between healthy and atypical neurodevelopment, making these algorithms cloud-ready so that they are accessible to users with limited computing resources.