Impact of HIV and antiretroviral exposure in pregnancy on neurodevelopment and growth: leveraging a well-characterized cohort to gain novel and comprehensive insights

About This Grant

PROJECT SUMMARY More than one million children who are HIV-exposed but uninfected (CHEU) are born to pregnant women with HIV (PWHIV) every year. CHEU have poorer early-life outcomes than HIV-unexposed peers, including significant neurodevelopmental deficits and a >2-fold risk of growth stunting. The pathophysiology and causes of adverse CHEU outcomes are incompletely understood, but mounting evidence suggests that adverse outcomes are multifactorial, with contributions from placental abnormalities, microbiome changes, exposure to maternal antiretrovirals, early-life infections, environmental exposures, and social determinants of health. Prior studies of the impacts of each of these individual factors and their contributions to CHEU outcomes have been limited by small sample sizes, poorly-characterized cohorts, short follow-up duration, outdated antiretroviral regimens, lack of advanced statistical analyses, and incomplete adjustment for confounders. There is a need for comprehensive analysis of well-characterized longitudinal studies that capture the complex pregnancy, placental, birth, early life, and environmental complexity of PWHIV and CHEU. Our central hypothesis is that adverse growth and neurodevelopmental outcomes in CHEU are complex and multifactorial, and that comprehensive analysis of large datasets from well-characterized cohorts is urgently needed to disentangle the contributions of individual factors and identify areas for intervention. We will leverage already-collected data from participants and linked placental, stool, blood, and hair sample analyses, and apply advanced statistical methods to comprehensively analyze existing robust clinical, laboratory, sociodemographic, and developmental outcomes data from our well- characterized cohort of PWHIV, their paired CHEU, and HIV-uninfected/HIV-unexposed comparators (n = 793 dyads) to identify multifactorial predictors of adverse neurodevelopmental and growth outcomes in CHEU through child age 6 years. Aims: 1) Identify clinical, laboratory, environmental, sociodemographic features that predict 1a) neurodevelopmental and 1a) growth outcomes in CHEU. 2) Estimate the effect of HIV exposure in utero and while breastfeeding on 2a) neurodevelopmental and 2b) growth outcomes in CHEU and evaluate whether this effect is mediated through placental abnormalities, and 3) Estimate effects of dolutegravir versus efavirenz antiretroviral exposure in pregnancy and breastfeeding on: 3a) neurodevelopmental and 3b) growth outcomes in CHEU. Leveraging existing data from an ongoing cohort, this uniquely comprehensive data analysis project will identify clinical, laboratory, environmental, and sociodemographic features associated with CHEU health outcomes and estimate the causal effects of HIV- and specific antiretroviral exposure. These aims directly address NIH priorities to understand mechanisms of comorbidities associated with HIV and complications of antiretroviral therapy and calls for comprehensive cohort studies to elucidate the complex co-occurring exposures in CHEU and identify potential interventions and has high potential for domestic and global impact to improve outcomes by informing antiretroviral selection and early identification and intervention for at-risk children.