Impact of maternal integrase inhibitor use on offspring fat and bone development

About This Grant

Project Summary Highly effective antiretroviral therapy (ART) has significantly reduced the mother-to-child transmission of HIV but has also increased the number of children who are HIV exposed uninfected (HEU) and exposed to ART during gestation. Current national and international ART prescription guidelines now recommend maternal use of integrase strand transfer inhibitor (InSTI)–based regimens throughout pregnancy. Importantly, while InSTI use is associated with fat tissue expansion and impaired bone mass in adults and adolescence with HIV, the consequences of in utero exposure to InSTIs on offspring fat and bone development remain unknown. A key barrier to our understanding of these effects is the recent adoption of InSTI use during pregnancy, which limits the number and age of children exposed to InSTIs available for study. Therefore, to address this gap, our laboratory utilized a preclinical mouse model of gestational exposure to maternal InSTI-based ART and found long-lasting changes in offspring weight and bone length, suggesting that early InSTI exposure can disrupt normal developmental pathways. Building on these findings, the proposed study will investigate the mechanisms underlying impaired fat and bone development following exposure to maternal InSTI-based regimens. Due to the early exposure and the long-lasting tissue changes, we hypothesize that maternal and lactation exposure to InSTI-based ART causes epigenetic alterations associated with adverse fat and bone development in HEU children. To test our hypothesis, we will use our preclinical mouse model to investigate the longitudinal impact of various InSTI-containing regimens on key offspring development stages and evaluate the tissue level mechanisms, including epigenetic changes, associated with structural (mass) changes. To ensure clinical relevance, we will also leverage data and samples from the Pediatric HIV/AIDS Cohort Study (PHACS) and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) to evaluate whether epigenetic changes in HEU children differ between InSTI-based and InSTI-sparing regimens and are dependent upon the antiretrovirals used in combination with InSTIs. If successful, results from this proposal will inform safer ART prescribing during pregnancy and guide strategies to optimize lifelong health among children exposed to HIV and ART in utero.