Impact of in utero HIV and antiretroviral exposure on the placenta and birth weight

About This Grant

PROJECT SUMMARY Significance: Providing antiretroviral therapy (ART) to pregnant women with HIV (WHIV) is a landmark global public health achievement, preventing millions of perinatal HIV infections. However, there are now >1 million children exposed to antiretrovirals (ARVs) born annually, a number expected to stabilize or increase over the next decade as WHIV and women exposed to HIV during conception and pregnancy are increasingly taking ARVs as treatment or prophylaxis against HIV (PrEP). To date, the effects and safety of ARVs taken in pregnancy are not fully established and prior research is limited by lack of objective measurement of ARV exposure, and data are lacking on the effects of ARVs on the placenta. Thus, there is a critical gap in knowledge about the impact of ARVs, including PrEP, and association with objective drug levels taken in pregnancy on the placenta and fetus, information needed for optimal ARV design and to advise women on the effects of ARVs taken as treatment or prevention during pregnancy to inform risk-benefit discussions. Innovation: We propose one of the first studies to simultaneously measure ARV levels in dried blood spots from pregnant women and their children’s hair to quantify drug exposure to PrEP and ART in utero and relate ARV levels to placental findings and birth weight. Distinct advantages of our proposed research over prior studies include 1) simultaneous collection and comparison of placentas from WHIV taking ART, HIV-uninfected women taking ARVs as PrEP, and HIV- uninfected women taking no ARVs, and 2) prospective enrollment and observation of pregnant women and children from these three groups to minimize bias, enhance rigor and reproducibility, and relate placental and birth outcomes to in utero exposures. Investigator team: PI Bebell has expertise in HIV epidemiology in pregnancy and placental effects. Co-I Ngonzi has expertise with HIV and pregnancy outcomes in Uganda. Biostatistician Correia has expertise in analyzing data from observational maternal-child outcomes studies in HIV-affected populations and mediation analysis. Approach: We will leverage stored dried blood spot and hair samples from the PI’s ongoing NIH-funded (R01HD112302) PACO cohort in Uganda, clinical and placental histopathology data from enrolled women and their children, established laboratory infrastructure at UCSF’s Hair Analytical Laboratory and AHRI’s pharmacology laboratory to elucidate the independent effects of HIV and ARV exposure on the placenta and birth weight through these Specific Aims: 1) Compare histologic placental abnormalities by ARV levels in neonatal hair and maternal DBS, and 2) Determine the effects of ARV exposure on birth weight and whether placental abnormalities mediate these effects. Determining the impact of ARVs in pregnancy on the placenta and birth weight and the possible mediating role of the placenta has great potential to improve child health through optimizing outcomes and inform choices for women accessing ARVs as treatment and prevention during pregnancy. By leveraging already-collected samples and data from an NIH-funded study, this proposal will inform practical strategies to improve ARV-related outcomes.