Evaluating timing and extent of prenatal exposure to dolutegravir and early childhood outcomes

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Despite strides in preventing vertical HIV transmission globally, 150,000 infants still acquired HIV in 2019. New antiretroviral therapy (ART) regimens containing dolutegravir (DTG) achieve rapid viral suppression in pregnant women living with HIV (WLHIV), which could facilitate elimination of vertical HIV transmission. The WHO recommends DTG for first-line ART in all populations, including pregnant WLHIV. In Kenya, rollout of DTG as first-line ART for pregnant WLHIV began in 2018. Safety data on prenatal DTG use are reassuring, yet studies to date have <1 year of follow-up and do not quantify DTG exposure. Evaluations of longer-term outcomes with measured DTG exposure are required. Assessing longer-term neurodevelopmental outcomes following ARV exposure also remains crucial. HIV-exposure in-utero may compromise HIV-exposed uninfected (HEU) children’s neurodevelopment due to maternal immune activation affecting the developing fetal brain. Neurologic damage caused by HIV exposure in utero could be reversed by ART. Yet, ART exposure may impact HEU infant neuro-related outcomes due to ART-related toxicity. To date, no studies compare neurodevelopment outcomes between HEU children with both HIV and ARV exposure and HIV-unexposed uninfected (HUU) children with only ARV exposure. We are conducting a safety evaluation (n=1300) in Kenya of infant PrEP exposure with neurodevelopmental assessment (R01HD100201, PrIMA-X). We propose using data from our ongoing PrEP safety evaluation and building a new cohort of HEU infants with DTG-ART exposure to evaluate if birth, growth, or neurodevelopment outcomes differ for HEU infants with both HIV and ARV exposure, HUU with only ARV exposure, and HUU with neither HIV nor ARV exposure. For Aim 1, we will establish a new cohort of pregnant WLHIV who initiate DTG at specific timepoints—pre-conception; 1st and 2nd trimester—and collect hair samples from WLHIV in pregnancy (monthly), and from mother-infant pairs at delivery, and along with breastmilk samples postpartum (6wks, 14wks; 6mos, 9mos) to assess cumulative DTG exposure. We will quantify DTG levels using validated assays and assess infant-to-maternal ratios of hair DTG levels (representing degree of transfer). Aim 2 will focus on evaluating infant outcomes (preterm delivery <37 weeks gestation, small for gestational age <10th percentile, stillbirth, neonatal death, growth) following DTG exposure during pregnancy/breastfeeding and will determine whether timing of DTG initiation or extent of DTG exposure are associated adverse birth/infant outcomes among pregnancies exposed to DTG and HIV. Aim 3 will additionally utilize data from our ongoing PrIMA-X study to evaluate whether perinatal, growth, and neurodevelopmental outcomes up to 36 months differ between HEU infants with ARV exposure (DTG-ART), HUU infants with only ARV exposure (PrEP), and HUU infants with neither HIV nor ARV exposure. This Project synergizes with the other P01 Projects which examine alternate biologic factors that may influence HEU outcomes. Project 1 will also provide a maternal/infant sample repository (hair, dried blood spots, and breastmilk) for future studies.