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

尽管全球在预防艾滋病毒垂直传播方面取得了进展，但2019年仍有15万婴儿感染艾滋病毒。新 含度鲁特韦（DTG）的抗逆转录病毒治疗（ART）方案可在妊娠期快速抑制病毒 感染艾滋病毒的妇女（WLHIV），这可以促进消除艾滋病毒的垂直传播。世卫组织 建议DTG对所有人群（包括孕妇WLHIV）进行一线ART。在肯尼亚， 2018年开始为孕妇提供一线抗逆转录病毒治疗。产前使用DTG的安全性数据令人放心，但研究 迄今为止，随访时间<1年，未量化DTG暴露。长期结果评价 需要测量DTG暴露。评估ARV治疗后的长期神经发育结局 曝光率也仍然至关重要。子宫内接触艾滋病毒可能损害未感染艾滋病毒的人 儿童的神经发育由于母体免疫激活影响发育中的胎儿大脑。神经系统 子宫内艾滋病毒暴露造成的损害可以通过抗逆转录病毒治疗逆转。然而，抗逆转录病毒治疗暴露可能会影响高浓缩铀婴儿 ART相关毒性导致的神经相关结局。迄今为止，没有研究比较神经发育结果， 同时接触艾滋病毒和抗逆转录病毒药物的高浓缩铀使用儿童与未接触艾滋病毒和 只有抗逆转录病毒药物。我们正在肯尼亚进行一项婴儿PrEP暴露的安全性评价（n=1300）， 神经发育评估（R 01 HD 100201，PrIMA-X）。我们建议使用我们正在进行的PrEP的数据 安全性评价和建立新的接触DTG-ART的高浓缩铀婴儿队列，以评价出生、生长 或神经发育的结果不同，高剂量组婴儿同时接触艾滋病毒和抗逆转录病毒药物，高剂量组婴儿仅接触抗逆转录病毒药物， 暴露和HUU既没有HIV也没有ARV暴露。对于目标1，我们将建立一个新的孕妇队列， 在特定时间点启动DTG的WLHIV-妊娠前;第一和第二个三个月-并收集头发样本 从妊娠期WLHIV（每月）、分娩时母婴对以及沿着母乳样本中 产后（6周，14周; 6个月，9个月），以评估累积DTG暴露。我们将量化DTG水平使用 验证的测定和评估头发DTG水平的婴儿与母亲的比率（代表转移程度）。目的 第2阶段将侧重于评估婴儿结局（早产<37周妊娠，小于胎龄<10周 百分位数、死产、新生儿死亡、生长）， 确定DTG开始时间或DTG暴露程度是否与不良出生/婴儿相关 妊娠期暴露于DTG和HIV的结果。Aim 3还将利用我们正在进行的数据 PrIMA-X研究，以评估长达36个月的围产期，生长和神经发育结局是否不同 在接触抗逆转录病毒药物的高浓缩铀婴儿（DTG-ART）、仅接触抗逆转录病毒药物的高浓缩铀婴儿（PrEP）和高浓缩铀婴儿（HUU）之间， 未接触艾滋病毒或抗逆转录病毒药物的婴儿。该项目与其他P01项目协同工作， 可能影响高浓缩铀结果的其他生物因素。项目1还将提供一份母婴样本 储存库（毛发、干血斑和母乳），供未来研究使用。

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.