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

评估产前接触多替拉韦的时间和程度以及儿童早期结局

• 批准号: 10381035
• 负责人: Jillian Pintye
• 金额: $ 119.46万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381035
• 关键词: 2019-nCoV; 37 weeks gestation; Address; Affect; Biological Assay; Biological Factors; Birth; Blood; Brain; Breast Feeding; COVID-19 vaccine; Child; Cytomegalovirus; Data; Enrollment; Evaluation; Exposure to; First Pregnancy Trimester; Frequencies; Future; Growth; HIV; HIV Infections; HIV Seronegativity; HIV-exposed uninfected infant; Hair; Human Milk; Immune; Individual; Infant; Kenya; Measures; Methods; Mothers; Nervous System Trauma; Neural Tube Defects; Outcome; Perinatal; Pharmaceutical Preparations; Population; Postpartum Period; Pregnancy; Pregnancy loss; Pregnant Women; Premature Birth; Regimen; Research; Research Infrastructure; Safety; Sampling; Second Pregnancy Trimester; Small for Gestational Age Infant; Spottings; Toxic effect; Viral; Woman; antiretroviral therapy; cohort; early childhood; fetal; follow-up; immune activation; in utero; infant outcome; microbiome; neonatal death; neurodevelopment; perinatal outcomes; postnatal; pre-exposure prophylaxis; prenatal; prenatal exposure; prepregnancy; prevent; repository; safety outcomes; safety study; stillbirth; transmission process

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.

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 150,000 名婴儿感染了艾滋病毒。 新 含有多替拉韦 (DTG) 的抗逆转录病毒治疗 (ART) 方案可实现孕妇快速病毒抑制 感染艾滋病毒的妇女（WLHIV），这可以促进消除艾滋病毒垂直传播。 WHO 建议将 DTG 作为所有人群的一线 ART，包括怀孕的 WLHIV。在肯尼亚，DTG 的推出 针对妊娠 WLHIV 的一线 ART 开始于 2018 年。产前 DTG 使用的安全数据令人放心，但研究 迄今为止，随访时间不足 1 年，且未量化 DTG 暴露。对长期结果的评估 需要测量 DTG 暴露。评估抗逆转录病毒治疗后的长期神经发育结果 曝光度也仍然至关重要。子宫内 HIV 暴露可能会危及 HIV 暴露未感染者 (HEU) 由于母体免疫激活影响发育中的胎儿大脑而影响儿童的神经发育。神经科 ART 可以逆转子宫内 HIV 暴露造成的损害。然而，ART 暴露可能会影响 HEU 婴儿 ART 相关毒性导致的神经相关结果。迄今为止，还没有研究比较神经发育结果 暴露于 HIV 和 ARV 的 HEU 儿童与未暴露于 HIV 的未感染 (HUU) 儿童之间的比较 仅抗逆转录病毒药物暴露。我们正在肯尼亚对婴儿 PrEP 暴露进行安全评估 (n=1300) 神经发育评估（R01HD100201，PrIMA-X）。我们建议使用我们正在进行的 PrEP 中的数据 安全性评估并建立一个新的接受 DTG-ART 暴露的 HEU 婴儿队列，以评估出生、生长、 暴露于 HIV 和 ARV 的 HEU 婴儿与仅暴露于 ARV 的 HUU 婴儿的神经发育结果不同 暴露，以及既未暴露于 HIV 也未暴露于 ARV 的 HUU。对于目标 1，我们将建立一个新的怀孕队列 WLHIV 在特定时间点启动 DTG——受孕前；第一个和第二个三个月——并收集头发样本 来自怀孕期间的 WLHIV（每月）、来自分娩时的母婴对以及母乳样本 产后（6 周、14 周；6 个月、9 个月）评估累积 DTG 暴露。我们将使用以下方法量化 DTG 水平 验证化验并评估头发 DTG 水平（代表转移程度）的婴儿与母亲的比率。目的 2 将重点评估婴儿结局（早产<孕37周、小于胎龄<10周） 怀孕/哺乳期间接触 DTG 后的百分位、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 暴露于 DTG 和 HIV 的妊娠结局。目标 3 将另外利用我们正在进行的数据 PrIMA-X 研究评估 36 个月内的围产期、生长和神经发育结果是否存在差异 暴露于 ARV 的 HEU 婴儿 (DTG-ART)、仅暴露于 ARV 的 HUU 婴儿 (PrEP) 和 HUU 之间 未接触过 HIV 或 ARV 的婴儿。该项目与其他 P01 项目协同作用，这些项目审查 可能影响 HEU 结果的替代生物因素。项目1还将提供母婴样本 用于未来研究的储存库（头发、干血斑和母乳）。