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.

尽管在全球范围内预防垂直艾滋病毒传播方面取得了长足的进步，但2019年仍有15万名婴儿获得艾滋病毒。 含有多拉特拉维尔（DTG）的抗逆转录病毒疗法（ART）方案在怀孕中实现了快速抑制病毒抑制 患有艾滋病毒（WLHIV）的妇女，可能有助于消除垂直艾滋病毒的传播。 WHO 在包括怀孕的WLHIV在内的所有人群中，建议用于一线艺术的DTG。在肯尼亚，DTG的推出 孕妇的一线艺术从2018年开始。有关产前DTG使用的安全数据令人放心，但是研究 迄今为止的随访<1年，并且没有量化DTG暴露。与长期结局的评估 需要测量的DTG暴露。评估ARV后的长期神经发育结果 暴露也至关重要。 HIV暴露于UTERO可能会损害未感染的HIV暴露于未感染的（HEU） 儿童的神经发育是由于遗传性免疫激活影响发育中的胎儿大脑的。神经系统 因艾滋病暴露造成的损害可能会被艺术逆转。然而，艺术曝光可能会影响HEU婴儿 由于与艺术相关的毒性，神经相关的结果。迄今为止，尚无研究比较神经发育结果 在HEU患有艾滋病毒和ARV暴露的儿童与未感染艾滋病毒的儿童之间 仅ARV暴露。我们正在肯尼亚对婴儿准备的安全评估（n = 1300）， 神经发育评估（R01HD100201，PRIMA-X）。我们建议使用正在进行的准备的数据 安全评估和建立新的HEU婴儿队列，以评估出生，成长，生长， 或神经发育结果与HIV和ARV暴露的HEU婴儿不同，HUU仅为ARV 暴露于艾滋病毒和ARV暴露的HUU。对于AIM 1，我们将建立新的怀孕队列 在特定时间点上启动DTG的WLHIV-PRE概念；第一和第二个三个月 - 收集头发样品 从怀孕（每月）的WLHIV以及分娩时的母亲成对，以及母乳样品 产后（6wks，14wks; 6mos，9mos）评估累积DTG暴露。我们将使用 经过验证的测定和评估头发DTG水平的婴儿与母亲比率（代表转移程度）。目的 2将专注于评估婴儿的结局（早产<37周妊娠，妊娠年龄<10 DTG暴露在怀孕/母乳喂养期间DTG暴露后的百分位数，死产，新生儿死亡，生长） 确定DTG计划的时间或DTG暴露程度是否与不良出生/婴儿有关 暴露于DTG和HIV的妊娠结局。 AIM 3将另外利用我们正在进行的数据 Prima-X研究评估围产期，生长和神经发育结局是否长达36个月不同 在ARV暴露（DTG-ART）的HEU婴儿之间 既没有艾滋病毒也不暴露于ARV的婴儿。该项目与其他检查的其他P01项目协同作用 可能影响HEU结果的替代生物学因素。项目1还将提供母亲/婴儿样本 存储库（头发，干血点和母乳）用于未来的研究。