Maternal and Infant Health and HAART Outcomes in the Mashi PMTCT Study, Botswana

描述（由申请人提供）：我们在博茨瓦纳感染艾滋病毒的妇女及其婴儿中进行了一项大型随机临床试验（“Mashi研究”），以评估围产期抗逆转录病毒预防策略和婴儿喂养方法，这些策略和方法可以最大限度地减少艾滋病毒-1母婴传播（MTCT），同时优化婴儿存活率。向怀孕期间的母亲和所有婴儿提供一个月的短期齐多夫定（ZDV）；母亲和婴儿也在分娩/出生时随机接受单剂量奈韦拉平（sd NVP）或安慰剂，婴儿随机接受6个月母乳喂养+ 6个月ZDV预防，或配方饲料（FF）加1个月ZDV。在大多数母亲和婴儿中，暴露于sd NVP导致NVP耐药病毒，并且人们一直关注这种耐药对随后成人和儿童基于NVP的联合抗逆转录病毒治疗（HAART）反应的影响。我们（在知情同意和IRB批准的情况下）收集了这一有价值的母亲和婴儿队列的补充数据，以解决其他重要的科学目标。我们现在建议使用这些数据和样本来解决以下新目标，并且需要一年的额外资金来完成这项工作：1)评估在开始含有nnrti的抗逆转录病毒治疗后36个月（3年）出现病毒学应答（血浆HIV-1 RNA < 400拷贝/ mL）的妇女比例，这些妇女之前在分娩期间接受过单剂量NVP和安慰剂。2)评估先前暴露于围产期单剂量NVP的婴儿在开始含nnrti的ART治疗后长达36个月（3年）出现病毒学应答（血浆HIV-1 RNA < 400拷贝/ mL）的儿童比例。3)确定haart前耐药病毒婴儿的比例（在有和没有接触过单剂量NVP的婴儿中），并确定可检测到的基线NVP耐药是否预示着随后的失败。4)通过婴儿HIV-1状态和随机喂养策略，在24月龄和48月龄时使用简化的儿科神经发育评估（改良的DST-II和PEDSTest）以及纵向生长数据来研究儿童的生长和发育结局。5)探讨重复妊娠的相关因素及重复妊娠的产妇决策。公共卫生相关性：感染艾滋病毒的妇女每年生育200万名儿童，每年有42万名儿童新感染艾滋病毒-1，所有感染艾滋病毒的儿童中近90%生活在撒哈拉以南非洲地区。博茨瓦纳是一个南部非洲国家，是世界上HIV-1感染率最高的国家之一；2005年，孕妇的艾滋病毒血清感染率为33.4%。因此，研究母婴传播预防干预措施对母婴健康的影响以及随后的治疗方案至关重要。本应用程序的目的是使用在博茨瓦纳随机临床试验（“Mashi研究”）中收集的数据和样本来回答几个新的、重要的临床研究问题。提出的新目标与出生时曾接触过单剂量奈韦拉平的艾滋病毒感染婴儿的HIV-1耐药性有关；既往单剂量奈韦拉平与安慰剂暴露的hiv感染妇女和婴儿的长期（长达6年）抗逆转录病毒治疗结果；小儿神经发育和生长结果，通过婴儿喂养方式和抗逆转录病毒暴露史。

DESCRIPTION (provided by applicant): We conducted a large randomized clinical trial (the "Mashi Study") among HIV-infected women and their infants in Botswana, to evaluate peripartum antiretroviral prophylaxis strategies and infant feeding approaches that would minimize mother to children transmission (MTCT) of HIV-1 while optimizing infant survival. Short-course zidovudine (ZDV) was provided to mothers during pregnancy and to all infants for one month; mothers and infants were also randomized to receive single-dose nevirapine (sd NVP) or placebo at delivery/birth, and infants were randomized to either 6 months of breastfeeding + 6 months ZDV prophylaxis, or to formula feed (FF) with one month of ZDV. Exposure to sd NVP leads to NVP-resistant virus in most mothers and infants, and there is ongoing concern about the implications of this resistance for subsequent adult and pediatric NVP-based combination antiretroviral treatment (HAART) response. We collected (with informed consent and IRB approvals) supplementary data in this valuable cohort of mothers and infants in order to address additional important scientific objectives. We now propose using these data and samples to address the following new objectives, and need one year of additional funding to do this work: 1) To assess the proportion of women with virologic response (plasma HIV-1 RNA < 400 copies / mL) by up to 36 months (3 years) after initiating NNRTI-containing ART among women who previously received single-dose NVP versus placebo during labor. 2) To assess the proportion of children with virologic response (plasma HIV-1 RNA < 400 copies / mL) by up to 36 months (3 years) after initiating NNRTI-containing ART among infants who were previously exposed to peripartum, single-dose NVP. 3) To determine the proportion of infants with pre-HAART drug-resistant virus (among infants with and without exposure to single dose NVP), and to ascertain whether detectable baseline NVP drug resistance predicts subsequent failure. 4) To study pediatric growth and developmental outcomes, by infant HIV-1 status and by randomized feeding strategy, using abbreviated pediatric neurodevelopmental assessments (modified DST-II and PEDSTest) at 24 and 48 months of age as well as longitudinal growth data. 5) To study factors associated with repeat pregnancy, and maternal decision-making around repeat pregnancy. PUBLIC HEALTH RELEVANCE: Two million children are born to HIV-infected women each year, 420,000 children are newly infected with HIV-1 annually, and nearly 90% of all HIV-infected children live in sub-Saharan Africa [1]. Botswana, a southern African nation, has one of the world's highest HIV-1 infection rates; in 2005, HIV seroprevalence among pregnant women was 33.4% [2]. Studies related to the impact of MTCT prevention interventions on maternal and infant health and subsequent treatment options are therefore critical. The purpose of this application is to answer several new, important clinical research questions using data and samples that were collected in a randomized clinical trial (the "Mashi Study") in Botswana. The proposed new objectives pertain to HIV-1 drug resistance among HIV-infected infants with prior single-dose nevirapine exposure around the time of birth; long-term (up to 6-year) antiretroviral treatment outcomes among HIV-infected women and infants with prior single-dose nevirapine vs. placebo exposure; and pediatric neurodevelopmental and growth outcomes, by infant feeding modality and antiretroviral exposure history.