Standard zidovudine plus infant nevirapine to prevent perinatal HIV in Thailand

描述(由申请人提供)：泰国第二次围产期艾滋病毒预防试验(PHPT-2)显示，在怀孕28周开始服用齐多夫定(ZDV)的基础上，对分娩开始时的妇女和48-72小时的婴儿单剂量服用奈韦拉平(SD-NVP)，可以将艾滋病毒围产期传播率降低到约2%。然而，在母亲身上检测到的暴露后NVP耐药突变引起了人们对基于非核苷逆转录酶抑制剂的治疗对自身健康的未来疗效的担忧。博茨瓦纳的一项研究结果表明，如果婴儿出生后立即给予SD-NVP，则可能不需要母亲的SD-NVP。这项研究的主要目的是测试是否可以省略母亲的SD-NVP，而不会失去预防围产期艾滋病毒传播的效果。没有产妇NVP和两个婴儿NVP剂量的方案，一个在出生后立即，另一个在48-72小时后，将与包括产妇在分娩期间的NVP剂量和相同的婴儿NVP剂量的方案进行疗效比较。ZDV的预防应从妊娠28周开始或之后尽快提供，产中负荷量，婴儿1周。所有婴儿都将接受配方奶喂养。为了降低选择NVP耐药突变的风险，暴露于NVP的母亲将按照世卫组织和泰国的指南接受ZDV加拉米夫定一个星期的疗程。第二个目标是研究HIV感染婴儿对NVP的耐药性突变，比较两种策略在母亲和婴儿中的安全性，并研究NVP在婴儿中的药代动力学。这项多中心、第三阶段、随机、双盲、对照试验将招募1398名自愿接受HIV-1感染的孕妇参加泰国公共卫生部(MoPH)预防计划，这些孕妇的CD4计数为200/mm3，分配到两个研究小组中的一个(每组699人，其中5%不可评估；功率：80%；小组间非劣势测试的增量阈值：1.5%)。根据出生时、1个月、2个月、4个月和6个月采集的样本的确认DNA-PCR结果，主要终点是婴儿的艾滋病毒状况。这项研究将建立在PHPT-1和PHPT-2的基础上，这是哈佛大学、法国IRD、泰国卫生部以及Mahidol大学和清迈大学通过39家公立医院网络进行的合作努力。如果孕妇NVP被证明是不必要的，将提供一种简单的方案来预防围产期艾滋病毒传播，避免耐药性突变，并保留孕妇未来的药物选择。这项研究将在具有或不具有ZDV背景的NVP是预防产中传播的核心组成部分的环境中具有重要的公共卫生影响，它还将提供关于接触后预防在预防产中传播艾滋病毒中的作用的关键科学知识。

DESCRIPTION (provided by applicant): The 2nd Perinatal HIV Prevention Trial (PHPT-2) in Thailand showed that a single dose of nevirapine (SD- NVP) to women at onset of labor and to infants at 48-72 hours in addition to zidovudine (ZDV) starting at 28 weeks' gestation, could reduce HIV perinatal transmission to about 2%. However, post-exposure NVP resistance mutations detected in mothers have raised concerns regarding future efficacy of Non Nucleoside Reverse Transcriptase Inhibitor based treatments for their own health. Results from a study in Botswana suggested that maternal SD-NVP may not be needed if the infant SD-NVP is administered immediately after birth. The study primary objective is to test whether maternal SD-NVP can be omitted without loss of efficacy in preventing perinatal HIV transmission. A regimen with no maternal NVP and two infant NVP doses, one immediately after birth, the other after 48-72 hours, will be compared for efficacy with a regimen including a maternal NVP dose during labor and identical infant NVP dosing. ZDV prophylaxis will be provided from 28 weeks gestation or as soon as possible thereafter, loading dose during labor and 1 week in the infants. All infants will be formula fed. To diminish the risk of selecting NVP resistance mutations, mothers exposed to NVP will receive a one week course of ZDV plus lamivudine, following WHO and Thai guidelines. The secondary objectives are to study HIV resistance mutations to NVP in HIV infected infants, to compare the safety of both strategies in mothers and infants and to study the pharmacokinetics of NVP in infants. This multicenter, phase III, randomized, double-blind, controlled trial will enroll 1398 consenting HIV-1 infected pregnant women, with CD4 count >200/mm3, participating in the Thai Ministry of Public Health (MoPH) prevention program, assigned to one of the 2 study arms (699 per arm including 5% non evaluable; power: 80%; delta threshold for non-inferiority testing between groups: 1.5%). The primary endpoint is infant HIV status based on confirmed DNA-PCR results on specimens drawn at birth, 1, 2, 4 and 6 months. The study will build upon PHPT-1 and PHPT-2, a collaborative effort between Harvard University, IRD- France, the Thai MoPH, and Mahidol and Chiang Mai Universities, through a network of 39 public hospitals. If maternal NVP proves unnecessary, a simple regimen will be available for the prevention of perinatal HIV transmission, resistance mutations avoided, and maternal future drug options preserved. This study will have important public health implications in settings where NVP, with or without ZDV background, is a central component of the prevention of intrapartum transmission, It will also provide key scientific knowledge on the role of post-exposure prophylaxis in the prevention of intrapartum HIV transmission.