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HIV预防试验（PHPT-2）显示，除了妊娠28周开始的齐多夫定（ZDV）外，在分娩开始时给妇女和48-72小时的婴儿单剂量奈韦拉平（SD- NVP）可将HIV围产期传播降低约2%。然而，在母亲中检测到的NVP暴露后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其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，如果婴儿在出生后立即给予SD-NVP，则可能不需要母体SD-NVP。本研究的主要目的是测试母体SD-NVP是否可以在不影响预防围产期HIV传播的情况下被省略。一种方案不含产妇NVP和两种婴儿NVP剂量，一种是在出生后立即给药，另一种是在48-72小时后给药，将与一种方案的疗效进行比较，该方案包括分娩时给药的产妇NVP和相同的婴儿NVP剂量。ZDV预防将从妊娠28周或之后尽快提供，在分娩时和婴儿1周时加载剂量。为减少选择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导方针，接受一周的ZDV加拉米夫定疗程。次要目的是研究HIV感染婴儿对NVP的HIV抗性突变，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、III期、随机、双盲、对照试验将招募1398名同意HIV-1感染的孕妇，CD4细胞计数为bbb200 /mm3，参与泰国公共卫生部（MoPH）预防计划，分配到两个研究组之一（每组699人，其中5%不可评估；效力：80%；组间非劣效性测试的δ阈值：1.5%）。主要终点是根据出生、1、2、4和6个月时采集的标本的DNA-PCR结果确定的婴儿艾滋病毒状况。该研究将以PHPT-1和PHPT-2为基础，PHPT-1和PHPT-2是哈佛大学、法国IRD、泰国卫生部以及玛希隆大学和清迈大学通过39家公立医院组成的网络共同努力的成果。如果产妇服用NVP被证明是不必要的，一种简单的方案将可用于预防围产期艾滋病毒传播，避免耐药性突变，并保留产妇未来的药物选择。在有或没有ZDV背景的NVP是预防产时传播的核心组成部分的情况下，这项研究将具有重要的公共卫生意义，它还将提供关于暴露后预防在预防产时艾滋病毒传播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.