A Randomized Trial of 17-Hydroxyprogesterone Caproate (17P) to Reduce Preterm Birth Among Women Receiving Antiretroviral Therapy in Pregnancy

摘要 17-羟孕酮己酸酯(17P)减少早产的临床研究 妊娠期的抗逆转录病毒治疗 早产(PTB)是全球新生儿死亡的最常见原因，也是全球新生儿死亡的第二大原因 5岁以下儿童死亡率。产妇艾滋病毒每年使150万次怀孕复杂化，并增加患肺结核的风险。 虽然怀孕期间的抗逆转录病毒治疗(ART)几乎可以消除母婴传播，但它 增加肺结核的风险，超出可归因于艾滋病毒本身的额外风险。这把我们带到了难以为继的境地 在太多情况下，阻止围产期艾滋病毒的代价是早产相关的新生儿 死亡。 孕激素可降低诊断为宫颈缩短的妇女患肺结核的风险 在经历过自发性肺结核的女性中也是如此。这是对这些适应症的标准护理 在美国。 这个应用程序有两个特定的目标。在目标1中，我们提出了一种安慰剂对照的双掩蔽随机试验 17-羟孕酮预防HIV感染孕妇肺结核的临床研究 在马拉维和赞比亚开始或继续进行抗逆转录病毒药物治疗。因为死产和早产 出生是相互竞争的风险，试验的主要结果将是37周前的活产 任何孕龄的妊娠或死产。试验有权评估17P是否具有相同的 在感染艾滋病毒的妇女中的预防效果与在既往有肺结核病史的妇女中一样(这是 这是FDA批准的)。我们的具体假设是，17P将使主要结果减少38%(即， 从24%到15%)。这项试验将随机分配800名同意接受治疗的妇女，比例为1：1。 肌肉注射活性药物或匹配的安慰剂。我们将跟踪女性怀孕的整个过程 母婴配对至产后42天。在本应用程序的目标2中，我们将研究 开始抗逆转录病毒治疗的时间和肺结核的风险之间的关系。我们的假设是，感染艾滋病毒的女性开始抗逆转录病毒治疗 与开始接受抗逆转录病毒治疗的产前护理的妇女相比，怀孕期间患肺结核的几率更高 在怀孕之前。 这项试验将利用马拉维的长期合作伙伴关系和强大的研究基础设施 赞比亚。如果我们的主要假设得到证实--17P在感染艾滋病毒的女性中也同样有效 在那些有早产史的人中，我们将确定一种干预措施，可以预防多达 全球每年有7万名早产儿。

ABSTRACT A Trial of 17-Hydroxyprogesterone Caproate (17P) to Reduce Preterm Birth Among Women Receiving Antiretroviral Therapy in Pregnancy Preterm birth (PTB) is the most common cause of neonatal death worldwide and the second leading cause of under-5 mortality. Maternal HIV complicates 1.5 million pregnancies per year and increases the risk of PTB. While antiretroviral therapy (ART) in pregnancy can virtually eliminate mother-to-child transmission, it increases the risk of PTB beyond the excess risk attributable to HIV itself. This has led us to the untenable place where, in too many instances, the price of stopping perinatal HIV is prematurity-related neonatal death. Prenatal progesterone reduces the risk of PTB among women diagnosed with shortening of the uterine cervix and among women who have experienced a prior spontaneous PTB. It is standard of care for these indications in the United States. This application has two specific aims. In Aim 1, we propose a placebo-controlled, double-masked randomized clinical trial of the drug 17-hydroxyprogesterone (17P) to prevent PTB among HIV-infected pregnant women initiating or continuing antiretroviral drug therapy (ART) in Malawi and Zambia. Because stillbirth and preterm birth are competing risks, the trial's primary outcome will be a composite of live birth prior to 37 weeks gestation or stillbirth at any gestational age. The trial is powered to assess whether 17P has the same prophylactic efficacy among HIV-infected women as it does among women with a prior PTB (an indication for which it is FDA approved). Our specific hypothesis is that 17P will reduce the primary outcome by 38% (i.e., from 24% to 15%). The trial will randomly allocate 800 consenting women in a 1:1 ratio to receive weekly intramuscular injections of either active drug or matched placebo. We will follow women through pregnancy and mother-infant pairs to 42 days postpartum. In Aim 2 of this application, we will study the relationship between timing of ART initiation and the risk of PTB. Our hypothesis is that HIV-infected women who start ART during pregnancy will have higher rates of PTB compared to women who enter antenatal care on ART started prior to conception. This trial will take advantage of longstanding partnerships and robust research infrastructure in Malawi and Zambia. If our primary hypothesis is confirmed – that 17P works as well among HIV infected women as it does among those with a prior preterm birth – we will have identified an intervention that could prevent as many as 70,000 preterm births per year worldwide.