Decreasing Adverse Birth Outcomes among HIV-infected Women on Antiretroviral Therapy

实施3种药物抗逆转录病毒疗法预防母婴传播的背景 艾滋病毒的传播(防止母婴传播)大大减少了全球艾滋病毒的垂直传播。然而， 最近的证据表明，接受抗逆转录病毒治疗的妇女有极高的死产、早产和 小于胎龄儿的。尽管不良生育结局的原因尚不清楚，但越来越多的人 的研究发现高血压是一个重要的危险因素，这让我们假设母亲 血管内皮细胞功能障碍导致接受抗逆转录病毒治疗的艾滋病毒感染妇女的不良分娩结局。 候选人16年前，我第一次为防止母婴传播领域做出贡献，当时我住在南非，经营着第一个 当地非政府组织为怀孕期间提供抗逆转录病毒预防。我决定在母婴传播公司从事研究工作 在我的传染病团契期间，在进行了一次大生产后，出现了不良的出生结果 博茨瓦纳的一项监测研究发现，不良生育结局和高血压的发生率高得惊人 在艾滋病毒得到很好控制的女性中。我正在申请为期5年的K23职业发展奖，这将建立 根据我的团契研究结果。K23证书将提供所需的培训和经验。 成为研究怀孕期间药物安全性的独立调查者，确定 不良分娩结局和改善艾滋病毒感染妇女妊娠结局的检测干预措施。 在我的主要导师罗杰·夏皮罗博士的指导下，进行了关于儿童的临床试验和研究 博茨瓦纳的死亡率和出生结局研究超过15年，一直是我的研究导师 从当住院医生开始。我们共同确定了一支优秀的指导团队，其中包括Paige Williams博士(a 具有孕期药物安全性研究专长的生物统计学家)和Raina Fichorova博士(妇产科医生 有20年产科免疫学实验室运营经验)。 使用博茨瓦纳正在进行的大型出生监测研究中收集的数据进行的研究，并创建了一个嵌套的 在这项监测研究的队列中，我的研究将1)确定高血压在不良妊娠中的作用 结果和2)评估低孕酮和慢性炎症作为不良反应机制的作用 出生结局。我将评估艾滋病毒状况、具体的抗逆转录病毒治疗方案和/或抗逆转录病毒治疗的开始时间 影响高血压、孕酮水平及慢性炎症标志物。这些综合分析是 设计更大的纵向队列以进一步阐明不利分娩机制的关键第一步 艾滋病病毒感染妇女接受抗逆转录病毒治疗的结果。这将导致采取干预措施来改善生育结果。 在感染艾滋病毒的妇女中。 培训研究目标得到一项培训计划的支持，该计划包括在 流行病学、不良分娩结局的病理生理学方面的进一步培训和赠款支持 开发计划通过哈佛大学的催化剂。

Background Implementation of 3-drug antiretroviral therapy (ART) for prevention of mother to child transmission of HIV (PMTCT) has dramatically decreased vertical transmission of HIV globally. However, recent evidence suggests that women on ART have exceptionally high risk of stillbirth, preterm delivery and small for gestational age infants. Though reasons for adverse birth outcomes are unknown, a growing number of studies have found that hypertension is an important risk factor, leading us to hypothesize that maternal endothelial dysfunction causes adverse birth outcomes among HIV-infected women on ART. Candidate I first contributed to the field of PMTCT 16 years ago when I lived in South Africa and ran the first local NGO to provide antiretroviral prophylaxis in pregnancy. I decided to pursue a research career in PMTCT and adverse birth outcomes during my Infectious Diseases fellowship, after performing a large birth surveillance study in Botswana that found strikingly high rates of adverse birth outcomes and hypertension among women with well-controlled HIV. I am applying for a 5-year K23 Career Development Award that builds on findings from my fellowship study. A K23 award will provide the necessary training and experience needed to become an independent investigator studying drug safety in pregnancy, identifying mechanisms underlying adverse birth outcomes and testing interventions to improve pregnancy outcomes among HIV-infected women. Mentoring My primary mentor, Dr. Roger Shapiro, has conducted clinical trials, research on childhood mortality, and birth outcomes research in Botswana for more than 15 years and has been my research mentor since residency. Together we have identified an excellent mentoring team including Dr. Paige Williams (a biostatistician with expertise in studies of drug safety in pregnancy) and Dr. Raina Fichorova (an OB/GYN with 20 years experience running a lab in obstetric immunology). Research Using data collected in an ongoing large birth surveillance study in Botswana, and creating a nested cohort within this surveillance study, my study will 1) establish the role of hypertension in adverse pregnancy outcomes and 2) evaluate the role of low progesterone and chronic inflammation as mechanisms of adverse birth outcomes. I will evaluate whether HIV-status, specific ART regimens and/or the timing of ART initiation influence hypertension, progesterone level and markers of chronic inflammation. These combined analyses are critical first steps in the design of a larger longitudinal cohort to further elucidate mechanisms of adverse birth outcomes among HIV-infected women on ART. This will lead to interventions to improve birth outcomes among HIV-infected women. Training The research objectives are supported by a training plan that includes obtaining an MSc in Epidemiology, further training in the pathophysiology of adverse birth outcomes and a grant support and development program through Harvard Catalyst.