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

接受抗逆转录病毒治疗可减少艾滋病毒感染妇女的不良分娩结果

• 批准号: 10202671
• 负责人: Rebecca Marie Zash
• 金额: $ 16.44万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202671
• 关键词: Anti-Retroviral Agents; Antihypertensive Agents; Area; Biology; Birth; Botswana; CD4 Lymphocyte Count; Child Mortality; Childhood; Chronic; Clinical; Cohort Studies; Communicable Diseases; Complex; Conceptions; Conduct Clinical Trials; Data; Discipline of obstetrics; Endothelium; Enrollment; Epidemiology; Fellowship; Functional disorder; Funding; Future; Grant; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV antiretroviral; Hypertension; Immunologist; Immunology; Immunosuppression; Inflammation; Interleukin-10; Interleukin-6; Intervention; K-Series Research Career Programs; Laboratories; Life; Link; Longitudinal cohort; Low Birth Weight Infant; Mediating; Mediation; Mediator of activation protein; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Mother-to-child HIV transmission; Nevirapine; Opportunistic Infections; Outcome; Outcomes Research; Pathway interactions; Pharmaceutical Preparations; Placenta; Population; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Birth; Prevention; Prevention therapy; Progesterone; Program Development; Prophylactic treatment; Public Health Schools; Publications; Regimen; Research; Research Personnel; Research Training; Residencies; Risk; Risk Factors; Role; Running; Serology; Site; Small for Gestational Age Infant; South Africa; Spontaneous abortion; Testing; Training; Vertical Disease Transmission; Woman; adverse birth outcomes; adverse outcome; adverse pregnancy outcome; antiretroviral therapy; career; catalyst; cohort; data infrastructure; design; early onset; early pregnancy; endothelial dysfunction; experience; fetal; high risk; immune activation; immune function; improved; infant morbidity/mortality; medication safety; mortality; neonatal outcome; novel; pediatric human immunodeficiency virus infection; pregnancy hypertension; prenatal exposure; programs; reproductive; response; stillbirth; study population; success; surveillance study; transmission process

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.

背景实施3种药物抗逆转录病毒疗法（ART）预防母婴传播 预防母婴传播艾滋病毒（PMTCT）已大大减少了全球艾滋病毒的垂直传播。然而，在这方面， 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胎、早产和 小于胎龄婴儿。虽然不良出生结果的原因尚不清楚，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，这使我们假设， 内皮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。 16年前，我第一次为预防母婴传播领域做出贡献，当时我住在南非， 当地非政府组织在怀孕期间提供抗逆转录病毒预防。我决定从事预防母婴传播的研究 在我的传染病奖学金期间，在进行了一次大型分娩后， 在博茨瓦纳进行的一项监测研究发现， 艾滋病控制良好的妇女中。我正在申请为期5年的K23职业发展奖， 我的奖学金研究的发现K23奖将提供必要的培训和经验， 成为研究妊娠期药物安全性的独立研究者， 不良生育结果和检测干预措施，以改善感染艾滋病毒的妇女的怀孕结果。 指导我的主要导师罗杰·夏皮罗博士进行了临床试验， 死亡率和出生结果研究在博茨瓦纳超过15年，一直是我的研究导师 我就一直在做实习医生我们一起确定了一个优秀的指导团队，包括Paige威廉姆斯博士（a 具有妊娠期药物安全性研究专业知识的生物统计学家）和Raina Fichorova博士（妇产科医师， 在产科免疫学实验室工作20年）。 研究使用在博茨瓦纳正在进行的大型出生监测研究中收集的数据，并创建一个嵌套的 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， 出生结果。我将评估艾滋病毒状况、特定的抗逆转录病毒疗法和/或抗逆转录病毒疗法开始的时间是否 影响高血压、孕酮水平和慢性炎症标志物。这些综合分析是 设计更大的纵向队列以进一步阐明不良出生机制的关键第一步 这将导致干预措施，以改善生育结果 感染艾滋病毒的妇女。 培训研究目标得到了培训计划的支持，其中包括获得硕士学位， 流行病学，在不良出生结果的病理生理学方面的进一步培训和赠款支持， 通过哈佛催化剂的发展计划。

项目成果

Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

• DOI: 10.1016/j.eclinm.2020.100573
• 发表时间: 2020-11
• 期刊: EClinicalMedicine
• 影响因子: 15.1
• 作者: Kanters S;Vitoria M;Zoratti M;Doherty M;Penazzato M;Rangaraj A;Ford N;Thorlund K;Anis PAH;Karim ME;Mofenson L;Zash R;Calmy A;Kredo T;Bansback N
• 通讯作者: Bansback N

What will it take to refute the possible safety signal for dolutegravir and neural tube defects?

如何反驳多替拉韦和神经管缺陷可能存在的安全信号？

• DOI: 10.1111/1471-0528.15864
• 发表时间: 2019
• 期刊: BJOG : an international journal of obstetrics and gynaecology
• 作者: Zash,RM