HIV Infection, Placental Inflammation, and Early Childhood Outcomes in HIV-exposed, Uninfected Infants in Uganda

乌干达暴露于 HIV 的未感染婴儿的 HIV 感染、胎盘炎症和早期儿童结局

• 批准号: 10543082
• 负责人: Lisa M Bebell
• 金额: $ 27.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-14 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543082
• 关键词: Africa; Africa South of the Sahara; Biology; Biometry; Birth; CD4 Lymphocyte Count; Career Choice; Caring; Cessation of life; Child; Child Health; Chronic; Classification; Clinical; Clinical Investigator; Clinical Trials Design; Cytomegalovirus; Data; Early treatment; Enrollment; Ensure; Functional disorder; Funding; Goals; Growth; HIV; HIV Infections; HIV-exposed uninfected infant; Haemophilus influenzae type b; Health; Histologic; Histology; Histopathology; Hospitalization; Immune; Immunology; Incidence; Infant; Infant Health; Infection; Inflammation; Inflammatory; Institution; Intervention; Late pregnancy; Learning; Life; Link; Malaria; Manuscripts; Maternal Health; Maternal and Child Health; Maternal-Fetal Exchange; Measures; Mediating; Mediation; Mediator; Mentors; Mentorship; Methods; Morbidity - disease rate; Mother-to-child HIV transmission; Mothers; Mycoplasma; Outcome; Participant; Pathologist; Pathology; Perinatal; Pharmaceutical Preparations; Pilot Projects; Placenta; Positioning Attribute; Pregnant Women; Prevalence; Prevention program; Prospective cohort; Publications; Publishing; Quasi-experiment; Regimen; Reporting; Research; Research Personnel; Risk; Role; Site; Source; Specimen; Streptococcus pneumoniae; Techniques; Training; Uganda; United States National Institutes of Health; Ureaplasma; Viremia; Woman; Work; adverse outcome; antibody transfer; antiretroviral therapy; career; co-infection; cohort; comparison group; early childhood; effective intervention; experience; global health; immune activation; improved; improved outcome; infant morbidity/mortality; infant outcome; innovation; intraamniotic infection; mortality; multidisciplinary; pathogen; placental infection; respiratory pathogen; skill acquisition; success; systemic inflammatory response; theories; vaccination strategy

PROJECT SUMMARY Background: Successful mother-to-child HIV transmission prevention programs have decreased the global incidence of congenital HIV. Yet, >1 million HIV-exposed, uninfected (HEU) children are born annually in sub- Saharan Africa and have poorer early-life outcomes than HIV-unexposed children. The pathophysiology of these poor outcomes is poorly understood, yet critical to developing effective interventions to improve outcomes for these children. I hypothesize that placental inflammation may contribute to adverse HEU child health outcomes by decreasing quality and quantity of transplacental antibody transfer and disrupting normal pathogen barrier functions. Candidate: My overarching career goal is to become an independent, NIH-funded clinical investigator with expertise in the contribution of maternal infections, the placenta, and inflammation to health outcomes of HIV-exposed children. My clinical work caring for women living with HIV (WLWH) and their infants and conducting research investigating maternal-child health outcomes has inspired this career path. I am well-prepared to undertake the scientific and training aims proposed here, having successfully published eight first-author manuscripts and completed a 50-placenta histology pilot study in Uganda in 2016. Mentoring: Dr. Ingrid Bassett (Primary Mentor) is an NIH-funded investigator who has successfully mentored 4 NIH K23 awardees. Dr. Drucilla Roberts (Co-mentor, Pathology) has been a perinatal pathologist for nearly 30 years and worked in Africa for over a decade. Drs. Mark Siedner (Global Health), Galit Alter (Immunology), Joseph Ngonzi (Uganda Site), Roger Shapiro (HEU Outcomes), Bethany Hedt-Gauthier (Biostatistics), and Elias Kumbakumba (Infant Outcomes) will provide additional focused mentorship to ensure my success. Research: I will enroll a prospective cohort of 300 WLWH on ART in late pregnancy and a comparison group of 150 HIV-uninfected pregnant women in Uganda and collect their placentas at birth. I will compare the prevalence of inflammatory placental abnormalities by maternal HIV serostatus and determine the correlates of inflammatory placental abnormalities in WLWH. Potential correlates include maternal factors (CD4 count, ART regimen, CMV viremia) and placental factors (detectable placental HIV and placental infections). I will measure transplacental respiratory pathogen antibody transfer as surrogate immune measures of placental function, and follow infants born to enrolled women for 12 months to determine the association of inflammatory placental abnormalities with HEU infant morbidity and mortality. Training: To achieve my aims and gain research independence, I require additional training in: 1) placental histopathology, biology, and immunology 2) causal inference theory, with a focus on mediation analysis, and 3) clinical trial design to conduct a larger R01-funded study of placental inflammation in Uganda. Based on my previous research experience and success, support from an exceptional mentoring team, strong institutional commitment, and an innovative research plan, I am well-positioned to become an independent clinical investigator focused on maternal-child health in WLWH.

项目摘要 背景：成功的母亲到儿童艾滋病毒传播预防计划已减少了全球 先天性艾滋病毒的发病率。然而，> 100万艾滋病毒暴露，未感染的（HEU）儿童每年出生 撒哈拉非洲的非洲和早期生活差，比艾滋病毒无暴露的孩子。病理生理 这些差的结果知之甚少，但对于制定有效的干预措施以改善 这些孩子的结果。我假设胎盘炎症可能导致不良的HEU儿童 通过降低移植抗体转移的质量和数量来破坏正常的健康结果 病原体屏障功能。候选人：我的总体职业目标是成为一名独立的NIH资助 临床研究者具有在孕产妇感染，胎盘和炎症对的贡献方面的专业知识 暴露于HIV的儿童的健康结果。我照顾患有艾滋病毒（WLWH）及其的妇女的临床工作及其 婴儿和研究孕产妇健康成果的研究激发了这一职业道路。我 在这里提出的科学和培训目的是成功发表的，这是为了进行科学和培训的目的 2016年在乌干达完成了八项第一名第一名手稿，并在乌干达完成了一项50个阶段的组织学试点研究。 指导：Ingrid Bassett博士（主要导师）是NIH资助的调查员，他成功指导了4 NIH K23获奖者。德鲁西拉·罗伯茨（Drucilla Roberts）博士（病理学）一直是近30名的围产期病理学家 多年，在非洲工作了十多年。博士。马克·西德纳（Mark Siedner）（全球卫生），盖利特（Galit Alter）（免疫学）， 约瑟夫·恩贡齐（Joseph Ngonzi）（乌干达遗址），罗杰·夏皮罗（HEU成果），伯大尼·赫特·盖迪尔（Biostatistics）和 Elias Kumbakumba（婴儿成果）将提供额外的专注指导，以确保我的成功。 研究：我将在怀孕后期的艺术和比较组中注册300 wlwh的预期队列 在乌干达，有150名HIV未感染的孕妇，并在出生时收集胎盘。我将比较 孕产妇HIV血清的炎症性胎盘异常的患病率，并确定 WLWH的炎症胎盘异常。潜在的相关性包括母体因素（CD4计数，ART 方案，CMV病毒血症）和胎盘因子（可检测的胎盘HIV和胎盘感染）。我会衡量的 移植呼吸道病原体抗体转移作为胎盘功能的替代免疫测量， 并跟随入学妇女出生的婴儿12个月以确定炎症性胎盘的关联 HEU婴儿发病率和死亡率异常。培训：实现我的目标并获得研究 独立性，我需要：1）胎盘组织病理学，生物学和免疫学2）因果关系 推论理论，重点是调解分析，以及3）临床试验设计，以进行较大的R01资助 乌干达胎盘炎症的研究。根据我以前的研究经验和成功，支持 从一个杰出的指导团队，强大的机构承诺和创新的研究计划中，我是 位置良好，成为一名专注于WLWH产妇健康的独立临床研究者。

项目成果

Stillbirth rate by maternal HIV serostatus and antiretroviral use in pregnancy in South Africa: An audit.

南非孕产妇艾滋病毒血清状态和妊娠期抗逆转录病毒使用情况的死产率：一项审计。

• 发表时间: 2021
• 期刊: South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde
• 作者: Maswime,S;Pule,C;Bebell,LM;Hedt-Gauthier,B;Chandiwana,N;Haberer,JE;Pattinson,R
• 通讯作者: Pattinson,R