Impact of maternal HIV on Mycobacterium tuberculosis infection among peripartum women and their infants

 描述(由申请人提供)： 这份K23指导的以患者为导向的研究职业发展奖提案描述了一项培训和研究计划，该计划将使候选人实现她的目标，即成为一名拥有艾滋病毒/结核病(TB)和母婴健康专业知识的独立临床调查员。 应聘者是一名受过内科和儿科培训的传染病内科医生，在评估结核病诊断以及艾滋病毒和结核病筛查算法的实施和评估方面具有经验。对于这个K23奖项，职业发展计划将为候选人提供先进的流行病学、生物统计学和卫生经济学建模方法的指导学习，同时调查母亲艾滋病毒是否与围产期妇女及其婴儿感染结核分枝杆菌(MTB)的风险增加相关，以及艾滋病毒和怀孕阶段是否影响潜伏性结核病(LTBI)感染测试的不一致性。 感染艾滋病毒的个人和婴儿从结核分枝杆菌感染发展为结核病的风险增加。孕期和产后期也与结核病风险增加有关。母亲艾滋病毒是否增加了围产期妇女及其婴儿对结核分枝杆菌感染的易感性，以及艾滋病毒和围产期对潜伏结核病检测的双重作用尚不清楚。 研究人员建议开发新的平行前瞻性队列，纳入艾滋病毒感染和未感染的孕妇及其婴儿。研究的具体目的是确定：(1)母亲艾滋病毒对母亲围产期结核分支杆菌感染风险和时间的影响，(2)母亲艾滋病毒对婴儿结核分支杆菌感染风险的影响，以及(3)母亲艾滋病毒状况和围产期对包括干扰素伽马释放试验(IGRA)和结核菌素皮肤试验(TST)在内的LTBI检测结果的影响。将使用IGRA估计和比较孕期、6周和产后1年内使用IGRA的HIV感染和未感染HIV的孕妇的母体结核分枝杆菌感染的发生率。IGRA将在6个月和12个月大时比较暴露于艾滋病毒和未暴露于艾滋病毒的婴儿中结核分枝杆菌感染的流行率。TST和IGRA的不一致性将在每个母亲队列中的怀孕、产后早期和产后晚期以及感染艾滋病毒的妇女和未感染的妇女之间进行比较。将评估母婴结核分枝杆菌感染和母体LTBI试验不一致的潜在辅助因素。 候选人建议进行培训，以提供实施前瞻性队列研究和在母婴队列中进行复杂的纵向数据分析的技能，作为她的研究建议的一部分，以及干预试验设计、成本效益和结果建模方面的培训，以为未来的方向提供基础，包括提交R01建议。将通过指导指导、授课课程、拟议的研究计划以及导师确定的更多合作国际艾滋病毒/结核病试验的机会来获得技能。 她在培训期间的具体目标是1)熟练掌握高级Logistic回归和线性混合模型，2)在孕产妇和儿童健康环境中发展与艾滋病毒/结核病相关的关键研究领域的内容专长，3)领导一项纵向流行病学研究，4)促进了解感染艾滋病毒的母亲及其子女感染结核的流行病学相关性，5)建立成本效益模型的基础，包括使用综合风险-效益母婴结果，以及6)产生原始数据和科学问题，同时扩大她的出版记录，以便在R01一级成功争取独立资助。候选人已经确定了一个由来自华盛顿大学、约翰·霍普金斯大学、内罗毕大学和疾控中心的导师(John-Stewart、Gupta、Kinuthia、Richardson博士)和合作者(Horne、Maleche-Obimbo、Cain、Levin博士)组成的跨学科团队，他们拥有艾滋病毒和儿童艾滋病和结核病流行病学、纵向队列研究和临床试验、结核病诊断、成本效益和传染病建模方面的专业知识。这位候选人所在的机构在肯尼亚有着悠久的合作研究历史。她的导师和机构已经承诺提供必要的资源，以成功地推进她的研究独立性。 研究结果将提供有关结核病流行病学和发病机制的重要数据，并为未来在母婴健康方面的结核病干预试验和模型提供信息。这 拟议的项目将为候选人的职业目标奠定基础，成为一名独立的临床研究人员，重点是通过循证预防战略改善艾滋病毒/结核病负担高地区妇女及其子女的健康。

 DESCRIPTION (provided by applicant): This K23 Mentored Patient-Oriented Research Career Development Award proposal describes a training and research program that will enable the Candidate to achieve her goal of becoming an independent clinical investigator with expertise in HIV/tuberculosis (TB) and maternal and child health. The Candidate is an Infectious Disease physician trained in Internal Medicine and Pediatrics, with experience in evaluating TB diagnostics, and implementation and evaluation of HIV and TB screening algorithms. For this K23 award, the career development plan will provide the Candidate with mentored learning in advanced epidemiologic, biostatistical, and health economics modeling methods while investigating whether maternal HIV is associated with increased risk of Mycobacterium tuberculosis (Mtb) infection in peripartum women and their infants, and if HIV and pregnancy stage influence latent tuberculosis (LTBI) infection test discordance. HIV-infected individuals and infants have an increased risk of progression from Mtb infection to TB disease. Pregnant and postpartum periods have also been associated with increased risk of TB. Whether maternal HIV increases susceptibility to Mtb infection among peripartum women and their infants, and the dual roles of HIV and peripartum stage on latent TB testing are unknown. The investigator proposes to develop new parallel prospective cohorts enrolling HIV-infected and uninfected pregnant women and their infants. Research Specific Aims are to determine the: (Aim 1) effect of maternal HIV on risk and timing of maternal peripartum Mtb infection, (Aim 2) influence of maternal HIV on risk of infant Mtb infection, and (Aim 3) effect of maternal HIV status and peripartum stage on LTBI test performance, including interferon gamma-release assays (IGRA) and tuberculin skin tests (TST). The incidence of maternal Mtb infection will be estimated and compared between HIV-infected and HIV-uninfected pregnant women using IGRA in pregnancy, and at 6 weeks, and 1 year postpartum. The prevalence of Mtb infection in HIV-exposed and HIV-unexposed infants will be compared at 6 and 12 months of age by IGRA. TST and IGRA discordance will be compared in pregnancy, early postpartum, and late postpartum within each maternal cohort and between HIV-infected and uninfected women. Potential cofactors for maternal and infant Mtb infection and maternal LTBI test discordance will be evaluated. The Candidate proposes training designed to provide her skills in implementing prospective cohort studies and conducting complex longitudinal data analysis in maternal-infant cohorts as part of her research proposal, as well as in interventional trial design, cost-effectiveness and outcomes modeling to provide a foundation for future directions including submitting an R01 proposal. Skills will be gained through directed mentorship, didactic coursework, the proposed research plan, as well as additional mentor-identified opportunities to collaborate on international HIV/TB trials. Her specific goals over the training period are to 1) gain proficiency in advanced logistic regression and linear mixed models, 2) develop content expertise in key areas of HIV/TB-related research in maternal child health settings, 3) lead a longitudinal epidemiologic study, 4) contribute to understanding epidemiologic correlates of Mtb infection in HIV-infected mothers and their children, 5) build a foundation in cost-effectiveness modeling including the use of composite risk-benefit maternal-infant outcomes, and 6) generate original data and scientific questions while expanding her publication record in order to successfully compete for independent funding at the R01 level. The Candidate has identified an interdisciplinary team of mentors (Drs. John-Stewart, Gupta, Kinuthia, Richardson) and collaborators (Drs. Horne, Maleche-Obimbo, Cain, Levin) from University of Washington, Johns Hopkins University, University of Nairobi, and CDC with expertise in HIV and TB epidemiology in women and children, longitudinal cohort studies and clinical trials, TB diagnostics, cost-effectiveness and infectious disease modeling. The Candidate's institution has a long-standing history of collaborative research in Kenya. Her mentors and institution have committed the resources needed to successfully advance her research independence. The research findings will provide important data regarding TB epidemiology and pathogenesis, and inform future TB interventional trials and models in the context of maternal/child health. This proposed project will provide the groundwork for the Candidate's career goal to become an independent clinical researcher with a focus on improving the health of women and their children in areas of high HIV/TB burden through evidence- based preventive strategies.