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

 描述（由申请人提供）： 这K23指导以患者为导向的研究职业发展奖的建议描述了一个培训和研究计划，将使候选人实现她的目标，成为一个独立的临床研究人员在艾滋病毒/结核病（TB）和孕产妇和儿童健康的专业知识。 候选人是接受过内科和儿科培训的传染病医生，具有评估结核病诊断以及实施和评估艾滋病毒和结核病筛查算法的经验。对于这个K23奖，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，同时调查孕产妇艾滋病毒是否与围产期妇女及其婴儿结核分枝杆菌（Mtb）感染风险增加有关，以及艾滋病毒和妊娠阶段是否影响潜伏性结核病（LTBI）感染测试不一致性。 艾滋病毒感染者和婴儿从结核分枝杆菌感染进展为结核病的风险增加。怀孕和产后时期也与结核病风险增加有关。孕产妇艾滋病毒是否会增加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阶段对潜伏性结核病检测的双重作用尚不清楚。 研究者建议开发新的平行前瞻性队列，招募HIV感染和未感染的孕妇及其婴儿。研究的具体目的是确定：（目的1）孕产妇HIV对孕产妇围产期Mtb感染风险和时间的影响，（目的2）孕产妇HIV对婴儿Mtb感染风险的影响，以及（目的3）孕产妇HIV状态和围产期阶段对LTBI测试性能的影响，包括干扰素γ释放测定（IGRA）和结核菌素皮肤试验（TST）。将在妊娠期、6周和产后1年使用IGRA的HIV感染和HIV未感染孕妇之间估计和比较母体Mtb感染的发生率。将通过IGRA比较6个月和12个月时暴露于HIV和未暴露于HIV的婴儿中Mtb感染的患病率。TST和IGRA的不一致性将在妊娠、产后早期和产后晚期在每个产妇队列内以及在HIV感染和未感染的妇女之间进行比较。将评价孕产妇和婴儿Mtb感染和孕产妇LTBI检测不一致性的潜在辅助因素。 候选人提出的培训旨在提供她在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方面的技能，作为她的研究提案的一部分，以及干预性试验设计，成本效益和结果建模，为未来的方向提供基础，包括提交R 01提案。技能将通过指导导师，教学课程，拟议的研究计划，以及额外的导师确定的机会，在国际艾滋病毒/结核病试验合作获得。 她在培训期间的具体目标是：1）熟练掌握先进的逻辑回归和线性混合模型，2）在母婴健康环境中开发艾滋病毒/结核病相关研究的关键领域的内容专业知识，3）领导纵向流行病学研究，4）有助于了解艾滋病毒感染母亲及其子女中结核分枝杆菌感染的流行病学相关性，5）建立成本效益建模的基础，包括使用复合风险-收益母婴结局，以及6）生成原始数据和科学问题，同时扩大她的出版记录，以成功竞争R 01水平的独立资金。候选人确定了一个跨学科的导师团队来自华盛顿大学、约翰霍普金斯大学、内罗毕大学和CDC的John-Stewart、Gupta、Kinuthia、Richardson博士和合作者（Horne、Maleche-Obimbo、Cain、Levin博士）在妇女和儿童艾滋病毒和结核病流行病学、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具有专长。候选人所在的机构在肯尼亚有着长期的合作研究历史。她的导师和机构已经承诺成功推进她的研究独立性所需的资源。 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，并为未来的结核病干预性试验和妇幼健康模型提供信息。这 该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，重点是通过基于证据的预防策略，改善艾滋病毒/结核病高负担地区妇女及其子女的健康状况。

 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.