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

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 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.