Tuberculosis Risk and Highly Active Antiretroviral Therapy Initiation

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DESCRIPTION (provided by applicant): TB remains an important public health problem worldwide, particularly among HIV-infected persons. The risk of TB and mortality increase shortly following highly active antiretroviral therapy (HAART) initiation, which is guided by CD4+ T lymphocyte count (CD4+ count). One hypothesis for this increased TB risk is that HAART rapidly restores inflammatory responses that "unmask" previously silent TB manifestations. The candidate's preliminary data show that the increased TB risk soon after starting HAART is not seen after appropriately adjusting for the most recent CD4+ count, suggesting an alternate hypothesis that pre-HAART CD4+ count has decreased enough to elevate TB risk. HIV-infection is also a risk factor for recurrent TB following completion of therapy for an initial TB episode, ad recurrent TB rates, in turn, are used to determine optimal TB treatment duration. It is unknown if the timing of HAART initiation in relation to the initial TB episode has an influence on the incidence of recurrent TB. Understanding the effect of HAART initiation on initial and recurrent TB risk is necessary to optimize the management of TB and HIV-infection. It will also increase biological and epidemiological understanding of TB. The aims of this study are: (1) to evaluate the short-term and long-term effects of HAART on TB risk with adjustment for the most recent CD4+ count using marginal structural models and (2) to evaluate the effect of the timing of HAART initiation in relation to the initial TB episode on recurrent TB risk with adjustment for the baseline CD4+ count at initial TB diagnosis. This award will support the candidate in pursuing her career development aims: (1) to strengthen existing knowledge and gain additional expertise in TB/HIV, biostatistics, and epidemiologic outcomes research; (2) to gain experience in the conduct of international research including international research collaboration, study design/methodology, and policy. The candidate's is primary mentor, Dr. Timothy Sterling, is an internationally recognized expert in TB research. He has successfully mentored several physician scientists and has the resources available to support this candidate. Her co-mentor, Dr. Bryan Shepherd, is an accomplished biostatistician who has expertise in HIV-infection. The resources available include the Vanderbilt Institute for Global Health and access to data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and the International epidemiologic Databases to Evaluate AIDS (IeDEA). In addition, the candidate will benefit from Vanderbilt's Clinical and Translational Science Award (CTSA) which is funded by the National Institutes of Health (NIH). The proposed studies will provide important insights into the epidemiology of TB/HIV and help optimize the treatment of HIV-related TB. This award will allow the candidate to build on her foundation of clinical TB/HIV research, develop new skills in epidemiologic research, and transition to independence as an investigator and leader of international database collaborations.