Tuberculosis Risk and Highly Active Antiretroviral Therapy Initiation

描述（由申请人提供）：结核病仍然是世界范围内一个重要的公共卫生问题，特别是在艾滋病毒感染者中。在以CD4+ T淋巴细胞计数（CD4+计数）为指导的高效抗逆转录病毒治疗（HAART）开始后不久，结核病和死亡率的风险增加。结核病风险增加的一个假设是，高效抗逆转录病毒疗法迅速恢复了炎症反应，从而“揭开”了以前沉默的结核病表现。候选人的初步数据表明，在对最近的CD4+计数进行适当调整后，在开始HAART治疗后不久未见结核病风险增加，这提出了另一种假设，即HAART治疗前CD4+计数已下降到足以提高结核病风险。艾滋病毒感染也是初次结核发作治疗结束后结核复发的一个危险因素，而结核复发率又被用来确定

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.