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的一个重要公共卫生问题，特别是在艾滋病毒感染者中。结核病和死亡率的风险增加后不久，高效抗逆转录病毒治疗（HAART）开始，这是由CD 4 + T淋巴细胞计数（CD 4+计数）的指导。对这种增加的结核病风险的一种假设是，HAART迅速恢复炎症反应，“揭露”以前沉默的结核病表现。候选人的初步数据显示，在适当调整最近的CD 4+计数后，开始HAART后不久，TB风险增加并没有被观察到，这表明了另一种假设，即HAART前的CD 4+计数已经降低到足以增加TB风险。艾滋病毒感染也是结核病首次发作治疗结束后结核病复发的一个危险因素，结核病复发率反过来被用来确定 最佳结核病治疗时间。尚不清楚HAART启动时间是否与初始TB相关 结核病的发病率与结核病的复发率有关。了解HAART启动对初始和复发性结核病风险的影响对于优化结核病和HIV感染的管理是必要的。它还将增加对结核病的生物学和流行病学的了解。本研究的目的是：（1）评估HAART对TB风险的短期和长期影响，并使用边缘结构模型调整最近的CD 4+计数;（2）评估HAART启动时间与初始TB发作相关的时间对复发TB风险的影响，并调整初始TB诊断时的基线CD 4+计数。该奖项将支持候选人追求她的职业发展目标：（1）加强现有的知识，并获得结核病/艾滋病毒，生物统计学和流行病学成果研究的额外专业知识;（2）获得国际研究的经验，包括国际研究合作，研究设计/方法和政策。候选人的主要导师蒂莫西·斯特林博士是国际公认的结核病研究专家。他已经成功地指导了几位医生科学家，并有可用的资源来支持这位候选人。她的共同导师Bryan Shepherd博士是一位有成就的生物统计学家，在艾滋病毒感染方面具有专业知识。可用的资源包括范德比尔特全球卫生研究所和北美艾滋病队列研究与设计合作组织（NA-ACCORD）以及评估艾滋病的国际流行病学数据库（IEDEA）。此外，候选人将受益于范德比尔特的临床和转化科学奖（CTSA），这是由美国国立卫生研究院（NIH）资助。拟议的研究将为结核病/艾滋病毒的流行病学提供重要的见解，并有助于优化艾滋病毒相关结核病的治疗。该奖项将允许候选人建立在她的临床结核病/艾滋病研究的基础上，发展流行病学研究的新技能，并过渡到独立作为国际数据库合作的研究者和领导者。

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.