Immunology and Outcomes after HAART in HIV/TB Coinfection

描述(由申请人提供)：相当大比例的艾滋病毒感染患者在开始接受高效抗逆转录病毒疗法(HAART)后的头6个月内死亡。减少这些早期死亡有可能极大地改善全球抗逆转录病毒治疗扩大工作的结果。然而，早期死亡患者对HAART的反应尚不清楚，因为以前的研究侧重于HAART前的风险因素或衡量早期死亡后反应的时间更新反应因素。因此，一些患者为什么会过早死亡的现有知识中仍然存在一个根本的差距。鉴于我们的长期目标是减少接受HAART治疗的成年人的早期死亡，因此提出了一项专门研究早期死亡机制的观察性队列研究。发现治疗前较低的CD4+T细胞计数与HAART启动后细胞免疫的定量和定性测量的延迟和病理上的快速恢复有关，这一发现提出了一个基本的问题，即细胞免疫恢复的速度是否与HAART启动后的早期死亡风险有关。在一种情况下，患者可能因快速免疫恢复和严重或致命的免疫重建炎症综合征(IRIS)而过早死亡。在另一种情况下，细胞免疫恢复延迟可能与无法控制机会性病原体和死亡有关。这项建议采用流行病学方法，以检查非常早期(即在最初的4周内)病毒学和免疫学反应与HAART启动后早期死亡风险之间的关系。这些关系将在患有晚期艾滋病毒感染(如HAART前的CD4+T细胞计数100个/mm3)和活动性结核病的成年人中进行检查。我们将在博茨瓦纳哈博罗内进行一项前瞻性队列研究，以评估这些人在HAART开始后前6个月内死亡的风险因素，首先关注HAART开始后前4周结核分枝杆菌特异性细胞免疫的恢复率。然后，我们将沿着对HAART的经典因果反应途径进行倒退，以确定非常早期的依从性和非常早期的病毒学反应是否与早期死亡有关，以便确定能够预防这一结果的具体干预措施。鉴于HAART启动后第一年的大部分死亡发生在晚期艾滋病毒疾病患者的前6个月，该项目有可能改善全球扩大工作的结果。公共卫生相关性：这项研究方案评估了晚期艾滋病毒疾病和活动性结核病(全球最重要的机会性感染)成年人在开始接受HAART后的前6个月内非常早期的HAART反应与死亡风险之间的关系。该项目是在博茨瓦纳哈博罗内进行的一项前瞻性队列研究，将为临床护理和公共卫生努力提供重要信息，旨在改善全球抗逆转录病毒治疗扩大工作的结果。

DESCRIPTION (provided by applicant): A substantial proportion of HIV-infected patients die within the first 6 months after initiating highly active antiretroviral therapy (HAART). Decreasing these early deaths has the potential to greatly improve outcomes in antiretroviral therapy scale-up efforts worldwide. However, responses to HAART among patients suffering early death are unclear, since previous studies have focused on pre-HAART risk factors or time-updated response factors that measure response after early deaths have occurred. Thus, a fundamental gap in existing knowledge of why some patients suffer early death remains. Given that our long-term goal is to decrease early deaths among adults treated with HAART, an observational cohort study specifically addressing mechanisms of early deaths is proposed. The finding that lower pre-treatment CD4+ T cell counts are associated with both delayed and pathologically rapid recovery of quantitative and qualitative measurements of cell mediated immunity after HAART initiation raises the fundamental question of whether or not the rate of cellular immune restoration relates to risk of early death after HAART initiation. In one scenario patients may be suffering early deaths via rapid immune recovery and severe or fatal immune reconstitution inflammatory syndrome (IRIS). In another scenario delayed recovery of cellular immunity may be associated with inability to control opportunistic pathogens and death. This proposal adopts an epidemiologic approach in order to examine the relationship between very early (i.e., within the first 4 weeks) virologic and immunologic responses and risk of early death after HAART initiation. These relationships will be examined in adults with advanced HIV infection (as indicated by a pre-HAART CD4 + T cell count < 100 cells/mm3) and active TB disease. We will conduct a prospective cohort study in Gaborone, Botswana to evaluate risk factors for death within the first 6 months after HAART initiation among these individuals, focusing first on the rate of recovery of Mycobacterium tuberculosis-specific cellular immunity in the first 4 weeks after HAART initiation. We will then proceed backwards along the classic causal pathway of response to HAART to determine if very early adherence and very early virologic responses are associated with early death in order to define specific interventions capable of preventing this outcome. Given that the majority of all deaths in the first year after HAART initiation occur in the first 6 months among patients with advanced HIV disease, this project has the potential to improve outcomes in global scale-up efforts. PUBLIC HEALTH RELEVANCE: This research proposal evaluates the relationship between very early response to HAART and risk of death in the first 6 months after HAART initiation among adults with advanced HIV disease and active tuberculosis (TB) disease, the most important opportunistic infection globally. Conducted as a prospective cohort study in Gaborone, Botswana, the project will yield important information to clinical care and public health efforts designed to improve the outcomes in global antiretroviral therapy scale-up efforts.