Immunology and Outcomes after HAART in HIV/TB Coinfection

描述（由申请人提供）：相当大比例的HIV感染患者在开始高效抗逆转录病毒治疗（HAART）后的前6个月内死亡。减少这些早期死亡有可能大大改善全世界抗逆转录病毒疗法推广工作的成果。然而，早期死亡患者对HAART的反应尚不清楚，因为以前的研究主要集中在HAART前的风险因素或时间更新的反应因素，这些因素可以衡量早期死亡发生后的反应。因此，关于为什么有些病人会过早死亡的现有知识仍然存在根本性的空白。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，建议进行一项专门针对早期死亡机制的观察性队列研究。较低的治疗前CD 4 + T细胞计数与HAART启动后细胞介导免疫的定量和定性测量的延迟和病理学快速恢复相关的发现提出了细胞免疫恢复速率是否与HAART启动后早期死亡风险相关的根本问题。在一种情况下，患者可能会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，细胞免疫的延迟恢复可能与无法控制机会性病原体和死亡有关。该提案采用流行病学方法，以研究极早期（即，前4周内）病毒学和免疫学应答以及HAART启动后早期死亡的风险。这些关系将在患有晚期HIV感染（如HAART前CD 4 + T细胞计数< 100个细胞/mm 3所示）和活动性TB疾病的成人中进行检查。我们将在博茨瓦纳哈博罗内进行一项前瞻性队列研究，以评估这些个体在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周内结核分枝杆菌特异性细胞免疫的恢复率。然后，我们将继续向后沿着经典的因果路径HAART的反应，以确定是否非常早期的依从性和非常早期的病毒学反应与早期死亡，以确定具体的干预措施，能够防止这种结果。鉴于HAART开始后第一年的大多数死亡发生在晚期艾滋病毒患者的前6个月，该项目有可能改善全球扩大努力的结果。公共卫生相关性：这项研究计划评估了对HAART的早期反应与HAART开始后前6个月内晚期HIV疾病和活动性结核（TB）疾病（全球最重要的机会性感染）成人死亡风险之间的关系。该项目作为一项前瞻性队列研究在博茨瓦纳哈博罗内进行，将为临床护理和公共卫生工作提供重要信息，旨在改善全球抗逆转录病毒疗法扩大工作的成果。

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.