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扩大抗逆转录病毒治疗工作的结果。然而，早期死亡患者对HAART的反应尚不清楚，因为以前的研究主要集中在HAART前的风险因素或测量早期死亡发生后反应的时间更新的反应因素。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差距。鉴于我们的长期目标是减少接受HAART治疗的成人的早期死亡，我们提出了一项专门研究早期死亡机制的观察性队列研究。治疗前较低的CD4+ T细胞计数与HAART启动后细胞介导免疫定量和定性测量的延迟和病理性快速恢复相关，这一发现提出了细胞免疫恢复速度是否与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）而遭受早期死亡。在另一种情况下，细胞免疫恢复延迟可能与无法控制机会致病菌和死亡有关。本建议采用流行病学方法，以检查早期（即在最初4周内）病毒学和免疫反应与开始HAART治疗后早期死亡风险之间的关系。这些关系将在晚期艾滋病毒感染（haart前CD4 + T细胞计数< 100细胞/mm3）和活动性结核病的成年人中进行检验。我们将在博茨瓦纳的哈博罗内进行一项前瞻性队列研究，以评估这些个体在HAART开始后的前6个月内死亡的危险因素，首先关注HAART开始后的前4周内结核分枝杆菌特异性细胞免疫的恢复率。然后，我们将沿着对HAART反应的经典因果途径进行回溯，以确定早期坚持治疗和早期病毒学反应是否与早期死亡有关，以便确定能够预防这种结果的具体干预措施。鉴于在HAART治疗开始后第一年的所有死亡中，大多数发生在晚期艾滋病毒疾病患者的头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：本研究计划评估晚期HIV疾病和活动性结核病（TB）（全球最重要的机会性感染）的成年人在开始HAART治疗后最初6个月内对HAART的早期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工作提供重要信息，以改善全球扩大抗逆转录病毒治疗工作的成果。

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.