CAUSES OF AND ASSOCIATIONS WITH DEATH DURING LONG TERM HAART IN AFRICA

说明（由申请人提供）：艾滋病毒是非洲15-64岁成年人死亡的主要原因。最近在非洲广泛采用高效抗逆转录病毒疗法（HAART）治疗艾滋病毒，降低了死亡率；然而，死亡率仍然高于工业化国家。在工业化国家，HAART已导致死亡原因从急性机会性感染转变为慢性疾病。在非洲，HAART治疗的死亡原因和从开始HAART治疗到持续时间内具体风险的变化尚不清楚。拟议的研究将确定HAART期间死亡率的发生率和风险，随时间变化的死亡相关因素，具体死亡原因，以及结核病和乙型肝炎在死亡因果途径中的作用。这些数据将用于模拟特定暴露的独立贡献，如HIV病毒血症、CD4计数、错过就诊和死亡后自我发起的治疗中断。这些数据将有助于在优化护理指南方面为公共卫生决策提供信息，并确定降低死亡率的潜在干预措施的优先次序。拟议的研究将在南非公司艾滋病诊所的抗逆转录病毒治疗队列中进行回顾性研究。该研究将在ART队列中进行8年的前瞻性随访，并常规获得尸检，约有50%的死亡工人获得尸检。边际结构模型将用于评估时变协变量的因果推断，并评估效应修正，以确定HAART治疗随时间变化的死亡风险。这项工作建立在PIs在非洲研究、纵向数据分析和艾滋病毒结果方面的经验基础上。在南非完成这项研究，加上有组织的指导和高级统计课程，将提供必要的经验和指导，以发展PI作为国际艾滋病毒治疗领域的独立调查员所需的技能和技术。仔细描述HAART治疗的长期结果并确定死亡风险和原因，对于优化治疗算法、制定预防战略和在非洲实施具有成本效益的艾滋病毒护理非常重要。由于资源有限，在大多数非洲国家实施工业化国家所存在的护理水平是不可行的。然而，目前尚不清楚分配资源以实现成果最大化的最佳方法。了解死亡的风险和原因有助于为旨在改善健康和生存的资源分配提供信息。

DESCRIPTION (provided by applicant): HIV is the leading cause of death among adults aged 15-64 in Africa. Recent wide-spread introduction of highly active antiretroviral therapy (HAART) to treat HIV in Africa has reduced mortality; however, mortality rates remain higher than in industrialized countries. In industrialized countries, HAART has lead to a shift in causes of death from acute opportunistic infections to chronic diseases. Causes of mortality on HAART and changes in specific risks over duration from HAART initiation are unknown in Africa. The proposed study will determine incidence and risks for mortality during HAART, changing factors associated with death over time, specific causes of death, and the role of both TB and hepatitis B in causal pathways to death. This data will be used to model the independent contributions of specific exposures such as HIV viremia, CD4 count, missed visits, and self initiated treatment interruption on death. These data will help to inform public health decisions regarding optimization of care guidelines and to prioritize potential interventions to reduce mortality. The proposed research will be conducted retrospectively within an ART cohort based in company HIV clinics in South Africa. The research will utilize 8 years of prospective follow-up in the ART cohort and routinely obtained autopsies, obtained for approximately 50% of workers who die. Marginal structural models will be used to assess causal inference for time varying covariates and effect modification will be assessed to identifying changing risks for death over time on HAART. This work builds on the PIs experience with research in Africa, longitudinal data analysis, and HIV outcomes. Completing this research in South Africa, along with structured mentorship and advanced statistics courses, will provide the necessary experience and guidance to develop skills and techniques needed for the PI to emerge as an independent investigator in the area of international HIV treatment. Careful description of long-term HAART outcomes and identification of risks for and causes of death is important to optimize treatment algorithms, develop prevention strategies, and implement cost-effective HIV care in Africa. Because of limited resources implementing a level of care as exists in industrialized countries is not feasible in most of Africa. However, the optimum approach to allocating resources to maximize outcomes is currently unclear. Knowledge of risks for and causes of mortality can contribute to informing resource allocation aimed at improving health and survival.