Immunology and Outcomes after HAART in HIV/TB Coinfection

HIV/TB 合并感染中 HAART 后的免疫学和结果

基本信息

批准号：
8041155
负责人：
GREGORY P. BISSON
金额：
$ 16.24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8041155
关键词：
AIDS/HIV problem Accounting Acid Fast Bacillae Staining Method Address Adherence Adopted Adult Aftercare Bacillus (bacterium)Botswana CD4 Lymphocyte Count CD4 Positive T Lymphocytes Cause of Death Cell Count Cells Cellular Immunity Cessation of life Clinical Cohort Studies Data Diagnosis Disease Epidemiology Future Genus Mycobacterium Goals Grant HIV HIV Infections HIV-1 Health Services Accessibility Heterogeneity Highly Active Antiretroviral Therapy Immune Immune response Immunologics Immunology Individual Inflammatory Interferon Type II Intervention Knowledge Life Literature Measurement Measures Medical Modeling Morbidity - disease rate Mycobacterium tuberculosis Opportunistic Infections Organism Outcome Pathway interactions Patient Care Patients Peripheral Blood Mononuclear Cell Prospective Studies Public Health Pulmonary Tuberculosis RNA Recovery Regimen Research Research Proposals Resources Risk Risk Factors Southern Africa Sputum Staging Syndrome Testing Time Tuberculosis Update Viral Load result advanced disease antiretroviral therapy base clinical care clinically relevant combat design high risk immune function improved mortality pathogen prevent primary outcome programs prospective public health relevance reconstitution response restoration scale up

项目摘要

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.

描述（由申请人提供）：在开始高度活跃的抗逆转录病毒疗法（HAART）后的头6个月内，很大一部分HIV感染的患者死亡。减少这些早期死亡的潜力有可能大大改善全球抗逆转录病毒疗法的量表。然而，由于先前的研究集中在预先升级的危险因素或早期死亡后的反应因素上，因此早期死亡的患者对HAART的反应尚不清楚。因此，现有知识的基本差距是为什么某些患者仍会遭受早期死亡。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针对早期死亡机制的观察人群研究。较低治疗前CD4+ T细胞计数较低的发现与HAART启动后细胞介导的免疫力的定量和定性测量的延迟和病理上快速恢复有关，这引发了基本问题，即与HAART启动后早期死亡的风险有关细胞免疫率是否相关。在一种情况下，患者可能通过快速免疫康复和严重或致命的免疫结构炎症综合征（IRIS）而遭受早期死亡。在另一种情况下，延迟恢复细胞免疫力可能与无法控制机会病原体和死亡有关。该提案采用了一种流行病学方法，以检查病毒学和免疫学反应的早期（即在最初的4周内）之间的关系，以及Haart启动后早期死亡的风险。这些关系将在患有晚期HIV感染的成年人中检查（如HaART CD4 + T细胞计数<100细胞/mm3）和活动性结核病疾病。我们将在博茨瓦纳Gaborone进行一项前瞻性队列研究，以评估这些个体HAART启动后的头6个月内的死亡风险因素，首先关注结核分枝杆菌特异性细胞免疫的恢复速率。然后，我们将沿着对Haart的经典因果关系途径向后进行，以确定早期依从性和早期病毒学反应是否与早期死亡有关，以定义能够防止这种结果的特定干预措施。鉴于HAART启动后第一年的所有死亡人数大多数在头6个月内发生在晚期艾滋病毒疾病的患者中，因此该项目有可能改善全球扩大努力的预后。公共卫生相关性：这项研究提案评估了HAART在HAART启动后6个月的早期反应与患有晚期艾滋病毒疾病和主动结核病（TB）疾病的最初的六个月（全球最重要的机会性感染）之间的关系。该项目是在博茨瓦纳（Botswana）的Gaborone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，旨在改善全球抗逆转录病毒治疗量表的结果。