Treatment to reduce inflammation and improve immune recovery among older HIV pts

减少老年艾滋病患者炎症并改善免疫恢复的治疗

• 批准号: 9038208
• 负责人: Jason V Baker
• 金额: $ 55.9万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038208
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Age; Aging; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Automobile Driving; Biological Markers; Blood; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cell Count; Clinical; Clinical Trials; Collagen; Connective Tissue Diseases; Data; Deposition; Disease; Epidemiologic Studies; Event; FCGR3B gene; Fibrosis; Frequencies; Funding; Goals; HIV; HIV Infections; HIV Seropositivity; Health; Homeostasis; Hypotension; Immune; Immunity; Immunologics; Immunophenotyping; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Intervention; Lead; Link; Losartan; Lymphoid Tissue; Malignant Neoplasms; Measures; Mediating; Methods; Modeling; Morbidity - disease rate; Multi-Institutional Clinical Trial; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Placebos; Plasma; Population; Production; Property; RNA; Randomized; Recovery; Renal Tissue; Research; Research Personnel; Reticular Cell; Risk; Risk Factors; Role; Staging; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Tissues; Transforming Growth Factor beta; Translational trial; United States National Institutes of Health; Viral; Work; antiretroviral therapy; blood pressure reduction; body system; cardiovascular disorder risk; clinical risk; clinically relevant; cytokine; disorder risk; effective therapy; epidemiologic data; experience; immune activation; immune function; improved; improved functioning; innovation; lymph nodes; monocyte; mortality; novel; older patient; peripheral blood; primary outcome; randomized placebo controlled trial; translational clinical trial; treatment effect

DESCRIPTION: Treated HIV positive patients are at increased risk for cardiovascular disease (CVD), cancer, and other HIV- associated non-AIDS conditions. Ongoing immune activation, despite effective treatment with antiretroviral therapy (ART), increases risk for CVD and non-AIDS conditions, but also contributes to lymphatic tissue fibrosis, limiting immune recovery that further increases risk for non-AIDS conditions. Biologic aging also leads to systemic inflammation and waning immune function, and, thus, non-AIDS conditions and poly-morbidity will continue to increase as the HIV population ages. Identifying safe treatments that target this pathology represents a major unmet need for older HIV positive patients. We propose a randomized placebo-controlled trial of losartan (100mg daily) among n=120 antiretroviral-treated HIV positive persons age >50 years receiving effective ART with undetectable HIV RNA levels. We will study the treatment effects of losartan on changes in IL-6 levels over 6 months and changes in peripheral blood CD4 count over 12 months. We hypothesize that losartan treatment will: a) reduce systemic inflammation that will be accounted for through reductions in monocyte activation within peripheral blood, and b) lead to immune recovery, as reflected in blood CD4+ count, via down-regulating immune activation and TGF-β-mediated fibrosis in lymphatic tissues that will improve T- cell homeostasis and survival of naive T-cells. Our investigative team has helped define the role of inflammation in non-AIDS disease risk as well as developed the model that links lymph node fibrosis with impaired T-cell homeostasis. This work directly informed our choice of outcomes, which both test fundamental HIV pathogenesis questions and will determine if losartan improves immune activation and immune recovery to a degree that may be clinically relevant. Our methods and hypotheses are innovative, our intervention is novel in the context of HIV infection, and our approach provides essential randomized data to inform and justify the expense of subsequent clinical outcome trials. In summary, this translational trial addresses a high priority HIV research agenda to identify disease-modifying strategies for non-AIDS conditions among older patients.

描述：接受治疗的 HIV 阳性患者患心血管疾病 (CVD)、癌症和其他与 HIV 相关的非艾滋病疾病的风险增加。尽管抗逆转录病毒疗法 (ART) 有效，但持续的免疫激活会增加 CVD 和非艾滋病疾病的风险，而且还会导致淋巴组织纤维化，限制免疫恢复，从而进一步增加非艾滋病疾病的风险。生物衰老还会导致全身炎症和免疫功能减弱，因此，随着艾滋病毒人口老龄化，非艾滋病疾病和多发病率将继续增加。确定针对这种病理学的安全治疗方法是老年艾滋病毒阳性患者未满足的主要需求。我们建议对 120 名年龄 > 50 岁、接受有效 ART 且 HIV RNA 水平未检测到的接受过抗逆转录病毒治疗的 HIV 阳性患者进行氯沙坦（每天 100 毫克）的随机安慰剂对照试验。我们将研究氯沙坦对 6 个月内 IL-6 水平变化和 12 个月内外周血 CD4 计数变化的治疗效果。我们假设氯沙坦治疗将：a）通过减少外周血中的单核细胞活化来减少全身炎症，b）通过下调淋巴组织中的免疫活化和TGF-β介导的纤维化来改善T细胞稳态和初始T细胞的存活，从而导致免疫恢复，如血​​液CD4+计数所反映。我们的研究团队帮助确定了炎症在非艾滋病疾病风险中的作用，并开发了将淋巴结纤维化与 T 细胞稳态受损联系起来的模型。这项工作直接影响了我们对结果的选择，这些结果既测试了基本的艾滋病毒发病机制问题，也将确定氯沙坦是否可以将免疫激活和免疫恢复改善到可能与临床相关的程度。我们的方法和假设是创新的，我们的干预措施在艾滋病毒感染的背景下是新颖的，我们的方法提供了必要的随机数据来告知和证明后续临床结果试验的费用是合理的。总之，这项转化试验解决了一个高度优先的艾滋病毒研究议程，以确定老年患者非艾滋病状况的疾病缓解策略。