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.

产品说明：接受治疗的HIV阳性患者患心血管疾病（CVD）、癌症和其他HIV相关非AIDS疾病的风险增加。尽管抗逆转录病毒疗法（ART）治疗有效，但持续的免疫激活会增加CVD和非AIDS疾病的风险，而且还会导致淋巴组织纤维化，限制免疫恢复，进一步增加非AIDS疾病的风险。生物老化还导致全身性炎症和免疫功能减弱，因此，随着艾滋病毒感染者年龄的增长，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是老年艾滋病毒阳性患者的一个主要未满足的需求。我们提出了一个随机安慰剂对照试验氯沙坦（100毫克，每天）n=120抗逆转录病毒治疗的艾滋病毒阳性的人，年龄>50岁，接受有效的艺术与检测不到的艾滋病毒RNA水平。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CD 4计数变化的治疗效果。我们假设氯沙坦治疗将：a）减少全身性炎症，这将通过外周血中单核细胞活化的减少来解释，和B）通过下调淋巴组织中的免疫活化和TGF-β介导的纤维化导致免疫恢复，如血液CD 4+计数所反映的，这将改善T细胞稳态和幼稚T细胞的存活。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受损的T细胞稳态联系起来的模型。这项工作直接告知了我们对结果的选择，这既测试了基本的HIV发病机制问题，也将确定氯沙坦是否改善免疫激活和免疫恢复到可能具有临床相关性的程度。我们的方法和假设是创新的，我们的干预措施在HIV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，以告知和证明后续临床结果试验的费用。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疾病的改善策略。