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

基本信息

批准号：
8883185
负责人：
Jason V Baker
金额：
$ 5.25万
依托单位：
HENNEPIN HEALTHCARE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-02 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883185
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-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 Testing Tissues Tumor Necrosis Factor-alpha United States National Institutes of Health Viral Work antiretroviral therapy 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

项目摘要

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：治疗的HIV阳性患者患心血管疾病（CVD），癌症和其他HIV与HIV相关的非AID疾病的风险增加。持续的免疫激活，尽管有效治疗了抗逆转录病毒疗法（ART），但仍会增加CVD和非AIDS条件的风险，但也有助于淋巴组织纤维化，限制免疫记录，从而进一步增加了非AIDS条件的风险。生物老化还会导致全身性炎症和免疫学功能减弱，因此，随着HIV人群的年龄，非AIDS条件和多发菌率将继续增加。确定针对这种病理的安全治疗代表了对年长的艾滋病毒阳性患者的主要未满足需求。我们提出了一项随机的安慰剂对照试验（每天100毫克）N = 120抗逆转录病毒治疗的HIV阳性人> 50岁以> 50岁，接受有效的HIV RNA水平有效的ART。我们将研究Losartan在6个月内IL-6水平变化的治疗效果以及在12个月内的外周血CD4计数变化。 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 immunorecovery, as reflected in blood CD4+ count, via down-regulating immuno activation and TGF-β-mediated fibrosis in lymphatic tissues that will improve T-cell homeostasis and survival of naive T-cells.我们的调查团队帮助定义了感染在非AIDS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。这项工作直接为我们选择结果提供了信息，这些结果既检验基本的HIV发病机理问题，又将确定劳萨坦是否会改善免疫激活和免疫回收，以在临床上相关的程度。我们的方法和假设是创新的，我们的干预在HIV感染的背景下是新颖的，我们的方法提供了必不可少的随机数据，以告知和证明随后的临床结果试验的费用。总而言之，这项翻译试验介绍了高优先级HIV研究议程，以确定老年患者中非AIDS条件的疾病调整策略。