Targeted anticoagulant therapy to reduce inflammation in treated HIV disease

靶向抗凝治疗可减少治疗艾滋病毒疾病中的炎症

• 批准号: 8846913
• 负责人: Jason V Baker
• 金额: $ 63.86万
• 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: 2014-09-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846913
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulant therapy; Biological Markers; Biology; Blood Coagulation Factor; Cardiovascular Diseases; Clinical; Clinical Trials Design; Coagulation Process; Complex; Cross-Over Studies; Data; Development; Disease; Dose; Down-Regulation; Epidemiologic Studies; Evaluation; Event; Experimental Designs; Factor Xa; Feasibility Studies; Fibrin fragment D; Future; Generations; Goals; HIV; HIV Infections; HIV Seropositivity; Immunologics; Inflammation; Inflammatory; Interleukin-6; Intervention; Laboratories; Life; Link; Mediating; Mediator of activation protein; Methods; Modeling; Mus; Oral; Organ; Outcome; PAR-2 Receptor; Participant; Pathogenesis; Pathway interactions; Patients; Persons; Placebo Control; Placebos; Positioning Attribute; Prevention strategy; Randomized; Reporting; Risk; Risk Factors; Risk Reduction; Role; Sentinel; Testing; Thromboplastin; Tissues; Viral; Work; antiretroviral therapy; cardiovascular disorder risk; clinical risk; clinically significant; cytokine; disorder risk; epidemiologic data; experience; follow-up; hexachlorocyclohexane x-factor; improved; innovation; macrophage; monocyte; mortality; novel; public health relevance; translational study; treatment effect; treatment strategy

 DESCRIPTION (provided by applicant): Understanding and mitigating persistent inflammation and coagulation activation is central to improving the quality and quantity of life for contemporary HIV-positive persons. Epidemiologic data demonstrate that HIV infection is associated with ongoing coagulation abnormalities that also predict long-term clinical event risk, though questions remain regarding the underlying pathogenesis. We propose a model where hypercoagulation contributes to disease risk by amplifying inflammatory pathways, in addition to the direct effects of thrombogenesis. We hypothesize that increased generation of activated factor X (FXa) contributes to a systemic elevation in pro-inflammatory cytokine levels (e.g. interleukin-6 [IL-6]) among HIV positive patients. This occurs, in part, via FXa activation of protease activated receptor 2 (PAR-2) on monocytes and tissue macrophages, which perpetuates innate inflammation. We will test this hypothesis with low dose of an oral antagonist to FXa (rivaroxaban at 10mg daily), using a randomized placebo-controlled cross-over trial design. Treatment effects within participants (compared to placebo) will be characterized over 4 months among n=40 HIV positive patients with viral suppression and D-dimer levels >100ng/mL. In aim 1, we will determine if inhibition of factor Xa down regulates systemic inflammation (reflected in interleukin-6 levels), as well as coagulation activity. In aim 2, we wil specifically study the effects of factor Xa inhibition on monocyte- mediated inflammation and tissue factor activity. In aim 3, we will study tolerability of rivaroxaban and estimate the potental clinical risk reduction predicted by the observed treatment effects. Supported by preliminary data, we proposed that FXa, PAR-2, and monocytes are key mediators linking hypercoagulation to systemic inflammation. This central hypothesis, our laboratory methods, and our interventional strategy are novel, innovative and have not been tested in the context of HIV infection. Findings will provide a clearer understanding of inflammation-coagulation cross talk in the context of treated HIV disease, and inform future development of treatment strategies to improve the quality and quantity of life for persons with HIV infection.

 描述（由申请人提供）：了解和减轻持续性炎症和凝血激活是提高当代HIV阳性者生活质量和数量的关键。流行病学数据表明，HIV感染与持续的凝血异常有关，这也预测了长期临床事件的风险，但关于潜在的发病机制仍存在疑问。我们提出了一个模型，其中高凝状态除了血栓形成的直接影响外，还通过放大炎症通路来增加疾病风险。我们假设，在HIV阳性患者中，活化因子X（FXa）的产生增加有助于促炎细胞因子水平（例如白细胞介素-6 [IL-6]）的全身性升高。这部分地通过单核细胞和组织巨噬细胞上的蛋白酶活化受体2（PAR-2）的FXa活化而发生，其使先天性炎症持续存在。我们将使用低剂量的口服FXa拮抗剂（利伐沙班，每日10 mg），采用随机安慰剂对照交叉试验设计来检验这一假设。将在n=40名病毒抑制和D-二聚体水平> 100 ng/mL的HIV阳性患者中，在4个月内表征参与者内的治疗效果（与安慰剂相比）。在目标1中，我们将确定因子Xa的抑制是否下调全身炎症（反映在白细胞介素-6水平上）以及凝血活性。在目标2中，我们将具体研究Xa因子抑制对单核细胞介导的炎症和组织因子活性的影响。在目标3中，我们将研究利伐沙班的耐受性，并估计通过观察到的治疗效果预测的潜在临床风险降低。在初步数据的支持下，我们提出FXa、PAR-2和单核细胞是连接高凝状态和全身炎症的关键介质。这一中心假设，我们的实验室方法和我们的干预策略是新颖的，创新的，尚未在艾滋病毒感染的背景下进行测试。研究结果将提供一个更清楚的了解炎症凝血串扰的背景下治疗艾滋病毒疾病，并告知未来的发展的治疗策略，以提高生活质量和数量的人与艾滋病毒感染。