Targeted anticoagulant therapy to reduce inflammation in treated HIV disease

 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艾滋病毒阳性者生活质量和数量的核心。流行病学数据表明，艾滋病毒感染与持续的凝血异常有关，这种异常也可以预测长期的临床事件风险，尽管潜在的发病机制仍然存在疑问。我们提出了一个模型，在这个模型中，除了血栓形成的直接影响外，高凝状态还通过放大炎症途径来增加疾病风险。我们假设，在HIV阳性患者中，激活因子X(FXA)的产生增加有助于全身性促炎细胞因子水平(例如，白细胞介素6[IL-6])的升高。这在一定程度上是通过FXA激活单核细胞和组织巨噬细胞上的蛋白酶激活受体2(PAR-2)来实现的，这将使先天炎症永久化。我们将使用低剂量的口服FXA拮抗剂(利伐沙班，每天10毫克)来验证这一假设，使用随机安慰剂对照的交叉试验设计。在n=40名病毒抑制和D-二聚体水平为100 ng/ml的HIV阳性患者中，参与者的治疗效果(与安慰剂相比)将在4个月内表征。在目标1中，我们将确定抑制Xa因子是否下调全身炎症(反映在白细胞介素6水平)以及凝血活性。在目标2中，我们将专门研究因子Xa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，并根据观察到的治疗效果评估潜在的临床风险降低。在初步数据的支持下，我们认为FXA、PAR-2和单核细胞是连接高凝状态与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都是新颖的、创新的，还没有在艾滋病毒感染的背景下进行测试。研究结果将使人们更清楚地了解在治疗艾滋病毒疾病的背景下炎症-凝血相互作用的情况，并为今后制定治疗战略以改善艾滋病毒感染者的生活质量和数量提供信息。

 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.