Effect of low dose methotrexate on endothelial function and inflammation in HIV

描述(由申请人提供)： 接受抗逆转录病毒治疗(ART)的艾滋病毒感染者患心血管疾病(CVD)的风险增加，这可能是因为尽管进行了积极的艾滋病毒治疗，炎症仍持续存在。类风湿性关节炎患者，如艾滋病毒携带者，心血管疾病风险增加，炎症水平高。小剂量甲氨蝶呤(LDMTX)对类风湿关节炎患者是一种安全的治疗方法，似乎可以降低心血管疾病的风险。心血管炎症减少试验(CIRT)最近得到了NHLBI的资助，招募了7500名受试者参加一项随机临床试验，以评估LDMTX对既往有心血管疾病和持续炎症患者的心血管事件和死亡率的二级预防效果。由于导致艾滋病毒感染环境中持续炎症的因素不同于普通人群和感染艾滋病毒的个人被排除在CIRT之外，因此其结果不能推广到美国日益增长的艾滋病毒携带者人口。NIAID艾滋病临床试验小组已同意为一项随机试验的临床试验网络基础设施和费用提供资金，以评估LDMTX干预艾滋病毒携带者的安全性和可行性(研究A5314)。我们正在向NHLBI提交这份申请，以支持我们提议的血管功能和炎症措施，因为这些领域更符合NHLBI的优先事项。作为A5314研究的一部分，我们建议评估LDMTX治疗对心血管疾病风险增加的病毒抑制、HIV感染患者的内皮功能、炎症和免疫激活的影响，以便同时收集有关LDMTX有效性和安全性的数据。这项研究还将提供LDMTX对心血管疾病风险影响的机械性见解，并将为更广泛的研究评估抗炎干预措施对艾滋病毒感染者心血管疾病风险的影响提供理论基础。它将利用现有的NIH资助的临床试验基础设施来执行这项试验，大大降低NHLBI的成本。我们的中心假设是，在接受稳定的抗逆转录病毒治疗(ART)的HIV感染者中，持续的炎症和免疫激活有助于增加心血管疾病风险。为了研究这一假设，我们将执行 一项随机、双盲、安慰剂对照的临床试验，旨在评估LDMTX在病毒抑制的艾滋病毒感染者中对稳定的抗逆转录病毒治疗的影响。这项研究有三个具体目的，以评估LDMTX治疗是否将(I)改善血管内皮功能(通过血流介导的臂动脉扩张来评估)；(Ii)降低hsCRP和IL-6水平，这是心血管疾病风险的炎性标记物；以及(Iii)降低免疫激活和衰老水平。我们预计LDMTX疗法将通过降低炎症来改善动脉功能，这项机械性的概念验证研究将证明炎症和免疫激活在艾滋病毒相关心血管疾病中的重要性，从而为未来的介入研究奠定基础，以确定降低接受治疗的艾滋病毒感染患者的心血管疾病风险的策略。 公共卫生相关性： 由于持续的炎症，接受有效抗逆转录病毒治疗的艾滋病毒感染者患心血管疾病(CVD)的风险增加。这项研究将通过评估使用低剂量甲氨蝶呤减轻炎症对接受治疗的艾滋病毒感染者的内皮功能、炎症和免疫激活的影响，来检验炎症导致艾滋病毒感染中的心血管疾病风险的假设。 (摘要结束)

DESCRIPTION (provided by applicant): HIV-infected individuals on antiretroviral therapy (ART) are at increased risk for cardiovascular disease (CVD), possibly due to inflammation that persists despite aggressive HIV treatment. Patients with rheumatoid arthritis, like those with HIV, have increased CVD risk and high levels of inflammation. Low-dose methotrexate (LDMTX) is a safe treatment for patients with rheumatoid arthritis that appears to reduce CVD risk. The Cardiovascular Inflammation Reduction Trial (CIRT) recently received funding from the NHLBI to enroll 7500 subjects in a randomized clinical trial to evaluate the effects of LDMTX on the secondary prevention of CVD events and mortality among patients with prior CVD and ongoing inflammation. Because the factors that contribute to persistent inflammation in the setting of HIV infection are different thn those in the general population and individuals with HIV infection are excluded from the CIRT, its results will not be generalizable to the growing population of individuals living with HIV in te United States. The NIAID AIDS Clinical Trials Group has agreed to fund the clinical trials network infrastructure and costs for a randomized trial to evaluate the safety and feasibility of a LDMTX intervention in individuals with HIV (study A5314). We are submitting this application to the NHLBI for support of our proposed measures of vascular function and inflammation, since these areas are more in line with the priorities of NHLBI. We propose to evaluate the effects of LDMTX treatment on endothelial function, inflammation, and immune activation in virally suppressed, HIV-infected individuals at increased CVD risk as part of study A5314, so data regarding the effectiveness and safety of LDMTX can be collected simultaneously. This study also will provide mechanistic insights into the effects of LDMTX on CVD risk and will provide a rationale for more extensive studies to evaluate anti-inflammatory interventions on CVD risk in individuals with HIV. It will leverage an existing NIH- funded clinical trials infrastructure to perform this trial at a significantly reduced cost to the NHLBI. Our central hypothesis is that persistent inflammation and immune activation contribute to increased CVD risk in HIV-infected individuals on stable antiretroviral therapy (ART). To investigate this hypothesis, we will perform a randomized, double-blind, placebo-controlled clinical trial to evaluate the effects of LDMTX in virally suppressed, HIV-infected individuals on stable ART. This investigation has three specific aims that assess whether treatment with LDMTX will (i) improve endothelial function, as assessed by flow-mediated vasodilation of the brachial artery; (ii) reduce hsCRP and interleukin-6 levels, inflammatory markers of CVD risk; and (iii) decrease levels of immune activation and senescence. We expect that LDMTX therapy will improve arterial function by lowering inflammation and that this mechanistic, proof-of-concept study will demonstrate the importance of inflammation and immune activation in HIV-associated CVD, thus forming the basis for future interventional studies to identify strategies that reduce CVD risk in individuals with treated HIV infection. PUBLIC HEALTH RELEVANCE: HIV-infected individuals on effective antiretroviral therapy are at increased cardiovascular disease (CVD) risk because of persistent inflammation. This study will test the hypothesis that inflammation drives CVD risk in HIV infection by evaluating the effects of reducing inflammation using low-dose methotrexate on endothelial function, inflammation, and immune activation in treated HIV-infected individuals. (End of Abstract)