Statins for Pulmonary and Cardiac Complications of Chronic HIV (The SPARC Trial)

描述(由申请人提供)：越来越多的证据表明，慢性阻塞性肺疾病(COPD)是HIV+患者呼吸损害的重要原因，随着HIV+人群继续老龄化，COPD可能会增加。在未感染艾滋病毒的人群中，COPD经常与包括动脉粥样硬化和肺动脉高压在内的心脏疾病共存。我们的工作表明，即使在不吸烟或接受抗逆转录病毒治疗的HIV+患者中也存在“心肺功能障碍”综合征，并与呼吸道症状增加和死亡率有关。HMG辅酶A还原酶抑制剂(他汀类)在肺和血管中具有抗炎和其他作用，可能有助于HIV患者的心肺功能障碍。这些药物在心血管疾病中的临床使用历史悠久，目前正在研究艾滋病毒、慢性阻塞性肺病和肺动脉高压。在初步分析中，在过去一年内接受他汀类药物治疗的HIV+患者往往具有更好的一氧化碳扩散能力，较少的呼吸道阻塞，较低的肺动脉压和心脏应变，较低的外周细胞因子，以及减少的痰中性粒细胞，尽管年龄较大，吸烟史与不使用他汀类药物的患者相似。我们假设他汀类药物治疗将减少炎症和减缓HIV患者心肺异常的进展。我们将在适应性反应设计中测试瑞舒伐他汀与安慰剂的效果，以确定效应大小，估计样本量，并开发一种新的复合终点，为全面试验做准备。我们将利用 我们现有的400多人的HIV+队列是通过我们的肺部HIV和肺部HIV微生物组项目建立的，这些项目是通过与我们当地的HIV诊所、多中心艾滋病队列研究和妇女机构间健康研究合作建立的。这项研究不仅将评估治疗方法，还将允许采用床边到床边的方法来确定艾滋病毒心肺功能障碍的机制。我们将进行一项试点研究，通过完成以下目标为未来的第三阶段临床试验奠定基础：目标1：建立一个由临床研究人员、统计学家和翻译科学家组成的网络，以研究艾滋病毒相关心肺疾病的间歇期。目的2：完成他汀类药物治疗HIV相关性心肺功能障碍的先导性研究，以确定他汀类药物的疗效大小以及对生理结局和生物标志物的影响。目的3：创建一个翻译核心，为未来对HIV感染中心肺功能障碍机制的床边到床边研究奠定基础。试验参与者将被随机分为治疗组和安慰剂组，分别接受3个月和6个月的肺功能、计算机断层扫描、超声心动图、颈动脉内膜中层厚度、血流介导的扩张和炎症生物标志物的测量。AIMS的成功完成将建立临床试验网络，提供概念验证数据，以及 建立一个翻译核心，以加强对艾滋病毒心肺功能障碍的了解，并指导对艾滋病毒一种重要并存疾病的治疗进行大规模临床试验。

DESCRIPTION (provided by applicant): Growing evidence indicates that chronic obstructive pulmonary disease (COPD) is an important cause of respiratory impairment in HIV+ persons and will likely increase as the HIV+ population continues to age. In the HIV-uninfected population, COPD frequently co-exists with cardiac disease including atherosclerosis and pulmonary hypertension. Our work has demonstrated that a syndrome of "cardiopulmonary dysfunction" exists even in non-smoking or antiretroviral-treated HIV+ individuals and is associated with increased respiratory symptoms as well as with mortality. HMG CoA reductase inhibitors (statins) have anti-inflammatory and other effects in the lungs and vasculature that might benefit cardiopulmonary dysfunction in HIV. These agents have a long history of clinical use in cardiovascular disease and are currently being investigated in HIV, COPD, and pulmonary hypertension. In preliminary analyses, HIV+ individuals who received statin therapy within the past year tended to have better diffusing capacity for carbon monoxide, less airway obstruction, lower pulmonary artery pressures and cardiac strain, lower peripheral cytokines, and decreased sputum neutrophils despite being older and having a similar smoking history to those not using statins. We hypothesize that statin therapy will decrease inflammation and slow progression of cardiopulmonary abnormalities in HIV. We will test effects of rosuvastatin compared to placebo in an adaptive response design to determine effect size, estimate sample size, and develop a novel composite endpoint in preparation for a full-scale trial. We will utilize our existing HIV+ cohorts of over 400 individuals established through our Lung HIV and Lung HIV Microbiome Projects via collaborations with our local HIV clinic, the Multicenter AIDS Cohort Study, and the Women's Interagency Health Study. The study will not only evaluate treatments, but will allow for a bedside- to-bench-to-bedside approach to determine mechanisms of cardiopulmonary dysfunction in HIV. We will perform a pilot study to establish the basis for a future, Phase III clinical trial by completing the following aims: Aim 1: To establsh a network of clinical investigators, statisticians, and translational scientists to study interventons in HIV-associated cardiopulmonary disease. Aim 2: To complete a pilot study of statin therapy in HIV-associated cardiopulmonary dysfunction to determine effect size and impact on physiologic outcomes and biomarkers. Aim 3: To create a translational core establishing infrastructure for future bedside- to-bench-to-bedside studies of mechanisms of cardiopulmonary dysfunction in HIV infection. Participants in the trial will be randomized to treatment or placebo with 3 and 6 month measures of pulmonary function, computed tomography, echocardiography, carotid intima media thickness, flow-mediated dilation and inflammatory biomarkers. Successful completion of the aims will establish a clinical trials network, provide proof-of-concept data, and establish a translational core to enhance understanding of HIV cardiopulmonary dysfunction and to guide a large-scale clinical trial of treatment for an important co-morbidity in HIV.