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+人群呼吸功能障碍的重要原因，并且随着HIV+人群的持续老龄化，可能会增加。在未感染hiv的人群中，慢性阻塞性肺病经常与心脏疾病共存，包括动脉粥样硬化和肺动脉高压。我们的工作表明，即使在不吸烟或抗逆转录病毒治疗的HIV+个体中也存在“心肺功能障碍”综合征，并且与呼吸道症状的增加以及死亡率有关。HMG辅酶a还原酶抑制剂（他汀类药物）在肺部和血管系统中具有抗炎和其他作用，可能有益于HIV患者的心肺功能障碍。这些药物在心血管疾病的临床应用已有很长的历史，目前正在HIV、COPD和肺动脉高压的研究中。在初步分析中，在过去一年内接受他汀类药物治疗的HIV+个体倾向于具有更好的一氧化碳扩散能力，更少的气道阻塞，更低的肺动脉压和心脏负荷，更低的外周细胞因子，痰中性粒细胞减少，尽管年龄更大，吸烟史与不使用他汀类药物的人相似。我们假设他汀类药物治疗将减少炎症和减缓艾滋病毒心肺异常的进展。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，并为全面试验准备一个新的复合终点。我们将利用

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.