REPRIEVE - CCC - Lead Application

描述(由申请人提供)：心血管疾病(CVD)在艾滋病毒感染患者中增加了50%-100%，经常发生在相对年轻的艾滋病毒患者中，尽管传统风险因素最小，且低密度脂蛋白正常。事实上，HIV中动脉粥样硬化形成的机制是独特的，与免疫激活有关，单核细胞激活和化学吸引指数的增加证明了这一点。此外，心脏CT血管成像(CCTA)的详细冠状动脉成像显示，非钙化斑块的患病率显著增加，具有高风险的形态学特征，包括阳性重塑和低CT密度。尽管艾滋病毒感染患者的心血管疾病显著增加，但目前还没有预防这种疾病的治疗策略。他汀类药物是预防艾滋病毒心血管疾病的一个有吸引力的选择。他汀类药物显示出降低低密度脂蛋白的强大作用，并被认为是唯一能减少单核细胞激活、趋化作用和内皮激活的药物，这些都是HIV动脉粥样硬化的潜在致病机制。在这笔赠款中，我们将进行一项多中心、随机、安慰剂对照的临床试验(缓释期)，作为HIV中心血管疾病的一级预防策略。5300名无已知心脏病、低密度脂蛋白130 mg/dL、Framingham Risk Score&lt；20的HIV感染者将被纳入。匹伐他汀已被证明可以安全有效地降低艾滋病毒中的低密度脂蛋白，并已知与抗逆转录病毒治疗的相互作用最小。主要终点将是他汀类药物对主要不良心脏事件(MACE)的影响，包括动脉粥样硬化或其他心血管疾病死亡、非致命性心肌梗死、不稳定心绞痛住院、冠状动脉或外周动脉血运重建、复苏的心脏骤停、非致命性中风。此外，我们将在800名受试者中进行一项嵌入式机制研究，使用详细的CCTA成像和复杂的生物标记物评估来确定他汀类药物治疗减少非钙化斑块体积和高危形态学特征的有效性和机制。具体炎症生物标志物的变化，包括单核细胞激活、内皮激活、动脉炎症和凝血，将在机制研究中确定，然后在初步研究中结合MACE进行评估，以提供有关他汀类药物在HIV中作用机制的迫切需要的信息。将确定详细的安全性指标，包括对血糖稳态、肝脏和肌肉的影响，并将探讨对非心血管事件的影响。这项试验也将与艾滋病临床试验小组合作进行 作为NIAID研究网络内的临床研究站点，包括来自Insight网络的站点。有5300名计划参与者，假设基准事件发生率为每年18/1000，试验的功率很好(90%)，可以检测到HR为0.65。这项新的试验将为HIV感染患者的一个关键问题提供急需的信息，并将作为研究针对其他炎症性疾病的定制初级预防策略的模型，在这些策略中，免疫介导的动脉粥样硬化是一个重要的促成因素。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is increased 50-100% among HIV- infected patients, occurring often among relatively younger HIV patients despite minimal traditional risk factors, and normal LDL. Indeed, the mechanisms of atherogenesis in HIV are unique and relate to increased immune activation, as demonstrated by increased indices of monocyte activation and chemoattraction. Moreover, detailed coronary imaging by cardiac computed tomography angiography (CCTA) demonstrates a significantly increased prevalence of non-calcified plaque, with high risk morphological characteristics, including positive remodeling and low CT attenuation. Despite the significant increase in CVD among HIV-infected patients, no treatment strategies as yet exist to prevent this disease. Treatment with statins represents an attractive option to prevent CVD in HIV. Statins demonstrate potent effects to lower LDL and are known to uniquely reduce monocyte activation, chemoattraction and endothelial activation, potential pathogenetic mechanisms of atherogenesis in HIV. In this grant, we will perform a multicenter, randomized placebo-controlled clinical trial (REPRIEVE) of pitavastatin, as a primary prevention strategy for CVD in HIV. 5300 HIV-infected subjects without known heart disease and with LDL<130 mg/dL and Framingham Risk Score < 20 will be enrolled. Pitavastatin has been shown to safely and effectively lower LDL in HIV and is known to have minimal interactions with antiretroviral therapy. The primary endpoint will be the effects of statin therapy on major adverse cardiac events (MACE) including atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary or peripheral arterial revascularization, resuscitated cardiac arrest, nonfatal stroke. In addition, we will perform an embedded mechanistic study among 800 subjects using detailed CCTA imaging and sophisticated biomarker assessments to determine efficacy and mechanisms of statin therapy to reduce non-calcified plaque volume, and high risk morphological features. Change in specific inflammatory biomarkers, including monocyte activation, endothelial activation, arterial inflammation and coagulation, will be determined in the mechanistic study and then assessed with regard to MACE in the primary study, to provide critically needed information on the mechanisms of statin effects in HIV. Detailed safety indices, including effects on glucose homeostasis, liver and muscle will be determined, and effects on non CVD events will be explored. The trial will be performed in collaboration with the AIDS Clinical Trial Group, as well as clinical research sites within the NIAID research network, including sites from the INSIGHT network. With 5300 planned participants the trial is well powered (90%) to detect a HR of 0.65, assuming a baseline event rate of 18/1000 PY. This novel trial will provide much needed information on a critical problem for HIV- infected patients and will serve as a model for the study of tailored primary prevention strategies for other inflammatory diseases in which immune mediated atherogenesis is an important contributing factor.