Effect of PCSK9 Inhibition on Cardiovascular Risk in Treated HIV Infection (EPIC-HIV Study)

项目摘要 感染艾滋病毒的人患心肌梗死的风险高2倍，同时心力衰竭的发生率也更高。 和心源性猝死。虽然这种过度风险背后的机制仍然知之甚少， 我们小组和其他人的研究表明，艾滋病毒感染背景下的动脉粥样硬化是明显的和 以FDG-PET/CT评估的动脉炎症加重和内皮异常为特征 通过血流介导的肱动脉血管扩张(FMD)评估其功能。这些血管评估 通过使用他汀类药物或低密度脂蛋白分离降低低密度脂蛋白-C，两者都得到了改善。枯草杆菌蛋白原转换酶可信 9(PCSK9)已成为降低胆固醇的重要药理作用靶点 在人群中和难以治疗的人群中。用单抗抑制PCSK9导致了 低密度脂蛋白-胆固醇降低约50-70%，总体耐受性良好，没有明显的副作用。什么时候 在他汀类药物治疗的基础上，抑制PCSK9将低密度脂蛋白降低到30 mg/dL的中位数，并显著 在一项对27,000名ASCVD患者的研究中，主要心血管事件减少了15%。两名特工 (volocumab，alirocumab)是FDA批准的。使用PCSK9抑制剂显著降低低密度脂蛋白的影响 关于HIV相关的动脉粥样硬化的研究仍不清楚。我们建议单中心，双盲，安慰剂- 在接受有效治疗的HIV患者中评估PCSK9抑制对心血管风险的影响的对照试验 已知有心血管疾病或有心血管疾病风险并有动脉炎症的感染者基线。我们建议 以下目标：目标1：确定抑制PCSK9是否可以改善动脉炎症 通过FDG-PET/CT对接受治疗和被抑制的艾滋病毒感染者进行研究。目的2：评估PCSK9的效果 在治疗和抑制的HIV中，通过FMD评估对内皮功能的抑制。我们将相互关联 血脂指标包括总胆固醇、高密度脂蛋白胆固醇、甘油三酯、非高密度脂蛋白胆固醇、载脂蛋白B的变化 载脂蛋白B、载脂蛋白A-I、免疫激活和炎症标志物[Lp(A)、LpPLA2、sCD14 和T细胞活化]用动脉炎症(目标1)和内皮功能(目标2)进行评估。目标3： 对抑制PCSK9对HIV中非钙化斑块的影响进行初步评估，通过 连续冠状动脉CT血管造影术。我们将把这些发现与血脂参数和标记物的变化联系起来。 在目标1中评估的炎症/免疫激活；此外，我们将确定 动脉FDG摄取与冠状动脉斑块的变化有关。此应用程序结合了(1) 成功的多学科团队，在研究干预方面有良好的合作记录和专业知识 艾滋病毒，(2)从现有艾滋病毒感染人群中快速招募受试者的能力，(3)利用资源 包括工业提供的研究药物/安慰剂。找出降低心血管疾病风险的新疗法是至关重要的 以提高艾滋病毒感染者的死亡率，这项研究的结果将为 未来的试验将评估抑制PCSK9对HIV临床事件的影响。

Project Summary HIV-infected individuals have a 2-fold higher risk of myocardial infarction along with higher rates of heart failure and sudden cardiac death. While the mechanism underlying this excess risk remains poorly understood, studies from our groups and others demonstrate that atherosclerosis in the setting of HIV is distinct and characterized by heightened arterial inflammation as assessed by FDG-PET/CT and abnormal endothelial function as assessed by flow-mediated vasodilation of the brachial artery (FMD). These vascular assessments are both improved by lowering of LDL-C using statins or LDL apheresis. Proprotein convertase subtilisin kexin 9 (PCSK9) has emerged as an important pharmacologic target for cholesterol lowering in the general population and in difficult-to-treat populations. Inhibition of PCSK9 with a monoclonal antibody has led to decreases in LDL-cholesterol of ~50-70% and are overall well tolerated without significant side effects. When added on top of statin therapy, PCSK9 inhibition reduced LDL to a median of 30 mg/dL and significantly reduced major cardiovascular events by 15% in a study of > 27,000 individuals with ASCVD. Two agents (Evolocumab, Alirocumab) are FDA-approved. The impact of significant LDL lowering using PCSK9 inhibition on HIV-associated atherosclerosis remains unknown. We propose a single center, double blind, placebo- controlled trial to assess the impact of PCSK9 inhibition on CV risk in the setting of effectively treated HIV- infected individuals with known CVD or at risk for CVD with arterial inflammation at baseline. We propose the following aims: Aim 1: To determine whether PCSK9 inhibition can improve arterial inflammation as assessed by FDG-PET/CT in treated and suppressed HIV-infected individuals. Aim 2: To assess the effect of PCSK9 inhibition on endothelial function as assessed by FMD in treated and suppressed HIV. We will correlate changes in lipid parameters including total cholesterol (TC), HDL-C, triglycerides, non-HDL-C, apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), markers of immune activation and inflammation [Lp(a), LpPLA2, sCD14 and T cell activation] assessed with both arterial inflammation (Aim 1) and endothelial function (Aim 2). Aim 3: To perform a pilot evaluation of the impact of PCSK9 inhibition on non-calcified plaque in HIV as measured by serial coronary CT angiography. We will correlate these findings with changes in lipid parameters and markers of inflammation/immune activation assessed in Aim 1; in addition, we will determine whether changes in arterial FDG uptake are associated with changes in coronary plaques. This application combines (1) a successful multidisciplinary team with a strong record of collaboration and expertise in studying interventions in HIV, (2) the ability to rapidly recruit subjects from existing HIV-infected cohorts, (3) leveraging of resources including study drug/placebo provided by industry. Identifying novel therapies to reduce CV risk are essential to improve mortality among HIV-infected individuals, and results from this study will form the groundwork for a future trial to evaluate the impact of PCSK9 inhibition on clinical events in HIV.