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

PCSK9 抑制对 HIV 感染治疗者心血管风险的影响（EPIC-HIV 研究）

• 批准号: 10337208
• 负责人: Priscilla Y. Hsue
• 金额: $ 72.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337208
• 关键词: Acute; Angiography; Aorta; Apolipoprotein A-I; Apolipoproteins B; Atherosclerosis; Blood Component Removal; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Cholesterol; Chronic; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Core Facility; Development; Endothelium; Event; FDA approved; Familial Hypercholesterolemia; Future; General Hospitals; General Population; HIV; HIV Infections; Heart; Heart Rate; Heart failure; Hepatitis C virus; High Density Lipoproteins; Image; Immunologic Markers; Impact evaluation; Impairment; Individual; Industry; Inflammation; Inflammatory; Infrastructure; Interleukin-6; Intervention; Intervention Studies; LDL Cholesterol Lipoproteins; Lipids; Lipoprotein (a); Low-Density Lipoproteins; Measures; Mediating; Monoclonal Antibodies; Morbidity - disease rate; Morphology; Myocardial Infarction; PET/CT scan; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Placebos; Population; Proprotein Convertases; Randomized; Recording of previous events; Reporting; Resistance; Resources; Risk; Risk Factors; Stroke; Subtilisins; T-Cell Activation; Triglycerides; Vasodilation; antibody inhibitor; brachial artery; cardiovascular disorder risk; cardiovascular risk factor; cohort; coronary computed tomography angiography; coronary plaque; cytokine; double-blind placebo controlled trial; experience; fluorodeoxyglucose positron emission tomography; high risk; imaging facilities; immune activation; improved; indexing; inflammatory marker; inhibitor; mortality; multidisciplinary; novel therapeutics; recruit; side effect; sudden cardiac death; ultrasound; uptake

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.

项目摘要 HIV感染者发生心肌梗死的风险高2倍，沿着发生心力衰竭的几率也更高 和心脏性猝死虽然对这种过度风险的机制仍然知之甚少， 我们的研究小组和其他人的研究表明，艾滋病背景下的动脉粥样硬化是独特的， 其特征在于通过FDG-PET/CT评估的动脉炎症加剧和异常内皮 通过肱动脉的血流介导的血管舒张（FMD）评估功能。这些血管评估 均通过使用他汀类药物或LDL单采术降低LDL-C得到改善。前蛋白转化酶枯草 9（PCSK 9）已成为一个重要的药理学目标，降低胆固醇的一般 人群和难治人群。用单克隆抗体抑制PCSK 9导致 LDL-胆固醇降低约50-70%，总体耐受性良好，无显著副作用。当 在他汀类药物治疗的基础上添加PCSK 9抑制剂，可将LDL降低至中位数30 mg/dL， 在对27，000例ASCVD患者的研究中，将主要心血管事件减少15%。两种药剂 （Evolocumab，Alibaba）是FDA批准的。使用PCSK 9抑制显著降低LDL的影响 艾滋病相关的动脉粥样硬化仍然未知。我们建议单中心，双盲，安慰剂- 一项对照试验，旨在评估在有效治疗的HIV背景下PCSK 9抑制对CV风险的影响- 已知患有CVD的感染个体或基线时有CVD动脉炎症风险的感染个体。我们建议 目的1：确定PCSK 9抑制是否可以改善评估的动脉炎症 通过FDG-PET/CT在治疗和抑制HIV感染个体中的应用。目的2：评估PCSK 9的作用 在治疗和抑制的HIV中通过FMD评估的对内皮功能的抑制。我们将相互关联 脂质参数变化，包括总胆固醇（TC）、HDL-C、甘油三酯、非HDL-C、载脂蛋白B 载脂蛋白B（ApoB）、载脂蛋白A-I（ApoA-I）、免疫活化和炎症标志物[Lp（a）、LpPLA 2、sCD 14 和T细胞活化]用动脉炎症（Aim 1）和内皮功能（Aim 2）评估。目标3： 进行一项初步评价，评价PCSK 9抑制对HIV中非钙化斑块的影响， 连续冠状动脉CT血管造影。我们将把这些发现与血脂参数和标志物的变化联系起来 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相关。本申请结合了（1）a 成功的多学科团队，在研究干预措施方面具有良好的合作记录和专业知识， HIV，（2）从现有HIV感染队列中快速招募受试者的能力，（3）利用资源 包括行业提供的研究药物/安慰剂。确定降低CV风险的新疗法至关重要 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，以评估PCSK 9抑制对HIV临床事件的影响。

项目成果

Association of Socioeconomic Status and Infarct Volume With Functional Outcome in Patients With Ischemic Stroke.

• DOI: 10.1001/jamanetworkopen.2022.9178
• 发表时间: 2022-04-01
• 期刊: JAMA NETWORK OPEN
• 影响因子: 13.8
• 作者: Ghoneem, Ahmed;Osborne, Michael T.;Abohashem, Shady;Naddaf, Nicki;Patrich, Tomas;Dar, Tawseef;Abdelbaky, Amr;Al-Quthami, Adeeb;Wasfy, Jason H.;Armstrong, Katrina A.;Ay, Hakan;Tawakol, Ahmed
• 通讯作者: Tawakol, Ahmed

Multimodality molecular imaging: Gaining insights into the mechanisms linking chronic stress to cardiovascular disease.

• DOI: 10.1007/s12350-020-02424-6
• 发表时间: 2021-06
• 期刊: Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology
• 作者: Osborne MT;Abohashem S;Zureigat H;Abbasi TA;Tawakol A
• 通讯作者: Tawakol A