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.

项目总结

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