Cholesterol and inflammation Lowering via BEmpedoic Acid, an ACL-inhibiting Regimen in HIV Trial (CLEAR HIV Trial)

HIV 试验中通过 BEmpedoic Acid（一种 ACL 抑制方案）降低胆固醇和炎症（CLEAR HIV 试验）

• 批准号: 10677867
• 负责人: Priscilla Y. Hsue
• 金额: $ 65.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677867
• 关键词: ATP Citrate (pro-S)-Lyase; Accounting; Acids; Adipose tissue; Anti-Inflammatory Agents; Anti-Retroviral Agents; Apolipoproteins B; Atherosclerosis; B-Lymphocytes; Biological Markers; Biology; Blood Component Removal; Cardiovascular Diseases; Carotid Artery Plaques; Cessation of life; Cholesterol; Chronic; Clinical; Coagulation Process; Collaborations; Core Facility; Coronary artery; Data; Diabetes Mellitus; Disease; Enrollment; Event; Evolution; FDA approved; Familial Hypercholesterolemia; Fibrin fragment D; Future; General Hospitals; General Population; Glycosylated hemoglobin A; HIV; HIV Infections; Hematopoietic; Heterozygote; High Density Lipoproteins; Immune response; Individual; Infiltration; Inflammation; Inflammatory; Interleukin-6; Intervention; Intervention Studies; Lipid-Laden Macrophage; Lipids; Low-Density Lipoproteins; Macrophage; Massachusetts; Measures; Multicenter Trials; Myocardial Infarction; Obesity; Outcome; Outcome Study; PET/CT scan; Participant; Patients; Persons; Pharmaceutical Preparations; Placebos; Population; Positron-Emission Tomography; Prediabetes syndrome; Process; Regimen; Reporting; Resources; Risk; Risk Factors; Safety; T-Lymphocyte; Therapeutic; Tissues; Translating; Triglycerides; Universities; Utah; aged; antiretroviral therapy; atorvastatin; burden of illness; cardiometabolism; cardiovascular disorder risk; cohort; coronary computed tomography angiography; coronary plaque; disability-adjusted life years; fluorodeoxyglucose positron emission tomography; follow-up; hematopoietic tissue; high risk; imaging facilities; immune activation; improved; indexing; inflammatory marker; inhibitor; monocyte; mortality; multidisciplinary; novel therapeutics; protective effect; randomized placebo controlled study; recruit; systemic inflammatory response

Project Summary Persons living with HIV infection (PLWH) have a 2-fold higher risk of myocardial infarction and are twice as likely to develop cardiovascular disease accounting for a significant global burden of disease. While the mechanism underlying this excess risk remains poorly understood, studies demonstrate that atherosclerosis in the setting of HIV is distinct and characterized by heightened arterial inflammation as assessed by FDG- PET/CT. HIV and antiretroviral medication can worsen cardiometabolic parameters. Thus a therapeutic strategy that can lower lipids, inflammation, and improve glycemic parameters may be even more advantageous in HIV. Bempedoic acid (BA, an inhibitor of ATP citrate lyase), is safely tolerated, significantly lowers LDL-C and inflammatory markers (on top of statin therapy), and is FDA approved for individuals with heterozygous familial hypercholesterolemia or with established ASCVD who require additional LDL-C lowering. Additionally, BA has a protective effect on glycemic parameters and may reduce adiposity. Given the key role of lipids and inflammation in atherosclerosis in HIV, the purpose of this proof-of-concept mechanistic trial is to evaluate the impact of BA on the biology of HIV-associated atherosclerosis. We will perform a randomized placebo controlled study of effectively treated PLWH aged 40 years and older with either known CVD or 1 CVD risk factor to study the effect of BA on arterial inflammation (assessed by FDG-PET/CT), lipid levels, biomarkers of inflammatory/immune activation, cardiometabolic indices, and non-calcified plaque in the coronary arteries (assessed by CCTA). This multicenter trial will include PLWH enrolled at UCSF, UCLA, and Univ. of Utah. Long term collaborators at MGH will serve as the core facility for the imaging end-points. We have 3 specific aims for the: Cholesterol and inflammation Lowering via BEmpedoic Acid, an ACL-inhibiting Regimen in HIV Trial (CLEAR HIV Trial): Aim 1: To determine whether BA can safely reduce arterial inflammation including carotid plaque as assessed by FDG-PET/CT; Aim 2: To determine whether BA improves cardiometabolic measures (lipid, inflammatory, glycemic and adipose parameters) among PLWH. Exploratory objectives will be to assess BA’s effect (vs. placebo) on glycemic as well as adipose tissue measures (HbA1c, HOMA IR, and adipose tissue volumes); Aim 3: To evaluate the impact of BA on non- calcified coronary plaque volume as measured by coronary CT angiography (CCTA) and to determine whether changes in arterial inflammation are correlated with reduction 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. Identifying novel therapies to reduce CV risk are essential to improve mortality among PLWH, and results from this study will form the groundwork for a future trial to evaluate the impact of additional reduction of LDL-C and inflammation using BA on clinical events in HIV.

项目概要 HIV 感染者 (PLWH) 发生心肌梗死的风险是普通人群的 2 倍，也是普通人群的两倍 可能发展为全球重大疾病负担的心血管疾病。虽然 这种过度风险背后的机制仍然知之甚少，研究表明，动脉粥样硬化 HIV 的情况是独特的，其特征是根据 FDG- 评估，动脉炎症加剧 PET/CT。 HIV 和抗逆转录病毒药物会使心脏代谢参数恶化。因此具有治疗作用 能够降低血脂、炎症和改善血糖参数的策略可能更加重要 对艾滋病毒有利。 Bempedoic Acid（BA，ATP 柠檬酸裂解酶的抑制剂）具有安全耐受性，显着 降低 LDL-C 和炎症标志物（在他汀类药物治疗的基础上），并经 FDA 批准用于患有以下疾病的个体 杂合子家族性高胆固醇血症或患有 ASCVD 且需要额外降低 LDL-C 的患者。 此外，BA 对血糖参数有保护作用，并可能减少肥胖。鉴于关键作用 HIV 动脉粥样硬化中的脂质和炎症的影响，这项概念验证机制试验的目的是 评估 BA 对 HIV 相关动脉粥样硬化生物学的影响。我们将进行随机 对 40 岁及以上患有已知 CVD 或 1 CVD 的 PLWH 进行有效治疗的安慰剂对照研究 研究 BA 对动脉炎症（通过 FDG-PET/CT 评估）、血脂水平、 炎症/免疫激活、心脏代谢指数和非钙化斑块的生物标志物 冠状动脉（由 CCTA 评估）。这项多中心试验将包括在加州大学旧金山分校 (UCSF)、加州大学洛杉矶分校 (UCLA) 和 大学。犹他州。 MGH 的长期合作者将作为成像端点的核心设施。我们 有 3 个具体目标： 通过 BEmpedoic Acid（一种 ACL 抑制剂）降低胆固醇和炎症 HIV 试验方案（CLEAR HIV 试验）： 目标 1：确定 BA 是否可以安全地减少动脉血流量 通过 FDG-PET/CT 评估炎症，包括颈动脉斑块；目标 2：确定 BA 是否 改善 PLWH 的心脏代谢指标（血脂、炎症、血糖和脂肪参数）。 探索性目标将是评估 BA（与安慰剂相比）对血糖和脂肪组织的影响 测量（HbA1c、HOMA IR 和脂肪组织体积）；目标 3：评估 BA 对非 通过冠状动脉 CT 血管造影 (CCTA) 测量钙化的冠状动脉斑块体积，并确定是否 动脉炎症的变化与冠状动脉斑块的减少相关。该应用程序结合了 (1) 一支成功的多学科团队，具有良好的合作记录和学习专业知识 HIV 干预措施，(2) 从现有 HIV 感染人群中快速招募受试者的能力，(3) 利用 包括研究药物/安慰剂在内的资源。确定降低心血管风险的新疗法对于 提高 PLWH 的死亡率，这项研究的结果将为未来的试验奠定基础 评估使用 BA 进一步降低 LDL-C 和炎症对 HIV 临床事件的影响。