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: 10560409
• 负责人: Priscilla Y. Hsue
• 金额: $ 69.81万
• 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/10560409
• 关键词: ATP Citrate (pro-S)-Lyase; Accounting; Acids; Adipose tissue; Anti-Inflammatory Agents; Apolipoproteins B; Atherosclerosis; B-Lymphocytes; Biological Markers; Biology; Blood Component Removal; Cardiovascular Diseases; Carotid Artery Plaques; Cessation of life; Characteristics; 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; HIV antiretroviral; HIV therapy; Hematopoietic; High Density Lipoproteins; Immune response; Individual; Infiltration; Inflammation; Inflammatory; Interleukin-6; Intervention; Intervention Studies; Lipid-Laden Macrophage; Lipids; Low-Density Lipoproteins; Massachusetts; Measures; Multicenter Trials; Myocardial Infarction; Obesity; Outcome; Outcome Study; PET/CT scan; Participant; Patients; Persons; Pharmaceutical Preparations; Placebos; 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; macrophage; 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.

项目摘要 患有艾滋病毒感染（PLWH）的人的心肌梗塞风险高2倍，是两倍 可能发展心血管疾病，以造成全球疾病的重大负担。而 该超出风险的基础机制仍然尚不清楚，研究表明，动脉粥样硬化 艾滋病毒的介绍是不同的，并以fdg-评估的伪像增强为特征。 宠物/CT。艾滋病毒和抗逆转录病毒药物可以更恶化的心脏代谢参数。那是一种治疗性 可以降低脂质，注射和改善血糖参数的策略可能会更多 be甲酸（BA，ATP柠檬酸裂解酶的抑制剂）是安全耐受的，明显的 降低LDL-C和炎症标记（在他汀类药物疗法之上），并获得FDA批准 杂合家族高胆固醇血症或与既有LDL-C降低的既定ASCVD”。 此外，BA对血糖参数具有保护作用，并可能降低肥胖。鉴于关键角色 艾滋病毒动脉粥样硬化中脂质和炎症的炎症，概念验证机械试验的目的是 评估BA对HIV相关动脉粥样硬化的生物学的影响。我们将执行一个随机的 安慰剂对照研究的有效治疗的PLWH具有已知CVD或1 CVD的40岁及以上的PLWH 研究BA对动脉炎症的影响（通过FDG-PET/CT评估），脂质水平， 炎症/免疫激活，心脏代谢指数和非鉴定斑块的生物标志物 冠状动脉（由CCTA评估）。该多中心试验将包括在UCSF，UCLA和 大学。犹他州。 MGH的长期合作者将作为成像终点的核心设施。我们 具有3个特定目标：胆固醇和炎症通过bem甲酸降低，一种抑制ACL 艾滋病毒试验中的方案（清除艾滋病毒试验）：目标1：确定BA是否可以安全减少动脉 FDG-PET/CT评估的炎症，包括颈动脉斑块；目标2：确定是否 PLWH中改善心脏代谢测量（脂质，炎症，血糖和脂肪参数）。 探索性目标将是评估BA的作用（与安慰剂）对血糖和脂肪组织的影响 措施（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）测量的钙化冠状斑块体积，并确定是否是否 动脉炎症的变化与冠状动脉斑块的减少相关。此应用程序结合在一起 （1）一个成功的多学科团队 艾滋病毒的干预措施，（2）能够从现有的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。识别新的疗法以降低简历风险对于 提高PLWH的死亡率，这项研究的结果将为以后的试验构成基础 评估使用BA额外减少LDL-C和炎症对HIV中临床事件的影响。