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

项目摘要 艾滋病毒感染者（PLWH）患心肌梗死的风险高2倍， 心血管疾病是全球疾病负担的一个重要组成部分。而 这种过度风险的潜在机制仍然知之甚少，研究表明， HIV的情况是不同的，其特征是通过FDG评估的动脉炎症加剧， PET/CT。艾滋病毒和抗逆转录病毒药物可使心脏代谢参数恶化。因此， 可以降低血脂、炎症和改善血糖参数的策略可能会更多 对艾滋病有利。Bempedoic acid（BA，一种ATP柠檬酸裂解酶抑制剂）是安全耐受的， 降低LDL-C和炎症标志物（在他汀类药物治疗的基础上），FDA批准用于患有 杂合子家族性高胆固醇血症或确诊ASCVD，需要额外降低LDL-C。 此外，BA对血糖参数具有保护作用，并可能减少肥胖。鉴于其关键作用 脂质和炎症在HIV动脉粥样硬化中的作用，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 在年龄≥ 40岁且经有效治疗的患有已知CVD或1例CVD的PLWH患者中开展的安慰剂对照研究 研究BA对动脉炎症（通过FDG-PET/CT评估），脂质水平， 炎症/免疫激活的生物标志物、心脏代谢指数和非钙化斑块， 冠状动脉（通过CCTA评估）。这项多中心试验将包括在加州大学旧金山分校，加州大学洛杉矶分校， Univ.来自犹他州。MGH的长期合作者将作为成像终点的核心设施。我们 有3个具体的目标：胆固醇和炎症降低通过BEMPEDOIC酸，一种ACL抑制 HIV试验中的方案（CLEAR HIV试验）：目的1：确定BA是否可以安全地减少动脉 通过FDG-PET/CT评估包括颈动脉斑块在内的炎症;目的2：确定BA是否 改善PLWH中的心脏代谢指标（脂质、炎症、血糖和脂肪参数）。 探索性目的是评估BA（与安慰剂相比）对血糖和脂肪组织的影响 指标（HbA 1c、HOMA IR和脂肪组织体积）;目的3：评价BA对非胰岛素抵抗的影响。 通过冠状动脉CT血管造影术（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)一个成功的多学科团队，在研究方面具有良好的合作记录和专业知识 （2）从现有HIV感染队列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CV风险的新疗法至关重要， 改善PLWH的死亡率，这项研究的结果将为未来的试验奠定基础， 评价使用BA额外降低LDL-C和炎症对HIV临床事件的影响。

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.