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)患心肌梗死的风险是前者的2倍，后者是前者的2倍 有可能发展为心血管疾病，占全球疾病负担的很大一部分。而当 这种额外风险背后的机制仍然知之甚少，研究表明动脉粥样硬化在 根据FDG的评估，HIV的环境是独特的，其特征是动脉炎症加剧。 PET/CT。艾滋病毒和抗逆转录病毒药物会恶化心脏代谢参数。因此，这是一种治疗 可以降低血脂、炎症和改善血糖参数的策略可能更多 在艾滋病方面有优势。苯培多酸(BA，一种ATP柠檬酸裂解酶的抑制剂)是安全耐受的，显著 降低低密度脂蛋白和炎症标志物(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已确诊的ASCVD，需要额外降低低密度脂蛋白胆固醇。 此外，BA对血糖参数有保护作用，可能会降低肥胖。考虑到关键角色 人类免疫缺陷病毒的动脉粥样硬化中的脂质和炎症，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。我们将进行一次随机的 有效治疗40岁及以上已知CVD或1例CVD的PLWH的安慰剂对照研究 研究BA对动脉炎症(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洛杉矶分校登记的PLWH和 大学。犹他州。MGH的长期合作伙伴将作为成像终端的核心设施。我们 有三个特定的目标：通过抑制ACL的苯丙酮酸降低胆固醇和炎症 HIV试验中的方案(Clear HIV试验)：目标1：确定BA是否可以安全地降低动脉 FDG-PET/CT评估包括颈动脉斑块在内的炎症；目标2：确定BA 改善PLWH患者的心脏代谢指标(脂质、炎症、血糖和脂肪参数)。 探索性目标将是评估BA对血糖和脂肪组织的影响(与安慰剂相比 测量(HbA1c、HOMA IR和脂肪组织体积)；目标3：评估BA对非 冠状动脉CT血管成像(CCTA)测量钙化斑块体积并确定 动脉炎症的变化与冠状动脉斑块的减少有关。此应用程序结合了 (1)成功的多学科团队，具有较强的协作能力和研究专长 艾滋病毒干预措施，(2)从现有艾滋病毒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。寻找新的治疗方法来降低心血管疾病风险是至关重要的 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进一步降低低密度脂蛋白和炎症对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.