DIET/EXERCISE, NIACIN, FENOFIBRATE FOR HIV LIPODYSTROPHY

饮食/运动、烟酸、非诺贝特治疗 HIV 脂肪代谢障碍

• 批准号: 8356764
• 负责人: ASHOK BALASUBRAMANYAM
• 金额: $ 0.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356764
• 关键词: Abdomen; Adipose tissue; Behavior Therapy; Body fat; Central obesity; Cholesterol; Cholesterol Esters; Clinical Research; Data; Dyslipidemias; Fasting; Fatty acid glycerol esters; Fenofibrate; Funding; Glucose; Grant; HIV; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Highly Active Antiretroviral Therapy; Hormonal; Hypertriglyceridemia; Insulin; Insulin Resistance; Intervention; Kinetics; LDL Cholesterol Lipoproteins; Leptin; Lipids; Lipoatrophy; Lipodystrophy; Lipolysis; Lipoproteins; Low-Density Lipoproteins; Measures; Metabolic; Metabolic Marker; National Center for Research Resources; Nicotinic Acids; Nonesterified Fatty Acids; Patients; Pattern; Placebo Control; Plasma; Principal Investigator; Proteins; Recommendation; Recruitment Activity; Regimen; Research; Research Infrastructure; Resources; Source; Time; Treatment Protocols; Triglycerides; United States National Institutes of Health; Visceral; X-Ray Computed Tomography; base; cardiovascular disorder risk; cardiovascular risk factor; cost; diet and exercise; effective therapy; evidence base; fatty acid oxidation; improved; lifestyle intervention; randomized placebo controlled trial; subcutaneous; treatment as usual

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT HYPOTHESIS In HIV patients with HAART-associated dyslipidemia , an intensive lifestyle intervention with diet and exercise can: A. Convert the lipid profile from atherogenic to cardioprotective; B. Decrease abdominal visceral fat mass; C. Improve hormonal, metabolic and lipoprotein markers associated with insulin resistance. SPECIFIC AIMS 1. To compare the effects of 1) usual care, 2) intensive diet and exercise intervention (DE), 3) DE + niacin, 4) DE + fenofibrate, and 5) DE + niacin + fenofibrate on fasting plasma triglyceride concentrations (Primary endpoint). (To achieve this Aim, we will recruit 240 HIV patients with hypertriglyceridemia who are on stable HAART regimens. We will assign them randomly to the five placebo-controlled treatment protocols (48 per group) and measure fasting plasma concentrations of triglycerides (primary lipid endpoint) as well as fasting plasma concentrations of HDL cholesterol, total cholesterol and LDL cholesterol (secondary lipid endpoints) at baseline and after 6 months of intervention.) 2. To compare the effects of the five treatment protocols on body fat distribution. (To achieve this Aim, we will measure, in the same subjects and at the same time points, regional fat distribution (ratio of abdominal visceral adipose mass to subcutaneous adipose mass) using computerized tomography.) 3. To compare the effects of the five treatment protocols on hormonal, lipoprotein and metabolic markers of insulin resistance. (To achieve this Aim, we will measure, in the same subjects, changes in the plasma concentrations of insulin, glucose, leptin, free fatty acids, and LDL and HDL subfractions, in the compositions of LDL and HDL, and in the activity of cholesteryl ester transfer protein.) BACKGROUND AND SIGNIFICANCE Highly active anti-retroviral therapy (HAART) is associated with dyslipidemia and insulin resistance in a large proportion of HIV-infected patients, and with anthropomorphic changes (lipoatrophy, central obesity) in a smaller subset. The dyslipidemia and insulin resistance place these patients at increased risk for cardiovascular disease. The mechanisms leading to the dyslipidemia, insulin resistance and anthropomorphic changes - collectively termed "HIV-lipodystrophy" - have been unclear. Numerous small studies have failed to delineate a course of therapy that can clearly reverse the dyslipidemia and attendant cardiovascular risk in the majority of patients. There is an urgent need for evidence-based, rational, effective therapy of this condition. Based on 1) our recent data on key mechanisms of altered lipid kinetics in HIV-lipodystrophy (specifically, elevated rates of lipolysis, inadequate fatty acid oxidation, and increased hepatic reesterification of triglycerides); 2) evidence that diet and exercise patterns of HIV patients are suboptimal to manage cardiovascular risk factors; and 3) the latest treatment recommendations for dyslipidemia and insulin resistance, we propose a randomized, placebo-controlled trial of intensive lifestyle modification and two lipid-lowering agents (niacin and fenofibrate). The long-term objective is to develop effective, safe, rational treatment of HIV-associated dyslipidemia and lipodystrophy.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 抽象的 假设 对于患有 HAART 相关血脂异常的 HIV 患者，通过饮食和运动进行强化生活方式干预可以： A. 将脂质谱从致动脉粥样硬化转变为心脏保护作用； B.减少腹部内脏脂肪量； C. 改善与胰岛素抵抗相关的激素、代谢和脂蛋白标志物。 具体目标 1. 比较 1) 常规护理、2) 强化饮食和运动干预 (DE)、3) DE + 烟酸、4) DE + 非诺贝特和 5) DE + 烟酸 + 非诺贝特对空腹血浆甘油三酯浓度的影响（主要终点）。 （为了实现这一目标，我们将招募 240 名接受稳定 HAART 治疗方案的高甘油三酯血症 HIV 患者。我们将他们随机分配到 5 种安慰剂对照治疗方案（每组 48 名），并测量空腹血浆甘油三酯浓度（主要血脂终点）以及空腹血浆 HDL 胆固醇、总胆固醇和 LDL 胆固醇浓度（次要指标）。 血脂终点）在基线和干预 6 个月后。） 2. 比较五种治疗方案对体脂分布的影响。 （为了实现这一目标，我们将使用计算机断层扫描在同一受试者和同一时间点测量区域脂肪分布（腹部内脏脂肪量与皮下脂肪量的比率）。） 3. 比较五种治疗方案对激素、脂蛋白和胰岛素抵抗代谢标志物的影响。 （为了实现这一目标，我们将在同一受试者中测量胰岛素、葡萄糖、瘦素、游离脂肪酸、LDL和HDL亚组分的血浆浓度、LDL和HDL的组成以及胆固醇酯转移蛋白的活性的变化。） 一、背景及意义 高效抗逆转录病毒治疗 (HAART) 与大部分 HIV 感染患者的血脂异常和胰岛素抵抗有关，并与一小部分患者的拟人化变化（脂肪萎缩、向心性肥胖）有关。血脂异常和胰岛素抵抗使这些患者患心血管疾病的风险增加。导致血脂异常、胰岛素抵抗和拟人化改变（统称为“HIV-脂肪营养不良”）的机制尚不清楚。 许多小型研究未能确定一个疗程可以明显逆转大多数患者的血脂异常和随之而来的心血管风险。迫切需要对这种情况进行循证、合理、有效的治疗。 基于 1) 我们最近关于 HIV 脂肪营养不良中脂质动力学改变的关键机制的数据（特别是脂肪分解速率升高、脂肪酸氧化不足和甘油三酯肝脏再酯化增加）； 2) 有证据表明，HIV 患者的饮食和运动模式对于管理心血管危险因素而言并非最佳选择； 3）针对血脂异常和胰岛素抵抗的最新治疗建议，我们提出了一项强化生活方式改变和两种降脂药（烟酸和非诺贝特）的随机、安慰剂对照试验。 长期目标是开发有效、安全、合理的治疗方法来治疗艾滋病毒相关的血脂异常和脂肪营养不良。