DIET/EXERCISE, NIACIN, FENOFIBRATE FOR HIV LIPODYSTROPHY

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 假设 在患有HAART相关血脂异常的HIV患者中，通过饮食和运动强化生活方式干预可以： A.将脂类从致动脉粥样硬化转变为心脏保护； B.减少腹部内脏脂肪量； 改善与胰岛素抵抗相关的激素、代谢和脂蛋白标记物。 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、5)DE+烟酸+非诺贝特对空腹血浆甘油三酯浓度(主要终点)的影响。 (为了实现这一目标，我们将招募240名患有高甘油三酯血症的艾滋病毒患者，他们正在接受稳定的HAART方案。我们将随机将他们分配到5个安慰剂对照治疗方案(每组48个)，并在基线和干预6个月后测量空腹血浆甘油三酯浓度(主要血脂终点)以及空腹血浆高密度脂蛋白胆固醇、总胆固醇和低密度脂蛋白胆固醇浓度(次级血脂终点)。) 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技术在相同受试者和同一时间点测量局部脂肪分布(腹部内脏脂肪质量与皮下脂肪质量的比率)。) 3.比较五种治疗方案对胰岛素抵抗激素、脂蛋白及代谢标志物的影响。 (为了实现这一目标，我们将在相同的受试者中测量胰岛素、葡萄糖、瘦素、游离脂肪酸、低密度脂蛋白和高密度脂蛋白亚组分的浓度、低密度脂蛋白和高密度脂蛋白的组成以及胆固醇酯转移蛋白的活性的变化。) 背景和意义 高效抗逆转录病毒疗法(HAART)在很大一部分HIV感染患者中与血脂异常和胰岛素抵抗有关，在较小一部分患者中与拟人化变化(脂肪萎缩、中心性肥胖)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。许多小规模研究未能确定一种能明显逆转大多数患者的血脂异常和伴随的心血管风险的治疗方案。迫切需要对这种情况进行循证、合理、有效的治疗。 基于1)我们关于HIV脂营养不良的脂代谢改变的关键机制的最新数据(特别是脂解率升高、脂肪酸氧化不足和甘油三酯肝脏再酯化增加)；2)证据表明HIV患者的饮食和运动模式对于控制心血管危险因素是次优的；以及3)针对血脂异常和胰岛素抵抗的最新治疗建议，我们提议进行一项针对强化生活方式和两种降脂药(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、合理的艾滋病毒相关血脂异常和脂肪营养不良的治疗方法。

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.