DIET/EXERCISE, NIACIN, FENOFIBRATE FOR HIV LIPODYSTROPHY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 假设 在HAART相关血脂异常的HIV患者中，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; 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（主要终点）的影响。 (To为了实现这一目标，我们将招募240名正在接受稳定HAART方案治疗的HIV高血糖患者。我们将他们随机分配到五个安慰剂对照治疗方案（每组48人），并在基线和干预6个月后测量甘油三酯的空腹血浆浓度（主要脂质终点）以及HDL胆固醇，总胆固醇和LDL胆固醇的空腹血浆浓度（次要脂质终点）。 2.比较5种治疗方案对体脂分布的影响。 (To为了达到这一目的，我们将在相同的受试者中，在相同的时间点，使用计算机断层扫描测量局部脂肪分布（腹部内脏脂肪量与皮下脂肪量的比率）。 3.比较5种治疗方案对胰岛素抵抗的激素、脂蛋白和代谢标志物的影响。 (To为了达到这一目的，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、LDL和HDL亚组分的血浆浓度、LDL和HDL组成以及胆固醇酯转移蛋白活性的变化。 背景和意义 高活性抗逆转录病毒治疗（HAART）与大部分HIV感染患者的血脂异常和胰岛素抵抗相关，并与较小子集的拟人化变化（脂肪萎缩，向心性肥胖）相关。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变化的机制-统称为“HIV-脂肪代谢障碍”-尚不清楚。 许多小型研究未能描绘出一个可以明显逆转大多数患者血脂异常和伴随的心血管风险的治疗过程。因此，迫切需要循证、合理、有效的治疗方法。 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（具体地，脂解速率升高、脂肪酸氧化不足和甘油三酯的肝再酯化增加）; 2）证据表明，HIV患者的饮食和运动模式对于管理心血管风险因素而言是次优的;和3）血脂异常和胰岛素抵抗的最新治疗建议，我们提出了一个随机，安慰剂对照试验的强化生活方式的改变和两种降脂药（烟酸和非诺贝特）。 长期目标是开发有效、安全、合理的HIV相关血脂异常和脂肪代谢障碍的治疗方法。

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.