Protease Inhibitor Related Dyslipidemia

描述（由申请人提供）：该文件是6年前资助的一个项目的更新，该项目响应RFA，旨在确定与hiv感染者心血管疾病相关的因素。我们最初的项目描述了CVD异常替代标志物（颈动脉内膜内侧厚度和冠状动脉钙评分）的预测指标，每隔3年进行一次。检查了抗逆转录病毒治疗方案、艾滋病毒疾病活动标志物、C-反应蛋白和脂质谱（包括常规脂质谱、富含甘油三酯的残余脂蛋白、Lp(a)、同型半胱氨酸、空腹血糖、游离脂肪酸和胰岛素水平）、BMI、人体测量体成分、BIA和DXA以及传统的危险因素（吸烟、饮食、血压、年龄、性别、家族史）。从我们最初的拨款和其他分析表明，传统的心血管危险因素是最常见的预测异常的替代标志物在这一患者群体；Pis或其他抗逆转录病毒药物引起的血脂异常的影响以及HIV及其相关炎症在这种风险增加中的作用尚不清楚。迄今为止，还没有HIV替代标志物研究对HIV感染患者进行了为期6年的随访，这可能是检测血脂异常或HIV对个体疾病进展影响的最佳方法。很明显，HIV感染本身诱导低HDL-胆固醇水平，我们有初步数据表明HIV感染个体具有致动脉粥样硬化的HDL亚群特征。与单独的HDL-C相比，hdl -亚群似乎对CVD风险有更大的预测价值。我们现在知道，在hiv感染人群中，与更严重的血脂异常相关的是选定的抗逆转录病毒药物，而不是药物类别，并建议检查这些药物（洛匹那韦/利托那韦、d4t、依非韦伦）以及传统和新出现的危险因素对HDL亚谱和CVD替代标志物的影响。慢性炎症标志物被认为是CVD的独立预测因子；它们还可以预测艾滋病毒感染的进展，并可能反映受感染个体的艾滋病毒疾病累积负担。我们建议扩大我们对慢性炎症的研究，将CRP亚型和sPLA2加入到CRP的测定中，以检查它们与动脉粥样硬化脂质谱和异常代物制造物的关系。我们建议在R01的延续中延长我们的替代标志物研究的持续时间，研究6年以上HIV感染人群中c-IMT和冠状动脉钙评分的进展，并记录HIV感染队列中HDL亚群和炎症标志物在新的资助期内的变化。在HIV感染队列中，纵向测定HDL亚群，同时测定6年的cIMT和冠状动脉钙评分对该项目来说是新颖的。

DESCRIPTION (provided by applicant): This submission is the renewal of a project that was funded 6 years ago in response to an RFA that sought to determine the factors associated with cardiovascular disease in HI V-infected individuals. Our original project described predictors of abnormal surrogate markers of CVD (carotid intimal medial thickness and coronary calcium score) done at a 3 year interval. Antiretroviral regimens, markers of HIV disease activity, C- reactive protein and lipid profiles (including conventional lipid profiles, triglyceride-rich remnant lipoproteins, Lp(a), homocysteine, fasting blood glucose, free fatty acids and insulin levels), BMI, body composition by anthropometery , BIA and DXA as well as traditional risk factors (smoking, diet, blood pressure, age, gender, family history) were examined. Analyses from our original grant as well as others have suggested that traditional cardiovascular risk factors are the most common predictors for abnormal surrogate markers in this patient population; the impact of the dyslipidemia induced by Pis or other antiretroviral agents and the role of HIV and its associated inflammation on this increased risk remain unclear. To date no HIV surrogate marker studies have followed HIV-infected patients for the 6 year period that may be optimal detect the impact of the dyslipidemia or HIV on progression of disease in individuals. It remains clear that HIV infection itself induces low HDL-cholesterol levels and we have preliminary data that suggest that HIV infected individuals have an atherogenic HDL subpopulation profile. It appears that HDL-subpopulations may have a greater predictive value for risk of CVD than HDL-C alone. We now know that it is selected antiretroviral agents, not classes of agents, that are associated with more severe dyslipidemia in HIV-infected populations and propose to examine the impact of these agents (lopinavir/ritonavir, d4t, efavirenz) as well as traditional and emerging risk factors on HDL subprofiles and on surrogate markers of CVD. Markers of chronic inflammation are considered to be independent predictors of CVD; they also predict progression in HIV-infection and may reflect the cumulative burden of HIV disease in an infected individual. We propose to expand our studies of chronic inflammation adding CRP isoforms and sPLA2 to the determination of CRP to examine the association of these with atherogenic lipid profiles and with abnormal surrogate makers in our cohort. We propose to extend the duration of our surrogate marker studies in this continuation of our R01, to study the progression of c-IMT and coronary calcium score in an HIV infected population over 6 years and to document the changes in HDL subpopulations and inflammatory markers over the new grant period in our HIV infected cohort. The longitudinal determination of HDL subpopulations, the simultaneous determination of both cIMT and coronary calcium scores at 6 years in an HIV infected cohort are novel to this project.