Protease Inhibitor Related Dyslipidemia

描述(由申请人提供)：本意见书是对6年前资助的一个项目的更新，该项目是对试图确定与HI V感染者心血管疾病相关因素的RFA的回应。我们最初的项目描述了CVD(颈动脉内膜中层厚度和冠状动脉钙化积分)的异常替代标记物的预测因素，每隔3年进行一次。观察抗逆转录病毒治疗方案、HIV疾病活动性标志物、C反应蛋白和血脂谱(包括常规脂谱、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以及传统危险因素(吸烟、饮食、血压、年龄、性别、家族史)。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该患者群体中异常替代标志物最常见的预测因素；由Pis或其他抗逆转录病毒药物引起的血脂异常的影响以及艾滋病毒及其相关炎症对这种增加的风险的作用尚不清楚。到目前为止，还没有关于艾滋病毒替代标记物的研究跟踪艾滋病毒感染者6年的时间，这可能是检测血脂异常或艾滋病毒对个体疾病进展的影响的最佳方法。很明显，艾滋病毒感染本身会导致低高密度脂蛋白水平，我们有初步数据表明，艾滋病毒感染者具有致动脉粥样硬化的高密度脂蛋白亚群。似乎高密度脂蛋白亚群对心血管疾病风险的预测价值可能比高密度脂蛋白单独存在时更大。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，而不是一类药物，并建议研究这些药物(洛匹那韦/利托那韦，d4T，efavirenz)以及传统和新出现的危险因素对高密度脂蛋白亚型和心血管疾病替代标记物的影响。慢性炎症标志物被认为是心血管疾病的独立预测因子；它们还预测艾滋病毒感染的进展，并可能反映受感染个人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添加到CRP的测定中，以检查这些与我们队列中的动脉粥样硬化脂质谱和异常替代标记物的相关性。我们建议在R01中延长替代标记物研究的持续时间，研究HIV感染人群中c-IMT和冠状动脉钙化积分的进展超过6年，并记录我们HIV感染队列中高密度脂蛋白亚群和炎症标记物在新的授权期内的变化。在HIV感染的队列中，对高密度脂蛋白亚群的纵向测定、6年后CIMT和冠状动脉钙化积分的同时测定对该项目来说是新的。

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.