Interactions Between Hepatitis C and Serum Lipid Homeostasis

描述（由申请人提供）：马萨诸塞州总医院（MGH）的使命是通过创新研究推进医疗保健，改善社区健康。超过400万美国人患有丙型肝炎病毒（HCV）感染，75%的人患有慢性疾病，严重影响了我们社区的健康。慢性丙型肝炎（CHC）感染导致失代偿性肝衰竭，肝细胞癌，是美国肝移植最常见的适应症。不幸的是，聚乙二醇干扰素（PEGIFN）和利巴韦林（RBV）的标准治疗仅在50%的基因型1患者中导致持续病毒学应答（SVR），基因型1是美国丙型肝炎的主要形式。无法治愈一半的患者促使研究HCV生命周期的治疗目标。初步研究结果表明，宿主脂质在HCV复制中起着重要作用，并可能成为治疗的靶点。该建议的具体目的是阐明HCV感染与宿主血脂之间的关系，并评估降脂治疗是否可以提高病毒学应答（VR）率。我们的长期目标是确定HCV-脂质相互作用，开发预测SVR的新方法并开发新的治疗方法。了解HCV的生命周期和改善CHC治疗将实现我们的机构使命。具体目标：1。证明我们的假设，CHC感染导致较低的血脂水平相比，未感染的控制。我们将进行一项横断面研究，使用国家健康和营养检查调查（NHANES）数据库以及先前存在的MGH CHC感染患者队列来检查HCV感染与血脂水平之间的关系。2.证明血脂水平是急性和慢性丙型肝炎感染患者VR的预测指标，并分析HCV治疗对血脂稳态的影响。利用现有的急性HCV队列，我们将评估感染期间血脂水平的变化。此外，我们假设低血脂水平与SVR率增加相关。我们将回顾性和前瞻性地评估两个单独的CHC患者队列，以确定血脂水平是否预测SVR。3.证明与单药治疗相比，氟伐他汀联合PEGIFN单药治疗终末期肾病（ESRD）CHC患者将改善VR率。氟伐他汀已被证明具有体外抗HCV活性，并与干扰素协同作用。为了测试氟伐他汀的体内抗HCV作用，我们将在ESRD患者中进行氟伐他汀与PEGIFN的临床试验。

DESCRIPTION (provided by applicant): The mission of the Massachusetts General Hospital (MGH) is to advance medical care through innovative research and improve the health of the community. More than 4 millions Americans have hepatitis C virus (HCV) infection and 75% develop chronic disease, significantly impacting the health of our community. Chronic hepatitis C (CHC) infection leads to decompensated liver failure, hepatocellular carcinoma and is the most common indication for liver transplantation in the United States. Unfortunately, standard therapy with pegylated interferon (PEGIFN) and ribavirin (RBV) leads to a sustained virologic response (SVR) in only 50% of genotype 1 patients, the predominant form of hepatitis C in Americans. The inability to cure half of patients has prompted investigation of the HCV life cycle for therapeutic targets. Preliminary findings reveal that host lipids play an important role in HCV replication and may be a target for therapy. The specific aims of this proposal are to elucidate the relationship between HCV infection and host serum lipids and evaluate whether lipid lowering therapy can improve virologic response (VR) rates. Our long-term goal is to define HCV-lipid interactions, develop novel methods for predicting SVR and develop new therapies. Understanding the HCV lifecycle and improving CHC treatment will fulfill our institutional mission. Specific Aims: 1. Demonstrate our hypothesis that CHC infection results in lower serum lipid levels compared to uninfected controls. We will perform a cross sectional study to examine the relationship between HCV infection and serum lipid levels using both the National Health and Nutrition Examination Survey (NHANES) database as well as a pre-existing MGH cohort of patients with CHC infection. 2. Demonstrate that lipid levels are predictive of VR in patients with both acute and chronic hepatitis C infection and to analyze the impact of HCV treatment on lipid homeostasis. Using an existing acute HCV cohort we will evaluate how serum lipid levels change during infection. In addition, we hypothesize that low serum lipid levels correlate with increased rates of SVR. We will retrospectively and prospectively evaluate two separate cohorts of patients treated for CHC to determine whether serum lipid levels predict SVR. 3. Demonstrate that the use of fluvastatin in combination with PEGIFN monotherapy in CHC patients with end stage renal disease (ESRD) will improve VR rate when compared to monotherapy alone. Fluvastatin has been shown to have in vitro anti-HCV activity and act synergistically with interferon. To test fluvastatin's in vivo anti-HCV action, we will perform a clinical trial of fluvastatin with PEGIFN in ESRD patients.