Interactions Between Hepatitis C and Serum Lipid Homeostasis

描述(申请人提供)：马萨诸塞州综合医院(MGH)的使命是通过创新的研究促进医疗保健，并改善社区的健康。超过400万美国人感染丙型肝炎病毒(丙型肝炎病毒)，75%患有慢性病，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功能衰竭、肝细胞癌，是美国肝移植最常见的适应症。不幸的是，标准的聚乙二醇化干扰素(PEGIFN)和利巴韦林(RBV)治疗只在50%的1型患者中产生了持续的病毒学应答(SVR)，而1型肝炎是美国人的主要丙型肝炎。无法治愈一半的患者促使人们研究丙型肝炎病毒的生命周期，以寻找治疗目标。初步研究结果显示，宿主脂质在丙型肝炎病毒复制中起重要作用，并可能成为治疗的靶点。这项建议的具体目的是阐明丙型肝炎病毒感染与宿主血脂的关系，并评估降脂治疗是否可以提高病毒学应答率(VR)。我们的长期目标是定义丙型肝炎病毒与脂质的相互作用，开发预测SVR的新方法，并开发新的治疗方法。了解丙型肝炎病毒的生命周期和改进CHC治疗将完成我们的机构使命。具体目的：1.证明我们的假设：与未感染的对照组相比，CHC感染会导致较低的血脂水平。我们将利用国家健康和营养检查调查(NHANES)数据库以及先前存在的丙型肝炎患者MGH队列，进行一项横断面研究，以检查丙型肝炎病毒感染和血脂水平之间的关系。2.证明血脂水平可预测急性和慢性丙型肝炎患者的VR，并分析丙型肝炎病毒治疗对脂质平衡的影响。利用现有的急性丙型肝炎病毒队列，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发生率增加相关。我们将对两组不同的CHC患者进行回顾性和前瞻性的评估，以确定血脂水平是否能预测SVR。3.在CHC合并终末期肾病(ESRD)患者中，联合应用氟伐他汀和聚乙二醇单用干扰素可提高VR率。氟伐他汀已被证明在体外具有抗丙型肝炎病毒的活性，并与干扰素具有协同作用。为了测试氟伐他汀在体内的抗丙型肝炎作用，我们将在终末期肾病患者中进行氟伐他汀和聚乙二醇干扰素的临床试验。

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.