Interactions Between Hepatitis C and Serum Lipid Homeostasis

丙型肝炎与血清脂质稳态之间的相互作用

• 批准号: 7849634
• 负责人: Kathleen Elizabeth Corey
• 金额: $ 2.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849634
• 关键词: Acute; Acute Hepatitis C; Affect; American; Antiviral Therapy; Caring; Chronic Disease; Chronic Hepatitis C; Clinical Trials; Coenzyme A; Communities; Community Health; Cross-Sectional Studies; Databases; End stage renal failure; General Hospitals; Genotype; Goals; Health; Hepatitis C; Hepatitis C virus; Homeostasis; In Vitro; Infection; Interferons; Investigation; Kinetics; Life Cycle Stages; Lipids; Liver Failure; Massachusetts; Medical; Methods; Mission; National Health and Nutrition Examination Survey; Oxidoreductase; Patients; Phase; Play; Population; Primary carcinoma of the liver cells; Research; Ribavirin; Role; Serum; Testing; United States; Viral; Virus Replication; anti-hepatitis C; cohort; fluvastatin; improved; in vivo; inhibitor/antagonist; innovation; lipid metabolism; liver transplantation; novel; response; therapeutic target

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.

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并改善社区健康。超过 400 万美国人感染丙型肝炎病毒 (HCV)，其中 75% 患有慢性疾病，严重影响我们社区的健康。慢性丙型肝炎 (CHC) 感染会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指征。不幸的是，聚乙二醇化干扰素 (PEGIFN) 和利巴韦林 (RBV) 的标准治疗仅对 50% 的基因 1 型患者（美国人丙型肝炎的主要形式）产生持续病毒学应答 (SVR)。一半患者无法治愈，促使人们对丙型肝炎病毒生命周期进行研究以寻找治疗靶点。初步研究结果表明，宿主脂质在 HCV 复制中发挥着重要作用，可能是治疗的目标。该提案的具体目的是阐明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。我们的长期目标是定义 HCV-脂质相互作用，开发预测 SVR 的新方法并开发新疗法。了解 HCV 生命周期并改善 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，即与未感染的对照相比，CHC 感染导致血清脂质水平降低。我们将利用国家健康和营养检查调查 (NHANES) 数据库以及 MGH 现有的 CHC 感染患者队列进行一项横断面研究，以检查 HCV 感染与血脂水平之间的关系。 2. 证明血脂水平可以预测急性和慢性丙型肝炎感染患者的 VR，并分析 HCV 治疗对血脂稳态的影响。使用现有的急性丙型肝炎队列，我们​​将评估感染期间血清脂质水平的变化。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 治疗患者队列，以确定血清脂质水平是否可以预测 SVR。 3. 证明与单独治疗相比，氟伐他汀联合 PEGIFN 单药治疗患有终末期肾病 (ESRD) 的 CHC 患者可提高 VR 率。氟伐他汀已被证明具有体外抗 HCV 活性，并与干扰素具有协同作用。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联合PEGIFN的临床试验。