Predicting Outcomes of Peginterferon & HCV

预测聚乙二醇干扰素的结果

• 批准号: 6895259
• 负责人: CHARLES D HOWELL
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895259
• 关键词: African American; biopsy; caucasian American; chronic disease /disorder; combination chemotherapy; computer program /software; gene expression; gene expression profiling; genetic markers; genetic regulation; health disparity; hepatitis C virus; host organism interaction; human tissue; immune response; interferon alpha; liver; microarray technology; racial /ethnic difference; ribavirin; virus diseases; virus infection mechanism

DESCRIPTION (provided by applicant): HCV is 2 times more prevalent in African Americans than in Caucasian Americans. In addition, African Americans appear to have worse outcomes from chronic HCV with both a higher incidence of primary HCC and higher death rate from cirrhosis 3, 4. Paradoxically, African Americans exhibit significantly lower rates of HCV clearance following treatment with pegylated interferon alpha plus ribavirin combination therapy relative to Caucasian Americans. The lower efficacy of lFN treatment in African-Americans is due, partly, to a higher prevalence of infection with HCV genotype 1. However, the efficacy of peginterferon plus ribavirin was lower in African Americans in a recent clinical trial limited to HCV genotype 1 patients. These results point to an important role for non-viral host factors. The basis for the racial disparities treatment efficacy has not been defined. There is compelling evidence that the host immune responses to HCV is crucial to the clearance of HCV infection during treatment. Thus, we hypothesize that differential expression of host immune genes in the livers based on race determines the racial disparity in HCV treatment outcomes. If so, we predict that measuring the antiviral, immune, and inflammatory gene expression profiles in liver biopsies might be able to predict the efficacy of antiviral therapy for chronic HCV in genotype 1. To test this hypothesis, the current project will utilize cDNA gene expression microarray technology to pursue the following 2 aims: 1) Define the alterations in host intrahepatic gene expression in vivo related to chronic HCV genotype 1 infection in previously untreated patients; 2) Determine the capacity of differentially expressed HCV-related gene in the liver biopsies taken from previously untreated patients to predict the efficacy of initial therapy with peginterferon plus ribavirin in African American and Caucasian HCV genotype 1 patients (NIDDK VIRAHEP-C cohort). These studies will provide new insights into the biological basis for the racial disparity in HCV treatment outcomes, and facilitate development of more effective treatments for HCV genotype 1.

描述（由申请人提供）：丙型肝炎病毒在非裔美国人中的流行率是白种人美国人的 2 倍。此外，非裔美国人的慢性 HCV 结局似乎更差，原发性 HCC 的发病率较高，肝硬化死亡率也较高 3, 4。矛盾的是，非裔美国人在接受聚乙二醇干扰素 α 加利巴韦林治疗后，HCV 清除率明显较低相对于白种美国人的联合疗法。 IFN 治疗在非裔美国人中疗效较低的部分原因是基因 1 型 HCV 感染率较高。然而，在最近一项仅限于基因 1 型 HCV 患者的临床试验中，聚乙二醇干扰素加利巴韦林在非裔美国人中的疗效较低。这些结果表明非病毒宿主因素的重要作用。种族差异治疗效果的基础尚未确定。有令人信服的证据表明，宿主对 HCV 的免疫反应对于治疗期间 HCV 感染的清除至关重要。因此，我们假设肝脏中基于种族的宿主免疫基因的差异表达决定了丙型肝炎治疗结果的种族差异。如果是这样，我们预测测量肝活检中的抗病毒、免疫和炎症基因表达谱可能能够预测基因型 1 慢性 HCV 抗病毒治疗的疗效。为了检验这一假设，当前项目将利用 cDNA 基因表达微阵列技术旨在实现以下 2 个目标： 1) 定义与先前未接受治疗的患者中与慢性 HCV 基因型 1 感染相关的体内宿主肝内基因表达的变化； 2) 确定取自先前未经治疗的患者的肝活检中差异表达的 HCV 相关基因的能力，以预测非裔美国人和白种人 HCV 基因型 1 患者（NIDDK VIRAHEP-C 队列）中聚乙二醇干扰素加利巴韦林初始治疗的疗效。这些研究将为HCV治疗结果种族差异的生物学基础提供新的见解，并促进针对基因1型HCV开发更有效的治疗方法。