Predicting Outcomes of Peginterferon & HCV

描述(申请人提供)：丙型肝炎病毒在非裔美国人中的流行率是白人的两倍。此外，非洲裔美国人患慢性丙型肝炎的预后似乎更差，有较高的原发性肝癌发病率和较高的肝硬变3，4期病死率。矛盾的是，与高加索裔美国人相比，非裔美国人在接受聚乙二醇化干扰素和利巴韦林联合治疗后，丙型肝炎病毒转阴率显著降低。在非洲裔美国人中，LFN治疗的疗效较低，部分原因是丙型肝炎病毒1型感染的发病率较高。然而，在最近一项仅限于丙型肝炎病毒1型患者的临床试验中，聚乙二醇干扰素联合利巴韦林对非裔美国人的疗效较低。这些结果指出了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，宿主对丙型肝炎病毒的免疫反应对于清除治疗过程中的丙型肝炎病毒感染至关重要。因此，我们假设，基于种族的宿主免疫基因在肝脏中的差异表达决定了丙型肝炎病毒治疗结果的种族差异。如果是这样的话，我们预测测量肝活检组织中抗病毒、免疫和炎症基因的表达谱可能能够预测抗病毒治疗1型慢性丙型肝炎的疗效。为了验证这一假说，本项目将利用cDNA基因表达微阵列技术追求以下两个目标：1)确定与既往未治疗患者慢性丙型肝炎病毒感染相关的宿主肝内基因表达的变化；2)确定从既往未治疗患者肝活检组织中差异表达的丙型肝炎病毒相关基因的能力，以预测非裔美国人和高加索人丙型肝炎病毒1型患者聚乙二醇干扰素加利巴韦林初始治疗的疗效(NIDDK VIRAHEP-C同源)。这些研究将为丙型肝炎病毒治疗结果种族差异的生物学基础提供新的见解，并促进开发更有效的丙型肝炎病毒1型治疗方法。

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.