Resistance to Antiviral Therapy in Chronic Hepatitis C

慢性丙型肝炎抗病毒治疗的耐药性

• 批准号: 6407021
• 负责人: NORAH A TERRAULT
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6407021
• 关键词: African American; caucasian American; chronic disease /disorder; combination chemotherapy; cooperative study; drug resistance; genetic susceptibility; hepatitis C; human subject; human therapy evaluation; immunotherapy; interferon alpha; liver disorder chemotherapy; patient oriented research; prognosis; racial /ethnic difference; ribavirin; virus genetics; virus load

DESCRIPTION (provided by applicant): An estimated 600,000 African-Americans have chronic hepatitis C virus (HCV) infection, representing 22% of the total infected population in the U.S. Prior studies suggest African-Americans with chronic HCV infection have a lower rate of response to anti-viral therapy than non-Hispanic whites. The difference is, in part, related to the predominance of genotype 1 among African-Americans. Response rates appear to higher with combination interferon plus ribavirin than with interferon monotherapy. However, the studies to date have included very low numbers of African-American subjects (<5%), limiting the interpretation of response rates. In the proposed study, the rate of sustained virological response (viral clearance) to pegylated interferon plus ribavirin will be compared in 200 African Americans and 200 non-Hispanic whites. The clinical, biochemical, or virological factors which predict sustained virological response to anti-viral therapy and reduced inflammatory activity on liver histology will be determined and early viral kinetics will be examined as a predictor of response or non-response. This collaborative study involving eight clinical centers will also provide the clinical data and biological specimens to coinvestigators focused on determining the virological, cellular, immunological and genetic factors that underlie the response to antiviral therapy in hepatitis C. Pegylated interferon plus interferon is chosen as the anti-viral intervention because combination therapy has been shown to be superior to interferon monotherapy and preliminary data indicate pegylated interferons are superior to standard interferons. Additionally, the convenience of once weekly dosing may improve compliance. Participants will undergo liver biopsy prior to study entry and at end of follow-up (96 wks). Virological analyses include HCV RNA quantitation (qualitative and quantitative) and HCV genotyping. Baseline assessments include demographic (using self-reporting of race/ethnicity) risk factor assessment, biochemistry and hematology, quality-of-life and fatigue assessments. Follow-up visits will include adverse events inquiry, assessment of compliance, collection of serum and peripheral blood mononuclear cells for virological analyses, and repeat liver biopys 48 weeks after completion of treatment. All study visits, including liver biopsies, will occur in the General Clinical Research Center. The primary treatment outcome is loss of HCV RNA at 96 weeks (48 weeks post-treatment). Secondary endpoints include loss of HCV RNA at 48 weeks; normalization of liver enzymes and improvement in histological inflammatory indices at 96 weeks; and tolerability (assessed by? adverse event inquiry and fatigue questionnaires). This study will accurately define the sustained response rates with optimal anti-viral therapy in African-Americans and provide important insights into the factors underlying differences in response compared to non-Hispanic whites. Moreover, the methodologies developed for patient outreach within the context of this collaborative study will serve as a model for enhancing participation of African Americans in clinical research.

描述（由申请人提供）： 估计有60万非洲裔美国人患有慢性丙型肝炎病毒（HCV） 感染，占美国总感染人口的22%。 研究表明，患有慢性HCV感染的非洲裔美国人 对抗病毒治疗的反应比非西班牙裔白人。区别在于， 在某种程度上，与基因型1在非裔美国人中的优势有关。 干扰素联合利巴韦林的应答率似乎高于 干扰素单一疗法然而，迄今为止的研究包括非常 非裔美国人受试者数量较少（<5%），限制了对 答复率。在拟议的研究中，持续的病毒学感染率 对聚乙二醇化干扰素加利巴韦林的应答（病毒清除）将是 在200名非裔美国人和200名非西班牙裔白人中进行了比较。临床上， 生物化学或病毒学因素，预测持续的病毒学 对抗病毒治疗的反应和降低肝脏炎症活性 组织学将被确定，并且早期病毒动力学将被检查为 反应或无反应的预测因子。这项合作研究涉及8个 临床中心还将提供临床数据和生物样本 致力于确定病毒学，细胞学， 免疫学和遗传学因素是抗病毒药物应答的基础 丙型肝炎的治疗选择聚乙二醇干扰素加干扰素作为 抗病毒干预，因为联合治疗已被证明是 上级于干扰素单药治疗，初步数据表明聚乙二醇 干扰素上级标准干扰素。 此外，每周一次给药的便利性可改善依从性。 受试者将在研究入组前和研究结束时接受肝活检。 随访（96周）。病毒学分析包括HCV RNA定量 （定性和定量）和HCV基因分型。基线评估包括 人口统计学（使用自我报告的人种/种族）风险因素评估， 生物化学和血液学、生活质量和疲劳评估。后续行动 访视将包括不良事件询问、依从性评估， 收集血清和外周血单核细胞用于病毒学 分析，并在治疗完成后48周重复肝活检。所有 研究访视，包括肝活检，将在一般临床 研究中心主要治疗结果是96周时HCV RNA的丢失 (48治疗后7周）。次要终点包括48岁时HCV RNA的丢失 周;肝酶正常化和组织学改善 炎症指数在96周;和耐受性（评估？不良事件 调查和疲劳问卷）。这项研究将准确地定义 非洲裔美国人接受最佳抗病毒治疗的持续应答率 并提供了重要的见解的因素的差异， 与非西班牙裔白人相比。此外，所开发的方法 在这项合作研究的背景下， 作为提高非裔美国人参与临床 research.