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: 6647230
• 负责人: NORAH A TERRAULT
• 金额: $ 35万
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6647230
• 关键词: African American; caucasian American; chronic disease /disorder; clinical research; clinical trials; 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(丙型肝炎病毒) 感染，占美国感染人口总数的22% 研究表明，患有慢性丙型肝炎病毒的非裔美国人的感染率较低 与非西班牙裔白人相比，对抗病毒治疗的反应。区别在于， 在一定程度上，这与非洲裔美国人中基因1的优势有关。 干扰素联合利巴韦林的有效率似乎高于 使用干扰素单一疗法。然而，迄今为止的研究包括非常多的 非裔美国人受试者人数较少(&lt；5%)，限制了对 应答率。在拟议的研究中，持续病毒学的比率 对聚乙二醇化干扰素和利巴韦林的应答(病毒清除)将是 相比之下，有200名非洲裔美国人和200名非西班牙裔白人。临床上， 预测持续病毒学的生化或病毒学因素 对抗病毒治疗的反应和肝脏炎症活动的减少 组织学将被确定，早期病毒动力学将被作为 响应或无响应的预测值。这项合作研究涉及八个人 临床中心还将提供临床数据和生物标本。 共同调查人员专注于确定病毒学，细胞学， 免疫和遗传因素是抗病毒反应的基础 丙型肝炎的治疗选择聚乙二醇化干扰素联合干扰素 抗病毒干预，因为联合治疗已被证明是 优于单一干扰素治疗，初步数据显示聚乙二醇化 干扰素优于标准干扰素。 此外，每周给药一次的便利性可能会提高依从性。 参与者将在进入研究之前和研究结束时接受肝脏活检。 随访(96周)。病毒学分析包括丙型肝炎病毒RNA定量 (定性和定量)和丙型肝炎病毒基因分型。基线评估包括 人口统计(使用种族/族裔自我报告)风险因素评估， 生化和血液学、生活质量和疲劳评估。跟进 访问将包括不良事件调查、遵从性评估、 血清和外周血单核细胞采集用于病毒学研究 分析，并在治疗完成48周后重复肝脏活检。全 研究访问，包括肝脏活检，将在普通临床进行 研究中心。主要治疗结果是96周时丙型肝炎病毒核糖核酸丢失。 (治疗后48周)。次要终点包括48岁的丙型肝炎病毒RNA丢失 肝酶正常化和组织学改善 96周时的炎症指数和耐受性(由？不良事件 询问和疲劳感问卷)。这项研究将准确定义 非洲裔美国人最佳抗病毒治疗的持续应答率 并提供了对潜在差异的因素的重要见解 与非西班牙裔白人相比，他们的反应。此外，制定的方法论 在这项合作研究的背景下，患者外展将起到作用 作为促进非裔美国人参与临床的典范 研究。