Ribavirin Pharmacokinetics, Race and HCV Treatment

利巴韦林药代动力学、种族和 HCV 治疗

• 批准号: 7440199
• 负责人: CHARLES D HOWELL
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7440199
• 关键词: Address; African American; Aftercare; American; Anemia; Area; Cessation of life; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical Research; Clinical Trials; Combined Modality Therapy; Dose; Drug Kinetics; Etiology; Exhibits; Future; Genotype; Hepatitis C virus; Hospital Mortality; Incidence; Infection; Interferon-alpha; Interferons; Kinetics; Lead; Liver Cirrhosis; Liver diseases; Maryland; Measures; Morbidity - disease rate; Numbers; Outcome; Patients; Pegylated Interferon Alfa; Pharmaceutical Preparations; Pilot Projects; Plasma; Polymerase; Population; Prevalence; Primary carcinoma of the liver cells; Probability; Prospective Studies; Protease Inhibitor; RNA Polymerase Inhibitor; Race; Rate; Relapse; Relative (related person); Relative Risks; Resistance; Ribavirin; Risk Factors; Serum; Testing; Time; Toxic effect; Treatment Efficacy; United States; Universities; Viral; Virus; Week; base; caucasian American; day; health disparity; hepatitis C virus NS3 protein; improved; mathematical model; mortality; novel; response; treatment duration; trend; viral RNA

DESCRIPTION (provided by applicant): Chronic hepatitis C virus (HCV) is the most common cause for liver cirrhosis and a major risk factor for primary hepatocellular carcinoma (HCC) in the United States. In the absence of highly effective treatment, the number of patients with decompensated liver cirrhosis and primary HCC related to HCV is projected to increase by 200% and the number of deaths by 300% by the year 2030. HCV is 2 times more prevalent and is associated with worse outcome in African Americans (AA) than in Caucasian Americans (CA). Ironically, AA infected with HCV genotype 1 exhibit significantly lower rates of HCV clearance following treatment pegylated interferon alfa (PEGIFNa) in combination with ribavirin. More effective treatments for HCV genotype 1 infections in AA are needed to reduce the future health disparity between AA and CA with HCV. When combined with IFN ribavirin decreases HCV relapse rate following treatment resulting in a 2-3 higher sustained virological rate by compared to IFN alone. Several recent studies lead us to hypothesize that ribavirin pharmacokinetics is different in AA and CA HCV genotype 1 patients and that this difference contributes to the lower efficacy of PEGIFN and ribavirin in AA: 1) there is a significant correlation between both the ribavirin dose and ribavirin serum concentration during treatment and virologic response rates in patients receiving PEGIFN combination therapy; 2) a recent mathematical model HCV RNA kinetics suggests ribavirin treatment is more important to HCV clearance in patients in whom IFN therapy is less effective such as AA infected with HCV genotype 1; 3) a pilot study by Brennan et al. found increased ribavirin clearance and lower ribavirin serum levels in AA compared to CA HCV patients. The long-term objective of this project is to reduce the disparity in the efficacy of treatment for HCV between AA and CA. The project has 2 specific aims: 1) to determine the relationship between ribavirin plasma levels and virologic response and anemia in AA and CA HCV genotype 1 patients during PEGIFN alfa-2a and ribavirin treatment in the Virahep-C study; and 2) to determine ribavirin pharmacokinetics in AA and CA infected with HCV genotype 1. In all probability, PEGIFN and ribavirin or a ribavirin-like drug will remain a component of future HCV treatments that include HCV polymerase and protease inhibitors. The results of this study will clarify the importance of ribavirin pharmacokinetics during PEGIFN and ribavirin treatment, help to optimize ribavirin dose, and ultimately improve the efficacy of HCV genotype 1 treatment in AA as well as in CA patients. This proposed study seeks to improve the efficacy of current therapy for chronic hepatitis C (HCV) in African Americans infected with genotype 1 of the virus, the most resistant to treatment. More effective treatments are necessary to reduce the disparities between African Americans and Caucasian Americans in sickness and deaths related to HCV liver disease.

描述(申请人提供)：慢性丙型肝炎病毒(丙型肝炎病毒)是最常见的原因，肝硬变和一个主要的危险因素，原发性肝细胞癌(肝癌)在美国。在缺乏高效治疗的情况下，到2030年，与丙型肝炎相关的失代偿性肝硬变和原发性肝癌患者的数量预计将增加200%，死亡人数将增加300%。在非裔美国人(AA)中，丙型肝炎病毒的流行率是白人(CA)的2倍，并且与更糟糕的结局有关。具有讽刺意味的是，感染丙型肝炎病毒1型的再生障碍性贫血在聚乙二醇化干扰素α(PEGIFNa)与利巴韦林联合治疗后，丙型肝炎病毒转阴率显著降低。需要对再生障碍性贫血中的丙型肝炎病毒1型感染进行更有效的治疗，以减少未来再生障碍性贫血和尖锐湿疣合并丙型肝炎之间的健康差距。当与干扰素联合使用时，利巴韦林可降低治疗后丙型肝炎病毒的复发率，导致持续病毒率比单独使用干扰素高2-3倍。最近的几项研究导致我们假设，利巴韦林在AA和CA丙型肝炎病毒1型患者中的药代动力学不同，这种差异导致佩格干扰素和利巴韦林治疗再生障碍性贫血的疗效较低：1)利巴韦林剂量和治疗期间利巴韦林血清浓度与接受佩格干扰素联合治疗的患者的病毒学缓解率显著相关；2)最近的一项数学模型丙型肝炎病毒RNA动力学表明，对于干扰素治疗效果较差的患者，如再生障碍性贫血感染丙型肝炎病毒1型，利巴韦林治疗对于丙型肝炎病毒的清除更为重要；3)Brennan等人进行的一项初步研究。发现与CA-HCV患者相比，AA患者的利巴韦林清除量增加，血清利巴韦林水平降低。该项目的长期目标是减少AA和CA之间治疗丙型肝炎的疗效差异。该项目有两个具体目标：1)在Virahep-C研究中，确定丙型肝炎病毒1型患者在佩格干扰素α-2a和利巴韦林治疗期间的血浆利巴韦林水平与病毒学反应和贫血的关系；以及2)确定感染1型丙型肝炎病毒的再生障碍性肝炎和尖锐湿疣患者的利巴韦林药代动力学。本研究的结果将阐明利巴韦林在聚乙二醇干扰素和利巴韦林治疗过程中药代动力学的重要性，有助于优化利巴韦林的剂量，并最终提高丙型肝炎病毒1型治疗AA和CA患者的疗效。这项拟议的研究旨在提高目前治疗慢性丙型肝炎(HCV)的疗效，这些患者感染了对治疗最具抵抗力的1型病毒的非裔美国人。有必要进行更有效的治疗，以减少非裔美国人和高加索美国人在与丙型肝炎相关的疾病和死亡方面的差异。