Ribavirin Pharmacokinetics, Race and HCV Treatment

描述（由申请人提供）：在美国，慢性丙型肝炎病毒（HCV）是导致肝硬化的最常见原因，也是原发性肝细胞癌（HCC）的主要危险因素。在缺乏高效治疗的情况下，预计到2030年，与HCV相关的失代偿性肝硬化和原发性HCC患者数量将增加200%，死亡人数将增加300%。非裔美国人（AA）的HCV患病率是白人美国人（CA）的2倍，其预后较差。具有讽刺意味的是，HCV基因型1的AA感染在聚乙二醇化干扰素α (PEGIFNa)联合利巴韦林治疗后，HCV清除率明显降低。需要对AA患者的HCV基因型1感染进行更有效的治疗，以减少AA和CA患者HCV之间未来的健康差异。当与干扰素联合使用时，利巴韦林降低治疗后HCV复发率，导致持续病毒学率比单独使用干扰素高2-3倍。最近的一些研究使我们推测，利巴韦林在AA和CA HCV基因型1患者中的药代动力学存在差异，这一差异导致PEGIFN和利巴韦林治疗AA的疗效较低：1)PEGIFN联合治疗患者治疗期间利巴韦林剂量和利巴韦林血清浓度与病毒学反应率之间存在显著相关性；2)最近的HCV RNA动力学数学模型表明，在干扰素治疗效果较差的患者中，利巴韦林治疗对HCV清除更重要，例如感染HCV基因型1的AA；3) Brennan等人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率增加，血清利巴韦林水平降低。该项目的长期目标是缩小AA和CA在HCV治疗疗效上的差异。该项目有两个具体目标：1)在Virahep-C研究中，确定PEGIFN α -2a和利巴韦林治疗期间AA和CA HCV基因型1患者的利巴韦林血浆水平与病毒学反应和贫血之间的关系；2)检测利巴韦林在基因1型HCV感染AA和CA的药代动力学。PEGIFN和利巴韦林或类似利巴韦林的药物很可能仍然是未来丙型肝炎病毒治疗的组成部分，包括丙型肝炎病毒聚合酶和蛋白酶抑制剂。本研究结果将阐明利巴韦林药代动力学在PEGIFN和利巴韦林治疗中的重要性，有助于优化利巴韦林剂量，最终提高HCV基因1型治疗AA和CA患者的疗效。这项拟议的研究旨在提高非洲裔美国人感染基因型1型慢性丙型肝炎（HCV）目前治疗的疗效，这种病毒对治疗的抵抗力最强。需要更有效的治疗方法来减少非裔美国人和白种人在与HCV肝病相关的疾病和死亡方面的差异。

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.