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）是肝硬化的最常见原因，也是原发性肝细胞癌（HCC）的主要风险因素。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%。HCV在非裔美国人（AA）中的流行率是白人美国人（CA）的2倍，并且与更差的结局相关。具有讽刺意味的是，在聚乙二醇干扰素α（PEGIFNa）与利巴韦林联合治疗后，HCV基因型1感染的AA表现出显著较低的HCV清除率。需要对AA中的HCV基因型1感染进行更有效的治疗，以减少AA和CA与HCV之间未来的健康差异。当与IFN病毒唑联合使用时，治疗后HCV复发率降低，与单独使用IFN相比，持续病毒学率高2-3倍。最近的几项研究使我们假设利巴韦林的药代动力学在AA和CA HCV基因型1患者中是不同的，并且这种差异有助于PEGIFN和利巴韦林在AA中的较低疗效：1）在治疗期间利巴韦林剂量和利巴韦林血清浓度与接受PEGIFN联合治疗的患者的病毒学应答率之间存在显著相关性; 2）最近的数学模型HCV RNA动力学表明，在IFN治疗效果较差的患者中，利巴韦林治疗对HCV清除更为重要，例如感染HCV基因型1的AA患者; 3）Brennan等人的初步研究发现，与CA HCV患者相比，AA患者中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减少AA和CA之间HCV治疗疗效的差异。该项目有2个具体目的：1）在Virahep-C研究中，确定PEGIFN α-2a和利巴韦林治疗期间，利巴韦林血浆水平与AA和CA HCV基因型1患者的病毒学应答和贫血之间的关系; 2）确定利巴韦林在感染HCV基因型1的AA和CA患者中的药代动力学。在所有的可能性，聚乙二醇干扰素和利巴韦林或利巴韦林样药物将仍然是未来的HCV治疗，包括HCV聚合酶和蛋白酶抑制剂的组成部分。本研究的结果将阐明利巴韦林的药物动力学在PEGIFN和利巴韦林治疗的重要性，有助于优化利巴韦林剂量，并最终提高丙型肝炎病毒基因型1治疗AA以及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，在非洲裔美国人感染的基因型1的病毒，最耐治疗。更有效的治疗是必要的，以减少非洲裔美国人和高加索美国人之间的疾病和死亡与HCV肝病的差异。

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.