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. ? ? ?
| Jin, Runyan; Fossler, Michael J; McHutchison, John G et al. (2012) Population pharmacokinetics and pharmacodynamics of ribavirin in patients with chronic hepatitis C genotype 1 infection. AAPS J 14:571-80 |
| Jin, Runyan; Cai, Ling; Tan, Ming et al. (2012) Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1. Am J Gastroenterol 107:1675-83 |
