A small-animal model for hepatitis C virus (HCV) infection was developed using severe combined immunodeficiency (SCID) mice encoding homozygous urokinase-type plasminogen activator (uPA) transplanted with human hepatocytes. Currently, limited information is available concerning the HCV clearance rate in the SCID mouse model and the virion production rate in engrafted hepatocytes. In this study, several cohorts of uPA +/+ /SCID +/+ mice with nearly half of their livers repopulated by human hepatocytes were infected with HCV genotype 1b and used to evaluate HCV dynamics by pharmacokinetic and pharmacodynamic analyses of a specific NS3-4A protease inhibitor (telaprevir). A dose-dependent reduction in serum HCV RNA was observed. At telaprevir exposure equivalent to that in clinical studies, rapid turnover of serum HCV was also observed in this mouse model and the estimated slopes of virus decline were 0.11-0.17 log 10 h "1 . During the initial phase of treatment, the log 10 reduction level of HCV RNA was dependent on the drug concentration, which was about fourfold higher in the liver than in plasma. HCV RNA levels in the liver relative to human endogenous gene expression were correlated with serum HCV RNA levels at the end of treatment for up to 10 days. A mathematical model analysis of viral kinetics suggested that 1 g of the chimeric human liver could produce at least 10 8 virions per day, and this may be comparable to HCV production in the human liver.
INTRODUCTIONHepatitis C virus (HCV) is a major cause for concern worldwide. More than 3 % of the world's population is chronically infected with HCV and 3-4 million people are newly infected each year (Wasley & Alter, 2000). Chronic HCV infection is relatively mild and progresses slowly; however, about 20 % of chronic hepatitis C (CHC) carriers progress to serious end-stage liver disease (Lauer & Walker, 2001;Liang et al., 2000;Poynard et al., 2003). The current standard treatment for HCV infection is administration of pegylated alpha interferon (PEG-IFN) in combination with ribavirin (RBV) for 48 weeks. The overall cure rates with this intervention are 40-50 % for patients with genotype 1 and more than 75 % for patients with genotypes 2 and 3 (Fried et al., 2002;Manns et al., 2001). Several compounds that inhibit specific stages of the virus life cycle have been clinically evaluated (Manns et al., 2007;Pereira & Jacobson, 2009). Telaprevir is a novel peptidomimetic slow-and tight-binding inhibitor of HCV NS3-4A protease, which was discovered using a structure-based drug design approach (Perni et al., 2006). A rapid decline in viral RNA was observed in CHC patients treated with telaprevir (Reesink et al., 2006) and an increased antiviral effect of a combination of telaprevir and PEG-IFN has been reported (Forestier et al., 2007). Recent clinical trials of telaprevir in combination with PEG-IFN and RBV have indicated a promising material advance in therapy for CHC patients (HĂ©zode et al., 2009;McHutchison et al., 2009). Firstgeneration HCV-specific agents have been...