Telaprevir is a potent inhibitor of hepatitis C virus (HCV) NS3-4A protease. However, the emergence of drug-resistant strains during therapy is a serious problem, and the susceptibility of resistant strains to interferon (IFN), as well as the details of the emergence of mutant strains in vivo, is not known. We previously established an infectious model of HCV using human hepatocyte chimeric mice. Using this system we investigated the biological properties and mode of emergence of mutants by ultra-deep sequencing technology. Chimeric mice were injected with serum samples obtained from a patient who had developed viral breakthrough during telaprevir monotherapy with strong selection for resistance mutations (A156F [92.6%]). Mice infected with the resistant strain (A156F [99.9%]) developed only low-level viremia and the virus was successfully eliminated with interferon therapy. As observed in patients, telaprevir monotherapy in viremic mice resulted in breakthrough, with selection for mutations that confer resistance to telaprevir (e.g., a high frequency of V36A [52.2%]). Mice were injected intrahepatically with HCV genotype 1b clone KT-9 with or without an introduced resistance mutation, A156S, in the NS3 region, and treated with telaprevir. Mice infected with the A156S strain developed lower-level viremia compared to the wildtype strain but showed strong resistance to telaprevir treatment. Although mice injected with wildtype HCV showed a rapid decline in viremia at the beginning of therapy, a high frequency (11%) of telaprevir-resistant NS3 V36A variants emerged 2 weeks after the start of treatment. Conclusion: Using deep sequencing technology and a genetically engineered HCV infection system, we showed that the rapid emergence of telaprevir-resistant HCV was induced by mutation from the wildtype strain of HCV in vivo. (HEPATOLOGY 2011;54:781-788)
Anemia was manageable by carefully adjusting the ribavirin dosage in the standard therapy that followed telaprevir monotherapy. This sequential regimen seems to be safer and more tolerable than the triple combination of telaprevir, peginterferon alpha, and ribavirin, especially among elderly females with low baseline hemoglobin.
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 (Hézode et al., 2009;McHutchison et al., 2009). Firstgeneration HCV-specific agents have been...
SUMMARY. Background: Telaprevir in combination with peginterferon and ribavirin is a promising advancement in chronic hepatitis C treatment. However, the safety, tolerability, pharmacokinetics and antiviral profiles of telaprevir alone beyond 2 weeks have not been studied. Methods: In a phase 1b study in Japan, 10 treatment-naïve patients infected with hepatitis C virus genotype 1b with high viral load (>5 log 10 IU/mL) received telaprevir 750 mg every 8 h (q8h) for 12 weeks. We examined the safety, tolerability, pharmacokinetics, hepatitis C virus (HCV) RNA levels and resistant variants of telaprevir. Results: Neither serious adverse events nor discontinuations of study drug owing to an adverse event occurred. The most common adverse drug reactions were rash (80%) and anaemia (70%). Telaprevir concentration reached its steady state within 2 days after the first administration without abnormal accumulation. Telaprevir alone provided potent antiviral activity: a median log 10 decrease of 2.325 at 16 h and 5.175 on Day 14. During the treatment, HCV RNA levels at the nadir were below the limit of the quantification in seven patients and undetectable in three of 10 patients. Viral breakthrough associated with mainly Ala 156 -substituted variants occurred in eight patients, and only one patient showed endof-treatment response. The selected variants reverted to the wild-type during the 24-week follow-up period. Conclusion: Telaprevir alone was well tolerated at 750 mg q8h for up to 12 weeks. The safety profile and emergence of resistant variants of genotype 1b under telaprevir monotherapy for 12 weeks will become increasingly important in evaluating an oral combination of telaprevir with other direct-acting antiviral agents.
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