Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo
✍ Scribed by Nobuhiko Hiraga; Michio Imamura; Hiromi Abe; C. Nelson Hayes; Tomohiko Kono; Mayu Onishi; Masataka Tsuge; Shoichi Takahashi; Hidenori Ochi; Eiji Iwao; Naohiro Kamiya; Ichimaro Yamada; Chise Tateno; Katsutoshi Yoshizato; Hirotaka Matsui; Akinori Kanai; Toshiya Inaba; Shinji Tanaka; Kazuaki Chayama
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 407 KB
- Volume
- 54
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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) C hronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, liver failure, and hepatocellular carcinoma. 1,2 The current standard treatment for patients chronically infected with HCV is the combination of peg-interferon (PEG-IFN) and ribavirin (RBV). [3][4][5] However, this treatment results in sustained viral response (SVR), defined as negative for HCV RNA 24 weeks after cessation of the therapy, in only about 50% of patients with genotype 1 HCV infection with high viral loads. [3][4][5] Given the low Abbreviations: HCV, hepatitis C virus; HSA, human serum albumin; PEG-IFN, peg-interferon; RBV, ribavirin; RT-PCR, reverse transcript-polymerase chain reaction; SCID, severe combined immunodeficiency; SVR, sustained viral response; uPA, urokinase-type plasminogen activator.