Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo.

Abstract

UNLABELLED:

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.

• Authors: 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
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 54 Issue 3 Pg. 781-8 (Sep 02 2011) ISSN: 1527-3350 [Electronic] United States
• PMID: 21626527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Association for the Study of Liver Diseases.

Chemical References

• Antiviral Agents
• NS3 protein, hepatitis C virus
• Oligopeptides
• Viral Nonstructural Proteins
• telaprevir

Topics

• Animals
• Antiviral Agents (pharmacology)
• Chimerism
• Drug Resistance, Viral
• Female
• Genotype
• Hepacivirus (drug effects, genetics)
• Humans
• Mice
• Mice, SCID
• Middle Aged
• Mutation
• Oligopeptides (pharmacology)
• Viral Nonstructural Proteins (chemistry, genetics)