Tracking the emergence of escape mutants during triple therapy for hepatitis C virus infection

• Project/Area Number: 24790702
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hiroshima University
• Principal Investigator: HAYES C.Nelson 広島大学, 医歯薬保健学研究院(医), 特任講師 (50572327)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ウィルス / ゲノム / 遺伝子 / 医療 / 免疫学

Research Abstract

150 million people worldwide have chronic hepatitis C virus infection. With new direct-acting antiviral (DAA) agents, the cure rate has increased to >70%. However, some patients develop resistance to DAA drugs. These experiments were conducted to determine when and how resistance mutations emerge, to identify the properties of common mutants alone and in combination, to examine the effect of resistance mutations on viral fitness, and to investigate the effectiveness of DAA drugs in different genotypes in monotherapy versus combination therapy. Analysis of viral mutations was performed by direct sequencing as well as ultra-deep sequencing. Results of this study suggest that resistance can emerge even under DAA combination therapy, but the presence of resistance mutations prior to therapy does not necessarily lead to treatment failure. These studies demonstrate that analysis of resistance variants is necessary but not sufficient to predict the outcome of DAA therapy.

Research Products

• [Journal Article] Interferon lambda 4 polymorphism effects on outcome of telaprevir, pegylated interferon and ribavirin combination therapy for chronic hepatitis C (2014)
  • Author(s): Nagaoki Y, Imamura M, Kawakami Y, Kan H, Fujino H, Fukuhara T, Kobayashi T, Ono A, Nakahara T, Naeshiro N, Urabe A, Yokoyama S, Miyaki D, Murakami E, Kawaoka T, Tsuge M, Hiramatsu A, Aikata H, Takahashi S, Hayes CN, Ochi H, Chayama K
  • Journal Title: Hepatology Research Volume: (印刷中) Issue: 14
  • DOI: 10.1111/hepr.12336
  • Peer Reviewed / Open Access
• [Journal Article] interferon lambda 4/interleukin-28B haplotype structure and its impact on susceptibility to hepatitis C virus and treatment response in the Japanese population (2014)
  • Author(s): Ochi H, Miki D, Hayes CN, Abe H, Hayashida Y, Kubo M, Chayama K
  • Journal Title: Journal of General Virology Volume: 95巻 Issue: 6 Pages: 1297-306
  • DOI: 10.1099/vir.0.060103-0
  • Peer Reviewed
• [Journal Article] Ultradeep sequencing study of chronic hepatitis C virus genotype 1 infection in patients treated with daclatasvir, peginterferon, and ribavirin (2014)
  • Author(s): Murakami, E. Imamura, M. Hayes, C. N. Abe, H. Hiraga, N. Honda, Y. Ono, A. Kosaka, K. Kawaoka, T. Tsuge, M. Aikata, H. Takahashi, S. Miki, D. Ochi, H. Matsui, H. Kanai, A. Inaba, T. McPhee, F. Chayama, K.
  • Journal Title: Antimicrob Agents Chemother Volume: 58 Issue: 4 Pages: 2105-2112
  • DOI: 10.1128/aac.02068-13
  • Peer Reviewed / Open Access
• [Journal Article] Emergence of resistant variants detected by ultra-deep sequencing after asuna- previr and daclatasvir combination therapy in HCV genotype 1 infected patients. (2014)
  • Author(s): Kosaka K,Imamura M, Hayes CN, Abe H, Hiraga N, Yoshimi S, Murakami M, Kawaoka T, Tsuge M, Aikata H, Miki D, Ochi H, Matsui H, Kanai A, Inaba T, Chayama K
  • Journal Title: Journal of Viral Hepatitis Volume: 印刷中
  • Peer Reviewed
• [Journal Article] A translational study of resistance emergence using sequential direct-acting antiviral agents for hepatitis C using ultra-deep sequencing (2013)
  • Author(s): Abe H, Hayes CN, Hiraga N, Imamura M, Tsuge M, Miki D, Takahashi S, Ochi H, Chayama K
  • Journal Title: Am J Gastroenterol Volume: 108 Issue: 9 Pages: 1464-1472
  • DOI: 10.1038/ajg.2013.205
  • Peer Reviewed
• [Journal Article] Interleukin-28B polymorphisms and hepatitis C virusclearance (2013)
  • Author(s): Chayama K, Hayes CN
  • Journal Title: Genome Medicine Volume: 5巻 Issue: 1 Pages: 6-6
  • DOI: 10.1186/gm410
  • Peer Reviewed
• [Journal Article] Changes in mRNA expression of hypothalamic appetite-regulating peptides during different phases of lactation in rats (2013)
  • Author(s): Suzuki Y,Nakahara K, Maruyama K, Okame R, Ensho T, Inoue Y,Murakami N.
  • Journal Title: J Mol Endocrinol Volume: 52 Issue: 1 Pages: 97-109
  • DOI: 10.1016/j.bbrc.2013.10.040
  • Peer Reviewed
• [Journal Article] HLA-DQB1*03 Confers Susceptibility to Chronic Hepatitis C in Japanese: A Genome-Wide Association Study. (2013)
  • Author(s): Miki D, Ochi H, Takahashi A, Hayes CN, Urabe Y, Abe H, Kawaoka T, Tsuge M, Hiraga N, Imamura M, Kawakami Y, Aikata H, Takahashi S, Akuta N, Suzuki F, Ikeda K, Kumada H, Karino Y, Toyota J, Tsunoda T, Kubo M, Kamatani N, Nakamura Y, Chayama K.
  • Journal Title: PLoS One. Volume: 8 Issue: 12 Pages: e84226-e84226
  • DOI: 10.1371/journal.pone.0084226
  • Peer Reviewed
• [Journal Article] Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice (2013)
  • Author(s): Shi, N. Hiraga, N. Imamura, M. Hayes, C. N. Zhang, Y. Kosaka, K. Okazaki, A. Murakami, E. Tsuge, M. Abe, H. Aikata, H. Takahashi, S. Ochi, H. Tateno-Mukaidani, C. Yoshizato, K. Matsui, H. Kanai, A. Inaba, T. McPhee, F. Gao, M. Chayama, K.
  • Journal Title: Gut Volume: 62 Issue: 7 Pages: 1055-1061
  • DOI: 10.1136/gutjnl-2012-302600
  • Peer Reviewed
• [Journal Article] Predictive value of the interferon lambda 4 polymorphism on outcome of telaprevir, pegylated interferon, and ribavirin therapy for older patients with genotype 1b chronic hepatitis C
  • Author(s): Fujino H, Imamura M, Nagaoki Y, Kawakami Y, Abe H, Hayes CN, Kan H, Fukuhara T, Kobayashi T, Masaki K, Ono A, Nakahara T, Honda Y, Naeshiro N, Urabe A, Yokoyama S, Miyaki D, Murakami E, Kawaoka T, Hiraga N, Tsuge M, Hiramatsu A, Hyogo H, Aikata H, Takahashi S, Miki D, Ochi H, Ohishi W, Chayama K
  • Journal Title: Journal of Gastroenterology Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in hepatitis C virus genotype 1 infectedpatients
  • Author(s): Kosaka K, Imamura M, Hayes CN, Abe H, Hiraga N, Yoshimi S, Murakami M, Kawaoka T, Tsuge M, Aikata H, Miki D, Ochi H, Matsui H, Kanai A, Inaba T, Chayama K
  • Journal Title: Journal of Viral Hepatitis Volume: (印刷中)
  • Peer Reviewed
• [Presentation] Early and late changes in gene expression profiles following infection with hepatitis B or C virus in human hepatocyte chimeric mice (2013)
  • Author(s): Hayes CN, Akamatsu S, Tsuge M, Miki D, Hiraga N, Abe H, Imamura M, Tahahashi S, Ochi H, Chayama K
  • Organizer: The 64nd annual meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Washington DC, U.S.A.
  • Year and Date: 2013-11-04
• [Presentation] Early and late changes in gene expression profiles following infection with hepatitis B or C virus in human hepatocyte chimeric mice (2013)
  • Author(s): Hayes CN, Akamatsu S, Tsuge M, Miki D, Hiraga N, Abe H, Imamura M, Takahashi S, Ochi H, Chayama K
  • Organizer: The 64nd annual meeting of the American Asso- ciation for the Study of Liver Diseases
  • Place of Presentation: ワシントンDC、アメリカ