Skip to main content

Advertisement

SpringerLink
Log in

Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region.

Methods

Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing.

Results

Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently.

Conclusions

History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ASV:

Asunaprevir

DAA:

Direct-acting antiviral agent

DCV:

Daclatasvir

HCV:

Hepatitis C virus

IFN:

Interferon

NS3:

Non-structural protein 3

NS5A:

Non-structural protein 5A

PCR:

Polymerase chain reaction

RAV:

Resistance-associated variant

SMV:

Simeprevir

SNP:

Single nucleotide polymorphism

SVR:

Sustained virological responses

References

  1. Lavanchy D. The global burden of hepatitis C. Liver Int Off J Int Assoc Study Liver. 2009;29(Suppl 1):74–81.

    Article  Google Scholar 

  2. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. New Engl J Med. 2011;364(25):2405–16.

    Article  CAS  PubMed  Google Scholar 

  3. Ogawa E, Furusyo N, Dohmen K, et al. Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure. J Viral Hepat. 2015;22(12):992–1001.

    Article  CAS  PubMed  Google Scholar 

  4. Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59(6):2083–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. McPhee F, Hernandez D, Yu F, et al. Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir. Hepatology. 2013;58(3):902–11.

    Article  CAS  PubMed  Google Scholar 

  6. Fridell RA, Qiu D, Wang C, et al. Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother. 2010;54(9):3641–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pawlotsky JM. NS5A inhibitors in the treatment of hepatitis C. J Hepatol. 2013;59(2):375–82.

    Article  CAS  PubMed  Google Scholar 

  8. Wang C, Sun JH, O’Boyle DR 2nd, et al. Persistence of resistant variants in hepatitis C virus-infected patients treated with the NS5A replication complex inhibitor daclatasvir. Antimicrob Agents Chemother. 2013;57(5):2054–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McPhee F, Hernandez D, Zhou N, et al. Virological escape in HCV genotype-1-infected patients receiving daclatasvir plus ribavirin and peginterferon alfa-2a or alfa-2b. Antivir Ther. 2014;19(5):479–90.

    Article  CAS  PubMed  Google Scholar 

  10. Krishnan P, Schnell G, Tripathi R, et al. Analysis of HCV genotype 1b resistance variants in Japanese patients treated with paritaprevir/ritonavir and ombitasvir. Antimicrob Agents Chemother. 2015;. doi:10.1128/AAC.02606-15.

    Google Scholar 

  11. McPhee F, Suzuki Y, Toyota J, et al. High sustained virologic response to daclatasvir plus asunaprevir in elderly and cirrhotic patients with hepatitis C virus genotype 1b without baseline NS5A polymorphisms. Adv Ther. 2015;32(7):637–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. New Engl J Med. 2014;370(20):1879–88.

    Article  PubMed  Google Scholar 

  13. Kanda T, Nakamoto S, Nakamura M, et al. Direct-acting antiviral agents for the treatment of chronic hepatitis C virus infection. J Clin Transl Hepatol. 2014;2(1):1–6.

    PubMed  PubMed Central  Google Scholar 

  14. Kai Y, Hikita H, Tatsumi T, et al. Emergence of hepatitis C virus NS5A L31 V plus Y93H variant upon treatment failure of daclatasvir and asunaprevir is relatively resistant to ledipasvir and NS5B polymerase nucleotide inhibitor GS-558093 in human hepatocyte chimeric mice. J Gastroenterol. 2015;50(11):1145–51.

    Article  CAS  PubMed  Google Scholar 

  15. Itakura J, Kurosaki M, Higuchi M, et al. Resistance-associated NS5A variants of hepatitis C virus are susceptible to interferon-based therapy. PLoS One. 2015;10(9):e0138060.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Maekawa S, Sakamoto M, Miura M, et al. Comprehensive analysis for viral elements and interleukin-28B polymorphisms in response to pegylated interferon plus ribavirin therapy in hepatitis C virus 1B infection. Hepatology. 2012;56(5):1611–21.

    Article  CAS  PubMed  Google Scholar 

  17. McPhee F, Friborg J, Levine S, et al. Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir. Antimicrob Agents Chemother. 2012;56(7):3670–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014;384(9941):403–13.

    Article  CAS  PubMed  Google Scholar 

  19. Lenz O, Verbinnen T, Lin TI, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54(5):1878–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kan H, Hiraga N, Imamura M, et al. Combination therapies with daclatasvir and asunaprevir on NS3-D168 mutated HCV in human hepatocyte chimeric mice. Antivir Ther. 2015;. doi:10.3851/IMP3009.

    PubMed  Google Scholar 

  21. Karino Y, Toyota J, Ikeda K, et al. Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir. J Hepatol. 2013;58(4):646–54.

    Article  CAS  PubMed  Google Scholar 

  22. Lenz O, de Bruijne J, Vijgen L, et al. Efficacy of re-treatment with TMC435 as combination therapy in hepatitis C virus-infected patients following TMC435 monotherapy. Gastroenterology. 2012;143(5):1176-8; e1-6.

  23. Akuta N, Sezaki H, Suzuki F, et al. Relationships between serum asunaprevir concentration and alanine aminotransferase elevation during daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. J Med Virol. 2015;. doi:10.1002/jmv.24360.

    Google Scholar 

  24. Kumada H, Suzuki F, Suzuki Y, et al. Randomized comparison of daclatasvir + asunaprevir versus telaprevir + peginterferon/ribavirin in Japanese HCV patients. J Gastroenterol Hepatol. 2015;. doi:10.1111/jgh.13073.

    Google Scholar 

  25. Fujii Y, Uchida Y, Mochida S. Drug-induced immunoallergic hepatitis during combination therapy with daclatasvir and asunaprevir. Hepatology. 2015;61(1):400–1.

    Article  CAS  PubMed  Google Scholar 

  26. Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology. 1999;117(5):1164–72.

    Article  CAS  PubMed  Google Scholar 

  27. Ikeda K, Saitoh S, Arase Y, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1643 patients using statistical bias correction with proportional hazard analysis. Hepatology. 1999;29(4):1124–30.

    Article  CAS  PubMed  Google Scholar 

  28. Asahina Y, Tsuchiya K, Tamaki N, et al. Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Hepatology. 2010;52(2):518–27.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Shintaro Ogawa, Kayoko Matsunami, and Shuko Murakami of Nagoya City University Graduate School of Medical Sciences.

Author information

Authors and Affiliations

  1. Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan

    Etsuko Iio, Noboru Shinkai, Kei Fujiwara, Shunsuke Nojiri & Yasuhito Tanaka

  2. Ootakanomori Hospital, Kashiwa, Japan

    Noritomo Shimada

  3. Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan

    Hiroshi Abe

  4. Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan

    Masanori Atsukawa

  5. Machida Municipal Hospital, Tokyo, Japan

    Kai Yoshizawa

  6. Kagawa Prefectural Central Hospital, Takamatsu, Japan

    Koichi Takaguchi

  7. Saga University Hospital, Saga, Japan

    Yuichiro Eguchi

  8. Shin-Kokura Hospital, Kitakyushu, Japan

    Hideyuki Nomura

  9. Kuramitsu Clinic, Akita, Japan

    Tomoyuki Kuramitsu

  10. Teine Keijinkai Hospital, Sapporo, Japan

    Jong-Hon Kang & Takeshi Matsui

  11. National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Noboru Hirashima

  12. Jikei University School of Medicine, Tokyo, Japan

    Akihito Tsubota

  13. Nagoya Red Cross Hospital, Nagoya, Japan

    Atsunori Kusakabe

  14. Japan Community Health Care Organization, Chukyo Hospital, Nagoya, Japan

    Izumi Hasegawa

  15. Toyokawa City Hospital, Toyokawa, Japan

    Tomokatsu Miyaki

Authors
  1. Etsuko Iio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noritomo Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroshi Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masanori Atsukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kai Yoshizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Koichi Takaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuichiro Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hideyuki Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tomoyuki Kuramitsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jong-Hon Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takeshi Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Noboru Hirashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Akihito Tsubota
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Atsunori Kusakabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Izumi Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tomokatsu Miyaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Noboru Shinkai
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kei Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Shunsuke Nojiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Yasuhito Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhito Tanaka.

Ethics declarations

Conflict of interest

Yasuhito Tanaka is currently conducting research sponsored by Merck Sharp & Dohme, Corp., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb, and AbbVie Inc. The other authors declare no conflicts of interest.

Financial support

This research was (partially) supported by the Research Program on Hepatitis from Japan Agency for Medical Research and development, AMED.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iio, E., Shimada, N., Abe, H. et al. Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol 52, 94–103 (2017). https://doi.org/10.1007/s00535-016-1225-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-016-1225-x

Keywords

Search

Navigation