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Safety and efficacy of dual therapy with daclatasvir and asunaprevir for older patients with chronic hepatitis C

  • Original Article–Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV)-infected patients. However, the safety and efficacy of the therapy for older patients are unknown.

Methods

One hundred seventy patients younger than 75 years and 139 patients aged 75 years or older with genotype 1 HCV infection were treated for 24 weeks with daclatasvir plus asunaprevir. Pretreatment drug-resistance-associated variants at NS5A-L31 and NS5A-Y93 were determined by the Invader assay. Virological response and adverse events according to age were analyzed.

Results

The sustained virological response (SVR) rate for older patients was similar to that for younger patients (97.1 and 92.4 % respectively). In multivariate regression analysis, prior simeprevir treatment (odds ratio 56.6 for absence; P < 0.001) was identified as a significant independent predictor of SVR. The SVR rate for patients with pretreatment resistance-associated variants (RAVs) at a low population frequency (less than 25 %) was similar to that for patients with no detectable RAVs. The frequency of adverse events was similar between younger and older patients. All 19 very elderly patients (85 years or older) completed the 24 weeks of treatment and achieved SVR.

Conclusions

Older patients have a virological response and tolerance of daclatasvir plus asunaprevir therapy similar to those of younger patients. Even though RAVs were detected, virological response similar to that for patients with no detectable RAVs may still be expected for patients with RAVs as long as the population frequency is low.

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Abbreviations

DAA:

Direct-acting antiviral

HCV:

Hepatitis C virus

PEG-IFN:

Pegylated interferon

RAV:

Resistance-associated variant

SVR:

Sustained virological response

References

  1. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705–14.

    Article  PubMed  Google Scholar 

  2. Huang CF, Yang JF, Dai CY, et al. Efficacy and safety of pegylated interferon combined with ribavirin for the treatment of older patients with chronic hepatitis C. J Infect Dis. 2010;201:751–9.

    Article  CAS  PubMed  Google Scholar 

  3. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.

    Article  CAS  PubMed  Google Scholar 

  4. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580–93.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Kumada H, Toyota J, Okanoue T, et al. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56:78–84.

    Article  CAS  PubMed  Google Scholar 

  7. Fried MW, Buti M, Dore GJ, et al. Once-daily simeprevir (TMC435) with peginterferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58:1918–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014;146:430–41.

    Article  CAS  PubMed  Google Scholar 

  9. Asahina Y, Tsuchiya K, Nishimura T, et al. α-Fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology. 2013;58:1253–62.

    Article  CAS  PubMed  Google Scholar 

  10. Tanaka Y, Hanada K, Mizokami M, et al. A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades. Proc Natl Acad Sci U S A. 2002;99:15584–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well. Ann Intern Med. 2004;140:370–81.

    CAS  PubMed  Google Scholar 

  12. Iwasaki Y, Ikeda H, Araki Y, Osawa T, et al. Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C. Hepatology. 2006;43:54–63.

    Article  CAS  PubMed  Google Scholar 

  13. Fujino H, Imamura M, Nagaoki Y, et al. Predictive value of the IFNL4 polymorphism on outcome of telaprevir, peginterferon, and ribavirin therapy for older patients with genotype 1b chronic hepatitis C. J Gastroenterol. 2014;49:1548–56.

    Article  CAS  PubMed  Google Scholar 

  14. Manns M, Pol S, Jacobson IM, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet. 2014;384(9954):1597–605.

    Article  CAS  PubMed  Google Scholar 

  15. Wei L, Zhang M, Xu M et al. A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin. J Gastroenterol Hepatol. 2016. doi:10.1111/jgh.13379

  16. Kao JH, Lee YJ, Heo J et al. All-oral daclatasvir plus asunaprevir for chronic hepatitis C virus (HCV) genotype 1b infection: a sub-analysis in Asian patients from the HALLMARK DUAL study. Liver Int. 2016. doi:10.1111/liv.13128

  17. Lok AS, Gardiner DF, Hézode C, et al. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol. 2014;60(3):490–9.

    Article  CAS  PubMed  Google Scholar 

  18. Jensen D, Sherman KE, Hézode C, et al. Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders. J Hepatol. 2015;63(1):30–7.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ikeda K, Saitoh S, Kobayashi M, et al. Distinction between chronic hepatitis and liver cirrhosis in patients with hepatitis C virus infection. Practical discriminant function using common laboratory data. Hepatol Res. 2000;18:252–66.

    Article  CAS  PubMed  Google Scholar 

  21. Prokunina-Olsson L, Muchmore B, Tang W, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45:164–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ochi H, Miki D, Hayes CN, et al. IFNL4/IL-28B haplotype structure and its impact on susceptibility to hepatitis C virus and treatment response in the Japanese population. J Gen Virol. 2014;95:1297–306.

    Article  CAS  PubMed  Google Scholar 

  23. Ochi H, Maekawa T, Abe H, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy—a genome-wide study of Japanese HCV virus patients. Gastroenterology. 2010;139:1190–7.

    Article  CAS  PubMed  Google Scholar 

  24. Yoshimi S, Ochi H, Murakami E, et al. Rapid, sensitive, and accurate evaluation of drug resistant mutant (NS5A-Y93H) strain frequency in genotype 1b HCV by invader assay. PLoS One. 2015;10:e0130022.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Arase Y, Ikeda K, Suzuki F, et al. Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C. Intervirology. 2007;50:16–23.

    Article  CAS  PubMed  Google Scholar 

  26. 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;58:902–11.

    Article  CAS  PubMed  Google Scholar 

  27. 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;58:646–54.

    Article  CAS  PubMed  Google Scholar 

  28. Hijikata M, Mizushima H, Akagi T, et al. Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol. 1993;67:4665–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Shimakami T, Welsch C, Yamane D, et al. Protease inhibitor-resistant hepatitis C virus mutants with reduced fitness from impaired production of infectious virus. Gastroenterology. 2011;140:667–75.

    Article  CAS  PubMed  Google Scholar 

  30. Akuta N, Suzuki F, Sezaki H, et al. Evolution of simeprevir-resistant variants in virological non-responders infected with HCV genotype 1b. J Med Virol. 2014;86:1314–22.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Rie Akiyama for her excellent technical assistance and Nobuko Yokoyama, Akemi Sada, and Emi Nishio for clerical assistance.

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Authors and Affiliations

  1. Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Reona Morio, Michio Imamura, Yoshiiku Kawakami, Kei Morio, Tomoki Kobayashi, Satoe Yokoyama, Yuki Kimura, Yuko Nagaoki, Tomokazu Kawaoka, Masataka Tsuge, Akira Hiramatsu, C. Nelson Hayes, Hiroshi Aikata, Shoichi Takahashi & Kazuaki Chayama

  2. Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan

    Daiki Miki, Hidenori Ochi & Kazuaki Chayama

  3. Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan

    Nami Mori, Shintaro Takaki & Keiji Tsuji

Authors
  1. Reona Morio
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  2. Michio Imamura
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  3. Yoshiiku Kawakami
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  4. Kei Morio
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  5. Tomoki Kobayashi
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  6. Satoe Yokoyama
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  7. Yuki Kimura
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  8. Yuko Nagaoki
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  9. Tomokazu Kawaoka
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  10. Masataka Tsuge
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  11. Akira Hiramatsu
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  12. C. Nelson Hayes
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  13. Hiroshi Aikata
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  14. Shoichi Takahashi
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  15. Daiki Miki
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  16. Hidenori Ochi
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  17. Nami Mori
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  18. Shintaro Takaki
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  20. Kazuaki Chayama
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Corresponding author

Correspondence to Kazuaki Chayama.

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Conflict of interest

Kazuaki Chayama has received honoraria from MSD, Bristol-Myers Squibb, Gilead Sciences, and AbbVie and research funding from Dainippon Sumitomo Pharma, TORAY, Eisai, Otsuka Pharma, Mitsubishi Tanabe Pharma, Daiichi Sankyo, and Bristol-Myers Squibb. Michio Imamura has received honoraria and research funding from Bristol-Myers Squibb. Masataka Tsuge has received research funding from Bristol-Myers Squibb.

Funding statement

This research is partially supported by research funding from the Research Program on Hepatitis from the Japan Agency for Medical Research and Development (Grant Number 15fk0210001h0002). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.

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Morio, R., Imamura, M., Kawakami, Y. et al. Safety and efficacy of dual therapy with daclatasvir and asunaprevir for older patients with chronic hepatitis C. J Gastroenterol 52, 504–511 (2017). https://doi.org/10.1007/s00535-016-1255-4

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  • DOI: https://doi.org/10.1007/s00535-016-1255-4

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