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.
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
Lavanchy D. The global burden of hepatitis C. Liver Int Off J Int Assoc Study Liver. 2009;29(Suppl 1):74–81.
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.
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.
Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59(6):2083–91.
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.
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.
Pawlotsky JM. NS5A inhibitors in the treatment of hepatitis C. J Hepatol. 2013;59(2):375–82.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Fujii Y, Uchida Y, Mochida S. Drug-induced immunoallergic hepatitis during combination therapy with daclatasvir and asunaprevir. Hepatology. 2015;61(1):400–1.
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.
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.
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.
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
Corresponding author
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
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00535-016-1225-x