Skip to main content

Advertisement

SpringerLink
Log in

Initial- and re-treatment effectiveness of glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C virus-genotype 1/2/3 infections

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

Abstract

Background

Glecaprevir and pibrentasvir (GLE/PIB) are potent antiviral agents for hepatitis C virus (HCV) pan-genotypic infections; however, their clinical effectiveness and safety remain limited in the real-world. This study aimed to evaluate viral responses and the safety of GLE/PIB for patients with chronic HCV-1/2/3 infections during both initial- (Arm A) and re-treatment (Arm B) with all-oral direct-acting antiviral agents (DAAs).

Methods

This prospective-observational cohort study included Japanese patients with chronic HCV-1/2/3 infections (n = 271: 183 in Arm A and 83 in Arm B), who had started receiving GLE/PIB. Primary end point was a sustained virological response (SVR) rate at week 12 (SVR12) after the end of GLE/PIB treatment (EOT).

Results

SVR12 was achieved by 99.4% of patients (180/181: modified intention-to-treat (mITT) analysis excluding 2 patients lost to follow-up) in Arm A. One patient with an HCV-3b infection who discontinued at week 8 failed to achieve SVR12. SVR12 was achieved by 97.7% of patients (85/87: mITT excluding 1 patient lost to follow-up) in Arm B. Virological relapse occurred in 2 patients with HCV-1b, presenting common 5 loci of resistance-associated substitutions (RASs) including A92 RASs in the NS5A lesion at baseline. Any adverse events (AEs) (grade ≥ 3) occurred in 8 patients (3.0%). 8 patients (3.0%) discontinued due to AEs, however, all of them achieved SVR12.

Conclusions

Initial and re-treatment with GLE/PIB are effective and safe for Japanese patients with HCV-1/2/3 in real-life settings. Further studies are required to elucidate the mechanism underlying treatment failures of GLE/PIB to completely eradicate HCV worldwide.

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

DAAs:

Direct-acting antiviral agents

HCV:

Hepatitis C virus

SVR:

Sustained virological response

IFN:

Interferon

DCV:

Daclatasvir

ASV:

Asunaprevir

GT:

Genotype

SOF:

Sofosbuvir

LDV:

Ledipasvir

PrO:

Paritaprevir/ritonavir plus ombitasvir

EBR:

Elbasvir

GZR:

Grazoprevir

DCV-TRIO:

DCV/ASV plus beclabuvir

RBV:

Ribavirin

NS:

Non-structural protein

GLE:

Glecaprevir

PIB:

Pibrentasvir

RASs:

Resistance-associated substitutions

ITT:

Intention-to-treat

HCC:

Hepatocellular carcinoma

EOT:

End of treatment

LLOQ:

Lower limit of quantification

eGFR:

Estimated glomerular filtration rate

CKD:

Chronic kidney disease

ALT:

Alanine aminotransferase

AFP:

Alpha-fetoprotein

CI:

Confidence interval

VEL:

Velpatasvir

VOX:

Voxilaprevir

References

  1. Manns P, Buti M, Gane E, Pawlotsky JM, et al. Hepatitis C virus infection. Nat Rev Dis Primers. 2017;3:17006.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Mizokami M, Yokosuka O, Takehara T, et al. Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. Lancet Infect Dis. 2015;15:645–53.

    Article  CAS  Google Scholar 

  4. Kumada H, Chayama K, Rodrigues L Jr, et al. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis. Hepatology. 2015;62:1037–46.

    Article  CAS  Google Scholar 

  5. Kumada H, Suzuki Y, Karino Y, et al. The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study. J Gastroenterol. 2017;52:520–33.

    Article  CAS  Google Scholar 

  6. Toyota J, Karino Y, Suzuki F, et al. Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection. J Gastroenterol. 2017;52:385–95.

    Article  CAS  Google Scholar 

  7. Omata M, Nishiguchi S, Ueno Y, et al. Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial. J Viral Hepat. 2014;21:762–8.

    Article  CAS  Google Scholar 

  8. Sato K, Chayama K, Alves K, et al. Randomized phase 3 Trial of ombitasvir/paritaprevir/ritonavir and ribavirin for hepatitis C virus genotype 2-infected Japanese patients. Adv Ther. 2017;34:1449–65.

    Article  CAS  Google Scholar 

  9. Terrault NA, Zeuzem S, Di Bisceglie AM, et al. Effectiveness of ledipasvir–sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response. Gastroenterology. 2016;151:1131–40.

    Article  CAS  Google Scholar 

  10. Sezaki H, Suzuki F, Hosaka T, et al. The efficacy and safety of dual oral therapy with daclatasvir and asunaprevir for genotype 1b in Japanese real-life settings. Liver Int. 2017;37:1325–33.

    Article  CAS  Google Scholar 

  11. Akuta N, Sezaki H, Suzuki F, et al. Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens. J Med Virol. 2017;89:1248–54.

    Article  CAS  Google Scholar 

  12. Suda G, Ogawa K, Yamamoto Y, et al. Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy. J Gastroenterol. 2017;52:1122–9.

    Article  CAS  Google Scholar 

  13. Iio E, Shimada N, Takaguchi K, et al. Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy. Hepatol Res. 2017;52:1122–9.

    Google Scholar 

  14. Poordad F, Felizarta F, Asatryan A, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology. 2017;66:389–97.

    Article  CAS  Google Scholar 

  15. Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis. 2017;17:1062–8.

    Article  CAS  Google Scholar 

  16. Zeuzem S, Foster GR, Wang S, et al. Glecaprevir–pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med. 2018;378:354–69.

    Article  CAS  Google Scholar 

  17. Chayama K, Suzuki F, Karino Y, et al. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis. J Gastroenterol. 2018;53:557–65.

    Article  Google Scholar 

  18. Toyada H, Chayama K, Suzuki F, et al. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection. Hepatology. 2018;67:505–13.

    Article  Google Scholar 

  19. Kumada H, Watanabe T, Suzuki F, et al. Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection. J Gastroenterol. 2018;53:566–75.

    Article  CAS  Google Scholar 

  20. Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology. JSH Guidelines for the Management of Hepatitis C Virus Infection. A 2017 update (Japanese).

  21. Ogasawara N, Kobayashi M, Akuta N, et al. Serial changes in liver stiffness and controlled attenuation parameter following direct-acting antiviral therapy against hepatitis C virus genotype 1b. J Med Virol. 2018;90:313–9.

    Article  CAS  Google Scholar 

  22. Ogura S, Saitho S, Kawamura Y, et al. Magnetic resonance laparoscopy: a new non-invasive technique for the assessment of chronic viral liver disease. Hepatol Res. 2013;43:836–45.

    Article  Google Scholar 

  23. Kidney Disease Improving Global Outcomes (KDIGO). KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3:S1–50.

    Article  Google Scholar 

  24. Kato N, Hijikata M, Ootsuyama Y, et al. Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA. 1990;87:9524–8.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Pawlotsky JM. Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens. Gastroenterology. 2016;151:70–86.

    Article  CAS  Google Scholar 

  27. Sarrazin C. The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol. 2016;64:486–504.

    Article  Google Scholar 

  28. Akuta N, Sezaki H, Suzuki F, et al. Favorable efficacy of glecaprevir plus pibrentasvir as salvage therapy for HCV failures to prior direct-acting antivirals regimens. J Med Virol. 2019;91:102–6.

    Article  CAS  Google Scholar 

  29. American Association for the Study of Liver disease (AASLD), Infectious Disease Society of America (IDSA). HCV guidance: recommendations for testing, managing, and treating hepatitis C. https://www.hcvguidelines.org/.

  30. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69:461–511.

    Article  Google Scholar 

  31. D’Ambrosio R, Pasulo L, Puoti M, et al. Real-life effectiveness and safety of glecaprevir/pibrentasvir among 723 Italian patients with chronic hepatitis C: the navigator-II study. J Hepatol. 2018 [Epub ahead of print].

  32. Krishnan P, Schnell G, Tripathi R, et al. Integrated resistance analysis of CERTAIN-1 and CERTAIN-2 studies in hepatitis C virus-infected patients receiving glecaprevir and pibrentasvir in Japan. Antimicrob Agents Chemother. 2018;62:e02217.

    Article  Google Scholar 

  33. Tellinghuisen TL, Marcotrigiano J, Rice CM. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature. 2005;435:374–9.

    Article  CAS  Google Scholar 

  34. Love RA, Brodsky O, Hickey MJ, Wells PA, Cronin CN. Crystal structure of a novel dimeric form of NS5A domain I protein from hepatitis C virus. J Virol. 2009;83:4395–403.

    Article  CAS  Google Scholar 

  35. Ascher DB, Wielens J, Nero TL, Doughty L, Marton CJ, Parker MW. Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. Sci Rep. 2014;4:04765.

    Article  Google Scholar 

  36. Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.

    Article  CAS  Google Scholar 

  37. Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798–801.

    Article  CAS  Google Scholar 

  38. 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  Google Scholar 

  39. Meissner E, Bon D, Prokunina-Olsson P, et al. IFNL4-ΔG genotype is associated with slower viral clearance in hepatitis C, genotype-1 patients treated with sofosbuvir and ribavirin. J Infect Dis. 2014;209:1700–4.

    Article  CAS  Google Scholar 

  40. Osawa M, Imamura M, Teraoka Y, et al. Real-world efficacy of glecaprevir plus pibrentasvir for chronic hepatitis C patient with previous direct-acting antiviral therapy failures. J Gastroenterol. 2018 [Epub ahead of print].

  41. Bourlière M, Gordon SC, Schiff ER, et al. Deferred treatment with sofosbuvir-velpatasvir-voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1. Lancet Gastroenterol Hepatol. 2018;3:559–65.

    Article  Google Scholar 

  42. Izumi N, Takehara T, Chayama K, et al. Sofosbuvir–velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 hepatitis C who failed direct-acting antivirals. Hepatol Int. 2018;12:356–67.

    Article  Google Scholar 

  43. Asselah T, Kowdley KV, Zadekis N, et al. Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol. 2018;16:417–26.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was partly supported by health sciences research grants from the Ministry of Health, Labor, and Welfare of Japan and AMED (Japan Agency for Medical Research and Development; Research on Hepatitis, grant number: 18fk0210002h0003). We would like to thank Editage (www.editage.jp) for English language editing.

Author information

Authors and Affiliations

  1. Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Hitomi Sezaki, Fumitaka Suzuki, Tetsuya Hosaka, Shunichirou Fujiyama, Yusuke Kawamura, Norio Akuta, Masahiro Kobayashi, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda & Hiromitsu Kumada

  2. Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan

    Mariko Kobayashi

Authors
  1. Hitomi Sezaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fumitaka Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tetsuya Hosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shunichirou Fujiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yusuke Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Norio Akuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masahiro Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshiyuki Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Satoshi Saitoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yasuji Arase
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kenji Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mariko Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hiromitsu Kumada
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HS: Study concept and design; data collection, analysis, and interpretation; and drafting of the manuscript. FS: Data collection, analysis, and interpretation and review of the manuscript. TH: Data collection, analysis, interpretation and review of the manuscript, and drafting of the manuscript. SF: Data collection and review of the manuscript. YK: Data collection and review of the manuscript. NA: Data collection and review of the manuscript. MK: Data collection and review of the manuscript. YS: Data collection and review of the manuscript. SS: Data collection and review of the manuscript. YA: Data collection and review of the manuscript. KI: Data collection and review of the manuscript. MK: Direct sequencing HCV genome, genotyping IL28B polymorphism, assistance with data collection, and review of the manuscript. HK: Study concept and design; data collection, analysis, and interpretation; and critical review of the manuscript

Corresponding author

Correspondence to Hitomi Sezaki.

Ethics declarations

Conflict of interest

Hiromitsu Kumada received honoraria for lectures from MSD K.K., Bristol-Myers Squibb, Gilead Sciences, AbbVie Inc., Glaxo Smith Klein K.K. and Dainippon Sumitomo Pharma. Fumitaka Suzuki received honoraria for lectures from Bristol-Myers Squibb and AbbVie Inc. Yoshiyuki Suzuki received honoraria for lectures from Bristol-Myers Squibb and AbbVie Inc. Kenji Ikeda received honoraria for lectures from Dainippon Sumitomo Pharma, Eisai Co., Ltd. Norio Akuta received honoraria for lectures from Bristol-Myers Squibb and AbbVie Inc. The other authors have no conflicts of interest to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 419 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sezaki, H., Suzuki, F., Hosaka, T. et al. Initial- and re-treatment effectiveness of glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C virus-genotype 1/2/3 infections. J Gastroenterol 54, 916–927 (2019). https://doi.org/10.1007/s00535-019-01575-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-019-01575-9

Keywords

Search

Navigation