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Journal of Gastroenterology

, Volume 54, Issue 2, pp 182–193 | Cite as

Long-term outcome of entecavir treatment of nucleos(t)ide analogue-naïve chronic hepatitis B patients in Japan

  • Fumitaka SuzukiEmail author
  • Tetsuya Hosaka
  • Yoshiyuki Suzuki
  • Hitomi Sezaki
  • Norio Akuta
  • Shunichiro Fujiyama
  • Yusuke Kawamura
  • Masahiro Kobayashi
  • Satoshi Saitoh
  • Yasuji Arase
  • Kenji Ikeda
  • Mariko Kobayashi
  • Rie Mineta
  • Yukiko Suzuki
  • Hiromitsu Kumada
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

We determined the antiviral potency and viral breakthrough rate after 10 years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection.

Methods

The cumulative rates of undetectable hepatitis B virus DNA (HBV-DNA, < 2.1 log copies/mL), alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroclearance, hepatitis B surface antigen (HBsAg) seroclearance, and viral breakthrough of 1094 nucleos(t)ide analogue-naïve CHB patients (HBeAg-positive: 47%) who were on continuous entecavir treatment for 10 years were calculated.

Results

The median age was 50 years and follow-up period was 5.5 years, with 999, 804, 591, 390, 182 and 87 patients followed up for at least 1, 3, 5, 7, 9 and 10 years, respectively. Incremental increases were noted in the rates of undetectable HBV-DNA, ALT normalization, HBeAg seroclearance, and HBsAg seroclearance, reaching 96, 79, 38 and 3.7%, respectively, by the tenth year. The mean decline in HBsAg level from baseline was − 0.08 log IU/mL/year. Multivariate analysis identified HBsAg level and genotype (A) as independent predictors of HBsAg seroclearance. Sixteen patients experienced viral breakthrough. The cumulative percentages of patients with viral breakthrough analyzed by the Kaplan–Meier test were 1.5 and 2.5% at years 5 and 10, respectively. There were no serious adverse events during treatment.

Conclusions

Long-term entecavir treatment of nucleos(t)ide analogue-naïve CHB patients was associated with an excellent viral response and a low rate of entecavir-resistant mutations at 10 years. Baseline HBsAg levels and genotype were predictors of HBsAg seroclearance during entecavir treatment.

Keywords

Hepatitis B virus Entecavir HBsAg seroclearance Resistance Viral breakthrough 

Abbreviations

CHB

Chronic hepatitis B

NA

Nucleos(t)ide analogue

TDF

Tenofovir disoproxil fumarate

HBV

Hepatitis B virus

HBeAg

Hepatitis B e antigen

ALT

Alanine aminotransferase

HBsAg

Hepatitis B surface antigen

PCR

Polymerase chain reaction

rt

Reverse transcriptase

nt

Nucleotide

HR

Hazard ratio

CI

Confidence interval

AST

Aspartate transaminase

GGT

γ-Glutamyltransferase

ROC

Receiver operating characteristic

HCC

Hepatocellular carcinoma

NAFLD

Nonalcoholic fatty liver disease

Notes

Acknowledgements

This study was supported in part by Okinaka Memorial Institute for Medical Research, and by grants from the Ministry of Health, Labor and Welfare of Japan and Japan Agency for Medical Research and Development.

Compliance with ethical standards

Conflict of interest

Dr. Suzuki F received lecture fees from Bristol-Myers Squibb, Gilead Sciences Inc. and Abbvie. Dr. Suzuki Y received lecture fees from Bristol-Myers Squibb. Dr. Akuta received lecture fees from Abbvie. Dr. Ikeda received lecture fees from Sumitomo Dainippon Pharma Co. Ltd, Olympus, Esai Co. Ldt, Otsuka Pharmaceuical, Nippon Kayaku Co. Ldt, and Bayer. Dr. Kumada received investigator, lecture and consulting fees from Bristol-Myers Squibb, Gilead Sciences Inc. Abbvie, MSD, and Sumitomo Dainippon Pharma Co. Ltd. The other authors declare that they have no conflict of interest.

Supplementary material

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References

  1. 1.
    Global hepatitis report, 2017. World Health Organization (WHO). 2017. http://apps.who.int/iris/bitstream/10665/255016/1/9789241565455-eng.pdf?ua=1.
  2. 2.
    Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology. JSH Guidelines for the Management of Hepatitis B Virus Infection. Hepatol Res. 2014;44(Suppl S1):1–58.Google Scholar
  3. 3.
    Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63:261–83.CrossRefGoogle Scholar
  4. 4.
    European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.CrossRefGoogle Scholar
  5. 5.
    Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1–98.CrossRefGoogle Scholar
  6. 6.
    Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196–206.CrossRefGoogle Scholar
  7. 7.
    Chan HL, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:185–95.CrossRefGoogle Scholar
  8. 8.
    Kobashi H, Takaguchi K, Ikeda H, et al. Efficacy and safety of entecavir in nucleoside-naive, chronic hepatitis B patients: phase II clinical study in Japan. J Gastroenterol Hepatol. 2009;24:255–61.CrossRefGoogle Scholar
  9. 9.
    Yokosuka O, Takaguchi K, Fujioka S, et al. Long-term use of entecavir in nucleoside-naive Japanese patients with chronic hepatitis B infection. J Hepatol. 2010;52:791–9.CrossRefGoogle Scholar
  10. 10.
    Ono A, Suzuki F, Kawamura Y, et al. Long-term continuous entecavir therapy in nucleos(t)ide-naïve chronic hepatitis B patients. J Hepatol. 2012;57:508–14.CrossRefGoogle Scholar
  11. 11.
    Arends P, Sonneveld MJ, Zoutendijk R, et al. Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. Gut. 2015;64:1289–95.CrossRefGoogle Scholar
  12. 12.
    Lampertico P, Soffredini R, Viganò M, et al. 5-Year entecavir treatment in NUC-naive, field practice patients with chronic hepatitis B showed excellent viral suppression and safety profile but no prevention of HCC in cirrhosis. J Hepatol. 2013;58:S306.CrossRefGoogle Scholar
  13. 13.
    Seto WK, Lam YF, Fung J, et al. Changes of HBsAg and HBV DNA levels in Chinese chronic hepatitis B patients after 5 years of entecavir treatment. J Gastroenterol Hepatol. 2014;29:1028–34.CrossRefGoogle Scholar
  14. 14.
    Luo J, Li X, Wu Y, et al. Efficacy of entecavir treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B patients in real life. Int J Med Sci. 2013;10:427–33.CrossRefGoogle Scholar
  15. 15.
    Grossi G, Viganò M, Loglio A, et al. Hepatitis B virus long-term impact of antiviral therapy nucleot(s)ide analogues (NUCs). Liver Int. 2017;37(Suppl 1):45–51.CrossRefGoogle Scholar
  16. 16.
    Shindo M, Chayama K, Mochida S, et al. Antiviral activity, dose-response relationship, and safety of entecavir following 24-week oral dosing in nucleoside-naive Japanese adult patients with chronic hepatitis B: a randomized, double-blind, phase II clinical trial. Hepatol Int. 2009;3:445–52.CrossRefGoogle Scholar
  17. 17.
    Suzuki F, Akuta N, Suzuki Y, et al. Selection of a virus strain resistant to entecavir in a nucleoside-naïve patient with hepatitis B of genotype H. J Clin Virol. 2007;39:149–52.CrossRefGoogle Scholar
  18. 18.
    Hara T, Suzuki F, Kawamura Y, et al. Long-term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in uncleos(t)ide-naïve chronic hepatitis B patients. J Viral Hepat. 2014;21:802–8.CrossRefGoogle Scholar
  19. 19.
    Suzuki F, Kumada H, Nakamura H. Changes in viral loads of lamivudine-resistant mutants and evolution of HBV sequences during adefovir dipivoxil therapy. J Med Virol. 2006;78:1025–34.CrossRefGoogle Scholar
  20. 20.
    Suzuki F, Suzuki Y, Hosaka T, et al. Efficacy of long-term tenofovir-based rescue therapy in patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs. J Gastroenterol. 2017;52:641–51.CrossRefGoogle Scholar
  21. 21.
    Hayashi S, Murakami S, Omagari K, et al. Characterization of novel entecavir resistance mutations. J Hepatol. 2015;63:546–53.CrossRefGoogle Scholar
  22. 22.
    Cho JY, Sohn W, Sinn DH, et al. Long-term real-world entecavir therapy in treatment-naïve hepatitis B patients: base-line hepatitis B virus DNA and hepatitis B surface antigen levels predict virologic response. Korean J Intern Med. 2017;32:636–46.CrossRefGoogle Scholar
  23. 23.
    Lam YF, Seto WK, Wong D, et al. Seven-year treatment outcome of entecavir in a real-world cohort: effects on clinical parameters, HBsAg and HBcrAg levels. Clin Transl Gastroenterol. 2017;8:e125.CrossRefGoogle Scholar
  24. 24.
    Brouwer WP, Xie Q, Sonneveld MJ, et al. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: a multicenter randomized trial (ARES study). Hepatology. 2015;61:1512–22.CrossRefGoogle Scholar
  25. 25.
    Boglione L, Cariti G, Di Perri G, et al. Sequential therapy with entecavir and pegylated interferon in a cohort of young patients affected by chronic hepatitis B. J Med Virol. 2016;88:1953–9.CrossRefGoogle Scholar
  26. 26.
    Hosaka T, Suzuki F, Kobayashi M, et al. Clearance of hepatitis B surface antigen during long-term nucleot(s)ide analog treatment in chronic hepatitis B: results from a nine-year longitudinal study. J Gastroenterol. 2013;48:930–41.CrossRefGoogle Scholar
  27. 27.
    Suzuki F, Arase Y, Suzuki Y, et al. Long-term efficacy of interferon therapy in patients with chronic hepatitis B virus infection in Japan. J Gastroenterol. 2012;47:814–22.CrossRefGoogle Scholar
  28. 28.
    Kobayashi M, Hosaka T, Suzuki F, et al. Seroclearance rate of hepatitis B surface antigen in 2,112 patients with chronic hepatitis in Japan during long-term follow-up. J Gastroenterol. 2014;49:538–46.CrossRefGoogle Scholar
  29. 29.
    Wong DK, Seto WK, Fung J, et al. Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos(t)ide analogues of different potency. Clin Gastroenterol Hepatol. 2013;1(1004–10):e1.Google Scholar
  30. 30.
    Viganò M, Invernizzi F, Grossi G, et al. Review article: the potential of interferon and nucleos(t)ide analogue combination therapy in chronic hepatitis B infection. Aliment Pharmacol Ther. 2016;44:653–61.CrossRefGoogle Scholar
  31. 31.
    Tenney DJ, Rose RE, Baldick CJ, et al. Two-year assessment of entecavir resistance in lamivudine-refractory hepatitis B virus patients reveals different clinical out-comes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007;51:902–11.CrossRefGoogle Scholar
  32. 32.
    Ono SK, Kato N, Shiratori Y, et al. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance. J Clin Investig. 2001;107:449–55.CrossRefGoogle Scholar
  33. 33.
    Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98–107.CrossRefGoogle Scholar
  34. 34.
    Papatheodoridis GV, Idilman R, Dalekos GN, et al. The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. Hepatology. 2017;66:1444–53.CrossRefGoogle Scholar
  35. 35.
    Papatheodoridis GV, Sypsa V, Dalekos G, et al. Eight-year survival in chronic hepatitis B patients under long-term entecavir or tenofovir therapy is similar to the general population. J Hepatol. 2018;68:1129–36.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  • Fumitaka Suzuki
    • 1
    • 2
    Email author
  • Tetsuya Hosaka
    • 1
  • Yoshiyuki Suzuki
    • 1
  • Hitomi Sezaki
    • 1
  • Norio Akuta
    • 1
  • Shunichiro Fujiyama
    • 1
  • Yusuke Kawamura
    • 1
  • Masahiro Kobayashi
    • 1
  • Satoshi Saitoh
    • 1
  • Yasuji Arase
    • 1
  • Kenji Ikeda
    • 1
  • Mariko Kobayashi
    • 3
  • Rie Mineta
    • 3
  • Yukiko Suzuki
    • 3
  • Hiromitsu Kumada
    • 1
  1. 1.Department of HepatologyToranomon HospitalTokyoJapan
  2. 2.Okinaka Memorial Institute for Medical ResearchTokyoJapan
  3. 3.Research Institute for HepatologyToranomon Branch HospitalKawasakiJapan

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