Skip to main content

Advertisement

SpringerLink
Log in

Finite nucleos(t)ide analog therapy in HBeAg-negative chronic hepatitis B: an emerging paradigm shift

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Potent nucleos(t)ide analogs (NUC), such as entecavir and tenofovir disoproxil fumarate, are able to suppress HBV DNA to undetectable level. These agents have no direct action on cccDNA, which is a very stable template for HBV production, hence long-term or even life-long NUC therapy is required in HBeAg-negative patients to maintain HBV suppression and to achieve the ultimate goal of HBsAg loss. However, there are concerns of indefinite or life-long NUC therapy, including drug resistance, financial burden, adherence and willingness for indefinite long-term NUC therapy. Patients lost to follow-up and hence, not monitored may risk severe relapse that may deteriorate to hepatic decompensation or even hepatic failure. This Review integrated the cumulated evidence and assessed the strategy of finite NUC therapy in HBeAg-negative patients which was first tried in early 2000s. Earlier Asian findings that 2-year NUC therapy is feasible and safe have founded APASL stopping rule for patients on NUC therapy over 2–3 years since 2008. Subsequent studies have supported the strategy of finite NUC therapy, which has finally been accepted as an option by American and European liver associations since 2016. More recent studies have further shown greatly increased HBsAg loss rate (up to 5-year 39%) after stopping NUC therapy. The cumulated evidence has shown that the paradigm shift from indefinite long-term therapy to finite NUC therapy in HBeAg-negative patients is emerging. More studies are needed to fine-tuning the strategy including research for the optimal duration of consolidation therapy, timing to stop and to start re-treatment.

Graphic abstract

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

Similar content being viewed by others

Abbreviations

ADV:

Adefovir

ALT:

Alanine aminotransferase

APASL:

Asian-Pacific Association for the Study of the Liver

CR:

Clinical relapse

ETV:

Entecavir

HBeAg:

Hepatitis B e antigen

HBsAg:

Hepatitis B surface antigen

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

INR:

International normalized ratio

LAM:

Lamivudine

NUC:

Nucleos(t)ide analogs

qHBsAg:

HBsAg quantity

TDF:

Tenofovir disoproxil fumarate

ULN:

Upper limit of normal

VR:

Virologic relapse

References

  1. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582–592

    CAS  PubMed  Google Scholar 

  2. Chen YC, Liaw YF. Pharmacotherapeutic options for hepatitis B. Expert Opin Pharmacother 2016;17:355–367

    CAS  PubMed  Google Scholar 

  3. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10:1–98

    CAS  PubMed  Google Scholar 

  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;67:370–398

    Google Scholar 

  5. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560–1599

    PubMed  Google Scholar 

  6. Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. J Hepatol 2009;51:581–592

    CAS  PubMed  Google Scholar 

  7. Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky JM. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol 2013;58:676–683

    CAS  PubMed  Google Scholar 

  8. Liaw YF, Chien RN, Yeh CT, Tsai SL, Chu CM. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology 1999;30:567–572

    CAS  PubMed  Google Scholar 

  9. Liaw YF. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia. J Hepatol 2009;51:403–410

    PubMed  Google Scholar 

  10. Liaw YF, Leung N, Guan R, Lau GKK, Merican I, McCaughan G, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int 2005;25:472–489

    PubMed  Google Scholar 

  11. Chotiyaputta W, Peterson C, Ditah FA, Goodwin D, Lok AS. Persistence and adherence to nucleos(t)ide analogue treatment for chronic hepatitis B. J Hepatol 2011;54:12–18

    CAS  PubMed  Google Scholar 

  12. Ford N, Scourse R, Lemoine M, Hutin Y, Bulterys M, Shubber Z, et al. Adherence to nucleos(t)ide analogue therapies for chronic hepatitis B infection: a systematic review and meta-analysis. Hepatol Commun 2018;2:1160–1167

    PubMed  PubMed Central  Google Scholar 

  13. Shin JW, Jung SW, Lee SB, Lee BU, Park BR, Park EJ, Park NH. Medication nonadherence increases hepatocellular carcinoma, cirrhotic complications, and mortality in chronic hepatitis B patients treated with entecavir. Am J Gastroenterol 2018;113:998–1008

    CAS  PubMed  Google Scholar 

  14. Lim SG, Aung MO, Chung SW, Soon CS, Mak BH, Lee KH. Patient preferences for hepatitis B therapy. Antivir Ther 2013;18:663–670

    PubMed  Google Scholar 

  15. Lam YF, Seto WK, Wong D, Cheung KS, Fung J, Mak LY, 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;26(8):e125

    Google Scholar 

  16. Ahn J, Lee HM, Lim JK, Pan CQ, Nguyen MH, Ray Kim W, et al. Entecavir safety and effectiveness in a national cohort of treatment-naïve chronic hepatitis B patients in the US—the ENUMERATE study. Aliment Pharmacol Ther 2016;43:134–144

    CAS  PubMed  Google Scholar 

  17. Lim SG, Wai CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut 2002;51:597–599

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2004;11:432–438

    CAS  PubMed  Google Scholar 

  19. Chien RN, Liaw YF. Short-term lamivudine therapy in HBeAg-negative chronic active hepatitis B in Taiwan. Antivir Ther 2006;11:947–952

    CAS  PubMed  Google Scholar 

  20. Chan HL, Wang H, Niu J, Chim AM, Sung JJ. Two-year lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B: a double-blind, placebo-controlled trial. Antivir Ther 2007;12:345–353

    CAS  PubMed  Google Scholar 

  21. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al. Asian-Pacific Consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008;2:263–283

    PubMed  PubMed Central  Google Scholar 

  22. Liu F, Wang L, Li XY, Liu YD, Wang JB, Zhang ZH, Wang YZ. Poor durability of lamivudine effectiveness despite stringent cessation criteria: a prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients. J Gastroenterol Hepatol 2011;26:456–460

    PubMed  Google Scholar 

  23. Ha M, Zhang G, Diao S, Lin M, Sun L, She H, et al. A prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients with stringent cessation criteria for adefovir. Arch Virol 2012;157:285–290

    CAS  PubMed  Google Scholar 

  24. Liaw YF, Kao JH, Piratvisuth T, Chan HL, Chien RN, Liu CJ, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012;6:531–561

    PubMed  Google Scholar 

  25. Jeng WJ, Sheen IS, Chen YC, Hsu CW, Chien RN, Chu CM, Liaw YF. Off therapy durability of response to entecavir therapy in hepatitis B e antigen negative chronic hepatitis B patients. Hepatology 2013;58:1888–1896

    CAS  PubMed  Google Scholar 

  26. Jeng WJ, Chen YC, Sheen IS, Lin CL, Hu TH, Chien RN, Liaw YF. Clinical relapse after cessation of tenofovir therapy in HBeAg-negative patients. Clin Gastroenterol Hepatol 2016;14:1813–1820

    CAS  PubMed  Google Scholar 

  27. Su TH, Yang HC, Tseng TC, et al. Distinct relapse rates and risk predictors after discontinuing tenofovir and entecavir therapy. J Infect Dis 2018;217:1193–1201

    CAS  PubMed  Google Scholar 

  28. Kuo MT, Hu TH, Hung CH, Wang JH, Lu SN, Tsai KL, Chen CH. Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir. Aliment Pharmacol Ther 2019;49:218–228

    CAS  PubMed  Google Scholar 

  29. Chen CH, Hsu YC, Lu SN, Liou JM, Liu CH, Chen CL, et al. The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients. J Viral Hepat 2018;25:590–597

    CAS  PubMed  Google Scholar 

  30. Chen CH, Hung CH, Wang JH, Lu SN, Hu TH, Lee CM. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients. Clin Microbiol Infect 2018;24:997–1003

    CAS  PubMed  Google Scholar 

  31. Chi H, Hansen BE, Yim C, Arends P, Abu-Amara M, van der Eijk AA, et al. Reduced risk of relapse after long-term nucleos(t)ide analogue consolidation therapy for chronic hepatitis B. Aliment Pharmacol Ther 2015;41:867–876

    CAS  PubMed  Google Scholar 

  32. Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2018;68:425–434

    CAS  PubMed  Google Scholar 

  33. Chang ML, Liaw YF, Hadziyannis SJ. Systematic review: cessation of long-term nucleos(t)ide analogue therapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Aliment Pharmacol Ther 2015;42:243–257

    CAS  PubMed  Google Scholar 

  34. Papatheodoridis G, Vlachogiannakos I, Cholongitas E, Wursthorn K, Thomadakis C, Touloumi G, Petersen J. Discontinuation of oral antivirals in chronic hepatitis B: a systematic review. Hepatology 2016;63:1481–1492

    CAS  PubMed  Google Scholar 

  35. Chen YC, Peng CY, Jeng WJ, Chien RN, Liaw YF. Clinical outcomes after interruption of entecavir therapy in HBeAg-negative chronic hepatitis B patients with compensated cirrhosis. Aliment Pharmacol Ther 2015;42:1182–1191

    CAS  PubMed  Google Scholar 

  36. Hung CH, Wang JH, Lu SN, Hu TH, Lee CM, Chen CH. Hepatitis B surface antigen loss and clinical outcomes between HBeAg-negative cirrhosis patients who discontinued or continued nucleoside analogue therapy. J Viral Hepat 2017;24:599–607

    CAS  PubMed  Google Scholar 

  37. Chang ML, Jeng WJ, Liaw YF. Clinical events after cessation of lamivudine therapy in patients recovered from hepatitis B flare with hepatic decompensation. Clin Gastroenterol Hepatol 2015;13:979–986

    CAS  PubMed  Google Scholar 

  38. Papatheodoridis G, Goulis J, Manolakopoulos S, Margariti A, Exarchos X, Kokkonis G, et al. Changes of HBsAg and interferon-inducible protein 10 serum levels in naive HBeAg-negative chronic hepatitis B patients under 4-year entecavir therapy. J Hepatol 2014;60:62–68

    CAS  PubMed  Google Scholar 

  39. Papatheodoridis G, Triantos C, Hadziyannis E, Zisimopoulos K, Georgiou A, Voulgaris T, et al. Serum HBsAg kinetics and usefulness of interferon-inducible protein 10 serum in HBeAg-negative chronic hepatitis B patients treated with tenofovir disoproxil fumarate. J Viral Hepat 2015;22:1079–1087

    CAS  PubMed  Google Scholar 

  40. Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut 2014;63:1325–1332

    CAS  PubMed  Google Scholar 

  41. Buti M, Tsai N, Petersen J, Flisiak R, Gurel S, Krastev Z, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci 2015;60:1457–1464

    CAS  PubMed  Google Scholar 

  42. Chan HL, Wong GL, Chim AM, Chan HY, Chu SH, Wong VW. Prediction of off-treatment response to lamivudine by serum hepatitis B surface antigen quantification in hepatitis B e antigen-negative patients. Antivir Ther 2011;16:1249–1257

    CAS  PubMed  Google Scholar 

  43. Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology 2012;143:629–636

    CAS  PubMed  Google Scholar 

  44. Patwardhan VR, Sengupta N, Bonder A, Lau D, Afdhal NH. Treatment cessation in noncirrhotic, e-antigen negative chronic hepatitis B is safe and effective following prolonged anti-viral suppression with nucleosides/nucleotides. Aliment Pharmacol Ther 2014;40:804–810

    CAS  PubMed  Google Scholar 

  45. Höner Zu Siederdissen C, Rinker F, Maasoumy B, Wiegand SB, Filmann N, Falk CS, et al. Viral and host responses after stopping long-term nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J Infect Dis 2016;214:1492–1497

    PubMed  Google Scholar 

  46. Papatheodoridis GV, Rigopoulou EI, Papatheodoridi M, Zachou K, Xourafas V, Gatselis N, Hadziyannis E, et al. DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B. Antivir Ther 2018;23:677–685

    CAS  PubMed  Google Scholar 

  47. Berg T, Simon KG, Mauss S, Schott E, Heyne R, Klass DM, et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients—FINITE study. J Hepatol 2017;67:918–924

    CAS  PubMed  Google Scholar 

  48. Chen CH, Hung CH, Wang JH, Lu SN, Lai HC, Hu TH, et al. The incidence of hepatitis B surface antigen loss between hepatitis B E antigen-negative noncirrhotic patients who discontinued or continued entecavir therapy. J Infect Dis 2019;219:1624–1633

    PubMed  Google Scholar 

  49. Berg T, Petersen J, FINITE [First investigation in stopping TDF treatment after long-term virological suppression in HBeAg-negative chronic hepatitis B] study authors. Reply to: “Stop-and-watch strategy after cessation of nucleos(t)ide analogue therapy in HBeAg-negative patients”. J Hepatol 2018;68:1104–1105

    PubMed  Google Scholar 

  50. Zimmer CL, Rinker F, Höner Zu Siederdissen C, Manns MP, Wedemeyer H, Cornberg M, et al. Increased NK cell function after cessation of long-term nucleos(t)ide analogue treatment in chronic hepatitis B is associated with liver damage and HBsAg loss. J Infect Dis 2018;217:1656–1666

    CAS  PubMed  Google Scholar 

  51. Rivino L, Le Bert N, Gill US, Kunasegaran K, Cheng Y, Tan DZ, et al. Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J Clin Invest 2018;128:668–681

    PubMed  PubMed Central  Google Scholar 

  52. Rinker F, Zimmer CL, Höner Zu Siederdissen C, Manns MP, Kraft ARM, Wedemeyer H, et al. Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J Hepatol 2018;69:584–593

    CAS  PubMed  Google Scholar 

  53. Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course and management. J Hepatol 2014;61:1407–1417

    PubMed  Google Scholar 

  54. Liaw YF, Jeng WJ, Chang ML. HBsAg kinetics in re-treatment decision for off-therapy hepatitis B flare in HBeAg-negative patients. Gastroenterology 2018;154:2280–2281

    PubMed  Google Scholar 

  55. Jeng WJ, Chang ML, Liaw YF. Off-therapy precipitous HBsAg decline predicts HBsAg loss after finite entecavir therapy in HBeAg-negative patients. J Viral Hepat 2019;26:1019–1026

    CAS  PubMed  Google Scholar 

  56. Liaw YF. Clinical utility of HBsAg quantitation in HBeAg-negative chronic HBV infection. Nat Rev Gastroenterol Hepatol 2019. https://doi.org/10.1038/s41575-019-0197-8

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The author thanks Ms. Su-Chiung Chu for assistance through the study and in preparing the manuscript and figures, Dr. Wen-Juei Jeng for providing Fig. 1, Ms. Li-Hua Lu for laboratory work and Ms. Chiou-Huei Lin for database maintenance.

Funding

The author has been supported by grants from the Chang Gung Medical Research Program (CMRPG1G0061-3) and the Prosperous Foundation, Taipei, Taiwan.

Author information

Authors and Affiliations

  1. Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199, Tung Hwa North Road, Taipei, 105, Taiwan

    Yun-Fan Liaw

Authors
  1. Yun-Fan Liaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yun-Fan Liaw.

Ethics declarations

Conflict of interest

No relevant conflict of interest.

Human or animal rights

This article is a Review, not a direct original study involving human or animal subjects.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liaw, YF. Finite nucleos(t)ide analog therapy in HBeAg-negative chronic hepatitis B: an emerging paradigm shift . Hepatol Int 13, 665–673 (2019). https://doi.org/10.1007/s12072-019-09989-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-019-09989-6

Keywords

Search

Navigation