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Current Hepatology Reports

, Volume 18, Issue 4, pp 512–521 | Cite as

Evidence-Based Approach to Stopping Oral Antiviral Therapy in Chronic HBV

  • Maximilian Wübbolding
  • Markus CornbergEmail author
  • Christoph Höner zu Siederdissen
Hepatitis B (J Lim, Section Editor)
  • 11 Downloads
Part of the following topical collections:
  1. Topical Collection on Hepatitis B

Abstract

Purpose of Review

To review the evidence for stopping antiviral therapy with nucleos(t)ide analogues (NA) in patients with chronic hepatitis B.

Recent Findings

HBsAg loss is usually stable even without anti-HBs seroconversion after stopping NA therapy. About 50% of HBeAg-positive patients who have achieved anti-HBe seroconversion and have stopped NA therapy remain in virological remission. Consolidation therapy increases the response rate. In HBeAg-negative hepatitis, stable virological remission is documented in 30% after NA discontinuation. Interestingly, some studies document unexpectedly high long-term HBsAg loss rates after stopping therapy.

Summary

Evidence supports NA discontinuation, especially after HBsAg seroclearance. In HBeAg-positive patients, NA can be stopped 12 months after anti-HBe seroconversion but severe flares have to be considered. NA discontinuation is also possible in selected HBeAg-negative patients if close monitoring can be guaranteed. The high rate of HBsAg loss needs further evaluation.

Keywords

Treatment discontinuation Nucleos(t)ide analogues HBeAg seroconversion HBeAg negative HBsAg loss 

Notes

Compliance with Ethical Standards

Conflict of Interest

Maximilian Wübbolding declares no potential conflicts of interest. Markus Cornberg reports personal fees for lectures and advisory boards from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag (Data Safety Board), Roche, Merck (MSD), Biogen, Falk Foundation, Boehringer Ingelheim, Siemens, and Spring Bank. Dr. Cornberg reports a grant from Roche. Christoph Höner zu Siederdissen reports travel grants from Gilead Sciences and Novartis.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    EASL. 2017 Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.CrossRefGoogle Scholar
  2. 2.
    Terrault NA, Lok ASF, McMahon BJ, Chang K, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Sarin S, Kumar M, Lau G, Abbas Z, Chan H, Chen C, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    • Liu J, Yang H, Lee M, Lu S, Jen C, Batrla-Utermann R, et al. Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma. Gut. 2014;63(10):1648–57 Describes the positive impact of HBsAg loss on HCC risk. PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Kim G, Lee HC, Kim M, Ha Y, Park EJ, An J, et al. Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance. J Hepatol. 2015;62(5):1092–9.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Chen YC, Jeng WJ, Chien RN, Chu CM, Liaw YF. Clinical outcomes after spontaneous and nucleos(t)ide analogue-treated HBsAg seroclearance in chronic HBV infection. Aliment Pharmacol Ther. 2016;43(12):1311–8.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    •• Yeo YH, Ho HJ, Yang H, Tseng T, Hosaka T, Trinh HN, et al. Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis. Gastroenterology. 2019;156(3):63–646.e9 Comprehensive meta-analysis about clinical factors associated with HBsAg seroclearance. CrossRefGoogle Scholar
  8. 8.
    Chi H, Wong D, Peng J, Cao J, Van Hees S, Vanwolleghem T, et al. Durability of response after hepatitis B surface antigen seroclearance during nucleos(t)ide analogue treatment in a multiethnic cohort of chronic hepatitis B patients: results after treatment cessation. Clin Infect Dis. 2017;65(4):680–3.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Kim G, Lim Y, 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(8):1325–32.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    • Papatheodoridis G, Vlachogiannakos I, Cholongitas E, Wursthorn K, Thomadakis C, Touloumi G, et al. Discontinuation of oral antivirals in chronic hepatitis B: a systematic review. Hepatology. 2016;63(5):1481–92 Systematic review of stopping NA therapy in HBeAg positive and negative patients. PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Summers J, Mason WS. Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy. Proc Natl Acad Sci U S A. 2004;101(2):638–40.PubMedCrossRefGoogle Scholar
  12. 12.
    Nie H, Evans AA, London WT, Block TM, Ren XD. Quantitative dynamics of hepatitis B basal core promoter and precore mutants before and after HBeAg seroconversion. J Hepatol. 2012;56(4):795–802.PubMedCrossRefGoogle Scholar
  13. 13.
    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(9):867–76.PubMedCrossRefGoogle Scholar
  14. 14.
    Pan X, Zhang K, Yang X, Liang J, Sun H, Li X, et al. Relapse rate and associated-factor of recurrence after stopping NUCs therapy with different prolonged consolidation therapy in HBeAg positive CHB patients. PLoS ONE. 2013;8(7):e68568.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Lee HW, Lee HJ, Hwang JS, Sohn JH, Jang JY, Han KJ, et al. Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B. Hepatology. 2010;51(2):415–21.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    • Liem KS, Fung S, Wong DK, Yim C, Noureldin S, Chen J, et al. Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study). Gut. 2019;  https://doi.org/10.1136/gutjnl-2019-318981. Largest prospective trial of stopping NA therapy. Did not show an effect on HBsAg. PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Chang M, Liaw Y, 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(3):243–57.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    • Höner Zu Siederdissen C, Hui AJ, Sukeepaisarnjaroen W, Tangkijvanich P, Su WW, Nieto GEG, et al. Contrasting timing of virological relapse after discontinuation of tenofovir or entecavir in hepatitis B e antigen-negative patients. J Infect Dis. 2018;218(9):1480–4 Head-to-head trial comparing relapse timings between ETV and TDF. PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Kuo M, Hu T, Hung C, Wang J, Lu S, Tsai K, et al. Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir. Aliment Pharmacol Ther. 2019;49(2):218–28.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Su T, Yang H, Tseng T, Liou J, Liu C, Chen C, et al. Distinct relapse rates and risk predictors after discontinuing tenofovir and entecavir therapy. J Infect Dis. 2018;217(8):1193–201.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Murata K, Asano M, Matsumoto A, Sugiyama M, Nishida N, Tanaka E, et al. Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection. Gut. 2018;67(2):362–71.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Jeng W, Chen Y, Sheen I, Lin C, Hu T, Chien R, et al. Clinical relapse after cessation of tenofovir therapy in hepatitis B e antigen-negative patients. Clin Gastroenterol Hepatol. 2016;14(12):181–1820.e1.CrossRefGoogle Scholar
  23. 23.
    Papatheodoridis GV, Rigopoulou EI, Papatheodoridi M, Zachou K, Xourafas V, Gatselis N, 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 (Lond ). 2018;23(8):677–85.CrossRefGoogle Scholar
  24. 24.
    •• Berg T, Simon K, 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(5):918–24 Prospective, randomized controlled study in Caucasian patients for stopping NA therapy. PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    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(10):1492–7.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    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(3):62–636.e1.CrossRefGoogle Scholar
  27. 27.
    • Jeng W, Chen Y, Chien R, Sheen I, Liaw Y. 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(2):425–34 NA stop in Asian patients and effects on HBsAg levels. PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    • Chen C, Hung C, Wang J, Lu S, Lai H, Hu T, 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(10):1624–33 NA stop in Asian patients and effects on HBsAg levels. PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Liaw Y, Jeng W, Chang M. HBsAg kinetics in retreatment decision for off-therapy hepatitis B flare in HBeAg-negative patients. Gastroenterology. 2018;154(8):2280–1.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Chang M, Liaw Y. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management. J Hepatol. 2014;61(6):1407–17.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, Giuberti T, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol. 2007;81(8):4215–25.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Boni C, Laccabue D, Lampertico P, Giuberti T, Viganò M, Schivazappa S, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012;143(4):96–973.e9.CrossRefGoogle Scholar
  33. 33.
    • 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(3):584–93 Importance of t-cells after stopping NA therapy. PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Cornberg M, Manns MP. Hepatitis: no cure for hepatitis B and D without targeting integrated viral DNA? Nat Rev Gastroenterol Hepatol. 2018;15(4):195–6.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    • Wooddell CI, Yuen M, Chan HL, Gish RG, Locarnini SA, Chavez D, et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med. 2017;9(409).  https://doi.org/10.1126/scitranslmed.aan0241. Influence of integrated HBV DNA for HBsAg production. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    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(2):668–81.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Wong WWL, Pechivanoglou P, Wong J, Bielecki JM, Haines A, Erman A, et al. Antiviral treatment for treatment-naïve chronic hepatitis B: systematic review and network meta-analysis of randomized controlled trials. Syst Rev. 2019;8(1):207.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Aguirre-Gamboa R, Joosten I, Urbano PCM, van der Molen RG, van Rijssen E, van Cranenbroek B, et al. Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits. Cell Rep. 2016;17(9):2474–87.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hung C, Wang J, Lu S, Hu T, Lee C, Chen C. 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(7):599–607.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Lampertico P, Berg T. Less can be more: a finite treatment approach for HBeAg-negative chronic hepatitis B. Hepatology. 2018;68(2):397–400.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Liu Y, Jia M, Wu S, Jiang W, Feng Y. Predictors of relapse after cessation of nucleos(t)ide analog treatment in HBeAg-negative chronic hepatitis B patients: A meta-analysis. Int J Infect Dis. 2019;86:201–7.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Qiu Y, Huang L, Yang W, Wang Z, Zhang B, Li Y, et al. Hepatitis B surface antigen quantification at hepatitis B e antigen seroconversion predicts virological relapse after the cessation of entecavir treatment in hepatitis B e antigen-positive patients. Int J Infect Dis. 2016;43:43–8.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Yao C, Lee C, Hung C, Wang J, Hu T, Lu S, et al. Combining age and HBsAg level predicts post-treatment durability of nucleos(t)ide analogue-induced HBeAg seroconversion. J Gastroenterol Hepatol. 2015 May;30(5):918–24.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Yao C, Hung C, Hu T, Lu S, Wang J, Lee C, et al. Incidence and predictors of HBV relapse after cessation of nucleoside analogues in HBeAg-negative patients with HBsAg ≤ 200 IU/mL. Sci Rep. 2017;7(1):1839.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Luo H, Zhang X, Cao L, Tan N, Kang Q, Xi H, et al. Serum hepatitis B virus RNA is a predictor of HBeAg seroconversion and virological response with entecavir treatment in chronic hepatitis B patients. World J Gastroenterol. 2019;25(6):719–28.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Chen E, Wang M, Tao Y, Wu D, Liao J, He M, et al. Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA. J Viral Hepat. 2019;26(5):586–95.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    van Bömmel F, Bartens A, Mysickova A, Hofmann J, Krüger DH, Berg T, et al. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology. 2015;61(1):66–76.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Carey I, Gersch J, Bruce M, Wang B, Moigboi C, Cloherty G, et al. Pre-genomic HBV RNA and HBcrAg play important role in the predicting clinical outcomes in chronic hepatitis B patients suppressed on antiviral therapy with nucleos (t)ide analogues. J Hepatol EASL Abstract. 2019;70(Supplement e33): 6.Google Scholar
  49. 49.
    Jung KS, Park JY, Chon YE, Kim H, Kang W, Kim BK, et al. Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients. J Gastroenterol. 2016;51(8):830–9.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Xia M, Liao G, Chen H, Wu Y, Fan R, Zhang X, et al. Plasma CXCL13 is a predictive factor for HBsAg loss and clinical relapse after discontinuation of nucleos(t)ide analogue treatment. Clin Immunol. 2019;198:31–8.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Kranidioti H, Manolakopoulos S, Kontos G, Breen MS, Kourikou A, Deutsch M, et al. Immunological biomarkers as indicators for outcome after discontinuation of nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B. J Viral Hepat. 2019;26(6):697–709.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    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(10):1656–66.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Blackburn SD, Wherry EJ. IL-10, T cell exhaustion and viral persistence. Trends Microbiol. 2007;15(4):143–6.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Das A, Ellis G, Pallant C, Lopes AR, Khanna P, Peppa D, et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol. 2012;189(8):3925–35.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    •• Zhang Z, Zhou Y, Yang J, Hu K, Huang Y. The effectiveness of TDF versus ETV on incidence of HCC in CHB patients: a meta analysis. BMC Cancer. 2019;19(1):511 Highlights the potential effect of antiviral therapy in HCC development. PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Jeng W, Sheen I, Chen Y, Hsu C, Chien R, Chu C, et al. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology. 2013 Dec;58(6):1888–96.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Maximilian Wübbolding
    • 1
  • Markus Cornberg
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  • Christoph Höner zu Siederdissen
    • 1
  1. 1.Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
  2. 2.German Center for Infection Research (DZIF), partner site Hannover-BraunschweigHannoverGermany
  3. 3.Centre for Individualised Infection Medicine (CIIM)HannoverGermany
  4. 4.Helmholtz Centre for Infection Research (HZI)BraunschweigGermany
  5. 5.Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC)Hannover Medical SchoolHannoverGermany

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