Skip to main content
SpringerLink
Log in

Hepatitis B: Wann ist eine Beendigung der Therapie mit Nukleos(t)idanaloga gerechtfertigt?

Hepatitis B: when is discontinuation of treatment with nucleos(t)ide analogues justified?

  • Schwerpunkt
  • Published:
Der Gastroenterologe Aims and scope

Zusammenfassung

Durch die Langzeitbehandlung der chronischen Hepatitis B mit Nukleos(t)idanaloga (NA) kann der Progress dieser chronischen Lebererkrankung effektiv verhindert, in vielen Fällen auch eine Regression der Fibrosestadiums erreicht und das Risiko der Entwicklung eines hepatozellulären Karzinoms (HCC) deutlich gesenkt werden. Etablierter Endpunkt der NA-Therapie ist das Erreichen eines HBsAg(„hepatitis B surface antigen“)-Verlustes (sog. funktionelle Heilung). Ein weiterer, in internationalen Leitlinien akzeptierter Endpunkt ist die HBeAg(„hepatitis B early antigen“)-Serokonversion bei zum Therapiebeginn HBeAg-positiven Patienten. Reaktivierungen der Krankheitsaktivität sowie HBeAg-Seroreversionen können jedoch, trotz einer 12-monatigen Konsolidierungsbehandlung, bei bis zu 50 % dieser Patienten im Verlauf nach Absetzen der NA-Behandlung auftreten. Bei Patienten mit kompensierter Leberzirrhose soll die Therapie ausschließlich bei Erreichen einer funktionellen Heilung beendet werden. Das Beenden der Langzeit-NA-Therapie bei Patienten mit HBeAg-negativer Hepatitis B vor Eintreten des HBsAg-Verlustes ist ein neues und umstrittenes Konzept, da es nach Absetzen der NA regelhaft zu einem Widerauftreten der HBV-Replikation kommt. Es hat sich jedoch gezeigt, dass es in Folge der HBV-Reaktivierung bei bis zu 30 % der Patienten zu einer funktionellen Heilung kommt sowie bei bis zu 50 % der Patienten zu einem Übergang in eine inaktive Phase ohne weitere Therapieindikation. Unter engmaschiger Kontrolle der Hepatitis-B-Virus-DNA und der Transaminasen und rechtzeitiger Retherapie im Falle eines schweren biochemischen Flares ist dieses auch als Autovakzinierung bezeichnete Konzept der relapsinduzierten funktionellen Heilung sicher anwendbar.

Abstract

Long-term treatment of chronic hepatitis B with nucleos(t)ide analogues (NA) can effectively prevent the progression of this chronic liver disease, in many cases also achieve regression of the fibrosis stage and significantly reduce the risk of developing hepatocellular carcinoma (HCC). The established endpoint of NA treatment is the achievement of loss of the hepatitis B surface antigen (HBsAg, a so-called functional cure). Another endpoint accepted in international guidelines is seroconversion of hepatitis B early antigen (HBeAg) in patients positive for HBeAg at the start of treatment; however, reactivation of disease activity as well as HBeAg seroreversion can occur in up to 50% of these patients after discontinuation of NA treatment, despite 12 months of consolidation treatment. In patients with compensated liver cirrhosis, treatment should only be discontinued when functional recovery is achieved. Stopping long-term NA treatment in patients with HBeAg-negative hepatitis B before HBsAg loss occurs is a new and controversial concept as hepatitis B virus (HBV) replication usually reoccurs after stopping NA; however, it has been shown that HBV reactivation leads to functional recovery in up to 30% of patients and to a transition to an inactive phase without further indications for treatment in up to 50% of patients. Under close monitoring of HBV DNA and transaminases and timely retreatment in cases of severe biochemical flares, this relapse-induced functional cure, a concept also known as autovaccination, can be safely applied.

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

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Literatur

  1. World Health Organization (2020) Hepatitis B. https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-b. Zugegriffen: 12.2020

  2. Weinbaum CM, Mast EE, Ward JW (2009) Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. Hepatology 49(Suppl):S35–S44

    Article  Google Scholar 

  3. Liaw YF, Chu CM (2009) Hepatitis B virus infection. Lancet 373:582–592

    Article  CAS  Google Scholar 

  4. Zoulim F (2018) Inhibition of hepatitis B virus gene expression: a step towards functional cure. J Hepatol 68:386–388

    Article  Google Scholar 

  5. Marcellin P, Gane EJ, Flisiak R, Trinh H, Petersen J, Gurel S et al (2014) Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials. Hepatology 60:313A–317A

    Article  Google Scholar 

  6. Lampertico P, Agarwal K, Berg T, Buti M, Janssen HLA, Papatheodoridis G et al (2017) EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 67:370–398

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Terrault NA, Lok ASF, McMahon BJ, Chang K‑M, Hwang JP, Jonas MM et al (2018) Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67:1560–1599

    Article  Google Scholar 

  9. Cornberg M, Sandmann L, Protzer U, Niederau C, Tacke F, Berg T, Glebe D, Jilg W, Wedemeyer H, Wirth S, Höner Zu Siederdissen C, Lynen-Jansen P, van Leeuwen P, Petersen J (2021) S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion – (AWMF-Register-Nr. 021-11). Z Gastroenterol 59(7):691–776

    Article  Google Scholar 

  10. Papatheodoridis G, Vlachogiannakos I, Cholongitas E, Wursthorn K, Thomadakis C, Touloumi G et al (2016) Discontinuation of oral antivirals in chronic hepatitis B: a systematic review. Hepatology 63:1481–1492

    Article  CAS  Google Scholar 

  11. Qiu YW, Huang LH, Yang WL et al (2016) 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 43:43–48

    Article  CAS  Google Scholar 

  12. Chi H, Hansen BE, Arends P, Abu-Amara M, Yim C, Feld JJ et al (2014) Long-term nucleos(t)ide analogue consolidation therapy reduces risk of relapse in chronic hepatitis B. Hepatology 60:1090A–1091A

    Google Scholar 

  13. Hadziyannis SJ, Seveastianos V, Rapti IN, Vassilopoulos D, Hadziyannis E (2006) Sustained biochemical and virological remission after discontinuation of 4 to 5 years of adefovir dipivoxil (ADV) treatment in HBeAg-negative chronic hepatitis B. Hepatology 44(Suppl 1):231A

    Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Liu F, Wang L, Li XY, Liu YD, Wang JB, Zhang ZH et al (2011) 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 26:456–460

    Article  Google Scholar 

  16. He D, Guo S, Chen W, Chen X, Yan G, Wang J et al (2013) Long-term outcomes after nucleos(t)ide analogues discontinuation in chronic hepatitis B patients with HBeAg-negative. BMC Infect Dis 13:458. https://doi.org/10.1186/1471-2334-13-458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim YJ, Kim K, Hwang SH, Kim SS, Lee D, Cheong JY et al (2013) Durability after discontinuation of nucleos(t)ide therapy in chronic HBeAg negative hepatitis patients. Clin Mol Hepatol 19:300–304

    Article  Google Scholar 

  18. Karakaya F, Özer S, Kalkan Ç, Tüzün EA, Çalışkan A, Keskin O et al (2017) Discontinuation of lamivudine treatment in HBeAg-negative chronic hepatitis B: a pilot study with long-term follow-up. Antivir Ther 22:559–570

    Article  Google Scholar 

  19. Cao J, Chi H, Yu T, Li Z, Hansen BE, Zhang X et al (2017) Off-treatment hepatitis B virus (HBV) DNA levels and the prediction of relapse after discontinuation of nucleos(t)ide analogue therapy in patients with chronic hepatitis B: a prospective Stop study. J Infect Dis 215:581–589

    Article  CAS  Google Scholar 

  20. Liem KS, Fung S, Wong DK, Yim C, Noureldin S, Chen J et al (2019) 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 68:2206–2213

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Seto WK, Hui AJ, Wong VW, Wong GL, Liu KS, Lai CL et al (2014) Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study. Gut 64:667–672

    Article  Google Scholar 

  23. Rivino L, Le Bert N, Gill US, Kunasegaran K, Cheng Y, Tan DZ, Becht E, Hansi NK, Foster GR, Su TH, Tseng TC, Lim SG, Kao JH, Newell EW, Kennedy PT, Bertoletti A (2018) Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J Clin Invest 128(2):668–681

    Article  Google Scholar 

  24. Papatheodoridis GV, Rigopoulou E, Papatheodoriri M, Zachou K, Xourafas V, Gatselis NK et al (2017) DARING-B: discontinuation of effective entecavir (ETV) or tenofovir (TDF) therapy in non-cirrhotic HBeAg-negative chronic hepatitis B (CHBe-) patients: final results of a prospective Greek study. Hepatology 66:492A

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. van Bömmel F, Berg T (2021) Risks and benefits of discontinuation of nucleos(t)ide analogue treatment: a treatment concept for patients with HBeAg-negative chronic hepatitis B. Hepatol Commun. https://doi.org/10.1002/hep4.1708

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Lampertico P, Berg T (2018) Less can be more: a finite treatment approach for HBeAg-negative chronic hepatitis B. Hepatology 68:397–400

    Article  Google Scholar 

  29. van Bömmel F, Stein K, Heyne R, Möller H, Petersen J, Buggisch P et al (2020) Response to discontinuation of long-term nucleos(t)ide analogue treatment in HBeAg negative patients: results of the Stop-NUC trial. J Hepatol 73(Suppl 1):S118–S119

    Article  Google Scholar 

  30. Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF (2018) 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 68:425–434

    Article  CAS  Google Scholar 

  31. Carey I, Gersch J, Wang BO, Moigboi C, Kuhns M, Cloherty G et al (2020) Pregenomic HBV RNA and hepatitis B core-related antigen predict outcomes in hepatitis B e antigen-negative chronic hepatitis B patients suppressed on nucleos(t)ide analogue therapy. Hepatology 72:42–57

    Article  CAS  Google Scholar 

  32. Fan R, Zhou B, Xu M, Tan D, Niu J, Wang H et al (2020) Chronic Hepatitis B Study Consortium. Association between negative results from tests for HBV DNA and RNA and durability of response after discontinuation of nucleos(t)ide analogue therapy. Clin Gastroenterol Hepatol 18:719–727

    Article  CAS  Google Scholar 

  33. Hsu Y‑C, Nguyen MH, Mo L‑R, Wu M‑S, Yang T‑H, Chen C‑C et al (2019) Combining hepatitis B core-related and surface antigens at end of nucleos(t)ide analogue treatment to predict off-therapy relapse risk. Aliment Pharmacol Ther 49:107–115

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Abteilung für Hepatologie, Medizinische Klinik II, Universitätsklinikum Leipzig, Liebigstraße 20, 04103, Leipzig, Deutschland

    F. van Bömmel & T. Berg

Authors
  1. F. van Bömmel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. van Bömmel.

Ethics declarations

Interessenkonflikt

F. van Bömmel und T. Berg geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

Stefan Zeuzem, Frankfurt am Main

Heiner Wedemeyer, Hannover

figure qr

QR-Code scannen & Beitrag online lesen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van Bömmel, F., Berg, T. Hepatitis B: Wann ist eine Beendigung der Therapie mit Nukleos(t)idanaloga gerechtfertigt?. Gastroenterologe 16, 417–432 (2021). https://doi.org/10.1007/s11377-021-00572-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11377-021-00572-w

Schlüsselwörter

Keywords

Search

Navigation