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Langzeittherapie der HBV-Infektion mit oralen Polymeraseinhibitoren

Long-term treatment of HBV infection with oral polymerase inhibitors

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Zusammenfassung

Das Ziel der Langzeitbehandlung der chronischen Hepatitis-B-Virus(HBV)-Infektion mit Nukleosid-/Nukleotidanaloga (NA) ist die Senkung der mit der Infektion assoziierten Morbidität und Letalität durch Verhinderung der Entstehung einer Leberzirrhose und eines hepatozellulären Karzinoms (HCC). Die NA-Behandlung ist aufgrund ihrer hohen Wirksamkeit, ihrer guten Verträglichkeit sowie ihres nachgewiesenermaßen günstigen Effekts auf Komplikationen der chronischen Hepatitis B weltweit zum Standard geworden. So wird beim Einsatz der hochaktiven Substanzen Entecavir bzw. Tenofovir eine komplette Suppression der HBV-Replikation bei fast allen HB-envelope-Antigen(eAg)-positiven und HBeAg-negativen Patienten (> 98 %) innerhalb von 2 Jahren erreicht. Die effektive Suppression der HBV-Replikation führt im Langzeitverlauf zu einem Rückgang der hepatischen inflammatorischen Aktivität und zum Stoppen der Fibroseprogression und häufig zu einer Regression der Fibrose. Auch sinkt ab einer Behandlungsdauer von 3–4 Jahren das Risiko einer HCC-Entstehung. Resistenzentwicklungen spielen inzwischen beim Einsatz hochaktiver Substanzen eine untergeordnete Rolle und treten unter Entecavir bei unvorbehandelten Patienten in etwa 1 % auf. Gegenüber Tenofovir sind bislang noch keine Resistenzen beobachtet worden. Eine serologische Response mit Verlust von HB-surface(s)-Ag kann als klinische Ausheilung der HBV-Infektion angesehen werden, wird jedoch selbst nach jahrelanger NA-Therapie nur selten erreicht. Die Dauer der Behandlung ist somit für die meisten HBeAg-positiven und fast alle HBeAg-negativen Patienten nicht definiert und wahrscheinlich lebenslang.

Abstract

Long-term treatment of chronic hepatitis B virus (HBV) infections with nucleoside/nucleotide analogues (NA) aims at decreasing mortality due to HBV infections by decreasing the incidence of liver cirrhosis and hepatocellular carcinomas (HCCs). The endpoint of long-term NA treatment is serologic response which allows cessation of treatment. Treatment of chronic HBV infections with NA has become the global standard due to the high antiviral efficacy, good tolerability, and their positive effect on long-term complications. Thus, complete suppression of HBV DNA can be achieved in almost all HB envelope antigen (eAg)-positive and HBeAg-negative patients (> 98 %), who receive entecavir or tenofovir for 2 years, while resistance development against entecavir is rare (approximately 1 %) and has to date not been observed against tenofovir. After 5 years of treatment, significant regression of fibrosis and even of cirrhosis was observed in the majority of patients. The risk of development of HCCs seems to be decreased after HBV replication suppression by NA treatment for 3–4 years. The limitation of long-term treatment with NA is the limited rate of serologic response, which does not seem to increase further between the 5th and 8th year of treatment. The duration of NA treatment is, thus, undefined for the majority of patients and is probably life long.

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Literatur

  1. Cornberg M, Protzer U, Petersen J et al (2011) Prophylaxis, diagnosis and therapy of hepatitis B virus infection – the German guideline. Z Gastroenterol 49:871–930

    Article  CAS  PubMed  Google Scholar 

  2. European Association For The Study Of The Liver (2012) EASL Clinical Practice Guidelines: management of chronic hepatitis B virus infection. J Hepatol 57:167–185

    Article  Google Scholar 

  3. Zoulim F, Locarnini S (2009) Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 137:1593–608

    Article  CAS  PubMed  Google Scholar 

  4. Gish R, Jia JD, Locarnini S, Zoulim F (2012) Selection of chronic hepatitis B therapy with high barrier to resistance. Lancet Infect Dis 12:341–353

    Article  PubMed  Google Scholar 

  5. Levrero M, Pollicino T, Petersen J et al (2009) Control of cccDNA function in hepatitis B virus infection. J Hepatol 51:581–592

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Yu XP, Guo RY, Su ML et al (2013) Dynamic changes of Treg and Th17 cells and related cytokines closely correlate with the virological and biochemical response in chronic Hepatitis B patients undergoing nucleos(t)ide analogues treatment. Hepat Mon 13(12):e15332

    Article  PubMed Central  PubMed  Google Scholar 

  8. Lok AS, McMahon BJ (2007) Chronic hepatitis B. Hepatology 45:507–539

    Article  CAS  PubMed  Google Scholar 

  9. Lok AS, McMahon BJ (2009) Chronic hepatitis B: update 2009. Hepatology 50:661–662

    Article  PubMed  Google Scholar 

  10. Marcellin P, Gane EJ, Flisiak R 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. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston. Abstract 229

  11. Snow-Lampart A, Chappell B, Curtis M et al (2011) No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus. Hepatology 53(3):763–773

    Article  CAS  PubMed  Google Scholar 

  12. Gordon SC, Krastev Z, Horban A et al (2013) Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load. Hepatology 58:505–513

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Chang TT, Lai CL, Kew Yoon S et al (2010) Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 51:422–430

    Article  CAS  PubMed  Google Scholar 

  14. Shouval D, Lai CL, Chang TT et al (2008) Three years of entecavir re-treatment of HBeAg (−) entecavir patients who previously discontinued entecavir therapy: results from study ETV-901. Hepatology 48(Suppl 1):Abstract 927

    Google Scholar 

  15. Tenney DJ, Rose RE, Baldick CJ et al (2009) Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology 49:1503–1514

    Article  CAS  PubMed  Google Scholar 

  16. Sherman M, Yurdaydin C, Sollano J et al (2006) Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 130:2039–2049

    Article  CAS  PubMed  Google Scholar 

  17. Lim YS, Yoo BC, Byun KS et al (2015) Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial. Gut. pii: gutjnl-2014-308435 (Epub ahead of print)

  18. Berg T, Marcellin P, Zoulim F et al (2010) Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis B virus infection. Gastroenterology 139:1207–1217

    Article  CAS  PubMed  Google Scholar 

  19. Berg T, Zoulim F, Moeller B et al (2014) Long-term efficacy and safety of emtricitabine plus tenofovir DF vs. tenofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients. J Hepatol 60:715–722

    Article  CAS  PubMed  Google Scholar 

  20. Petersen J, Ratziu V, Buti M et al (2012) Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: an international multicenter cohort study. J Hepatol 56(3):520–526

    Article  CAS  PubMed  Google Scholar 

  21. Marcellin P, Gane E, Buti M et al (2013) Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-lable follow-up study. Lancet 381:468–475

    Article  CAS  PubMed  Google Scholar 

  22. Chen YC, Chu CM, Liaw YF (2010) Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B. Hepatology 51:435–444

    Article  PubMed  Google Scholar 

  23. Lampertico P, Liaw YF (2012) New perspectives in the therapy of chronic hepatitis B. Gut 61:18–24

    Article  Google Scholar 

  24. Scaglione SJ, Lok AS (2012) Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology 142:1360–1368

    Article  PubMed  Google Scholar 

  25. Kao JH (2014) HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated interferon? Liver Int 34:112–119

    Article  CAS  PubMed  Google Scholar 

  26. Papatheodoridis G, Goulis J, Manolakopoulos S et al (2014) 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 60:62–68

    Article  CAS  PubMed  Google Scholar 

  27. Lee JM, Ahn SH, Kim HS et al (2011) Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir. Hepatology 53:1486–1493

    Article  PubMed  Google Scholar 

  28. Bömmel F van, Bartens A, Mysickova A et al (2015) Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology 61:66–76

    Article  PubMed  Google Scholar 

  29. Chan HL, Wong ML, Hui AY et al (2003) Use of hepatitis B virus DNA quantitation to predict hepatitis B e antigen reversion in cases of chronic hepatitis B. J Clin Microbiol 41:4793–4795

    Article  PubMed Central  PubMed  Google Scholar 

  30. Tseng TC, Liu CJ, Su TH et al (2012) Young chronic hepatitis B patients with nucleos(t)ide analogue-induced hepatitis B e antigen seroconversion have a higher risk of HBV reactivation. J Infect Dis 206:1521–1531

    Article  PubMed  Google Scholar 

  31. Wong VW, Wong GL, Yan KK et al (2010) Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis. Hepatology 51:1945–1953

    Article  CAS  PubMed  Google Scholar 

  32. Buster EH, Hansen BE, Lau GK et al (2009) Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology 137:2002–2009

    Article  CAS  PubMed  Google Scholar 

  33. Gish RG, Chang TT, Lai CL et al (2010) Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. J Viral Hepat 17:16–22

    Article  CAS  PubMed  Google Scholar 

  34. Marcellin P, Heathcote EJ, Buti M et al (2008) Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 359:2442–2455

    Article  CAS  PubMed  Google Scholar 

  35. Gish RG, Chang TT, Lai CL et al (2013) Quantitative hepatitis B surface antigen analysis in hepatitis B e antigen-positive nucleoside-naive patients treated with entecavir. Antivir Ther 18:691–698

    Article  CAS  PubMed  Google Scholar 

  36. Marcellin P, Buti M, Krastev Z et al (2014) Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate. J Hepatol 61:1228–1237

    Article  CAS  PubMed  Google Scholar 

  37. Zoutendijk R, Reijnders JG, Brown A et al (2011) Entecavir treatment for chronic hepatitis B: adaptation is not needed for the majority of naïve patients with a partial virological response. Hepatology 54:443–451

    Article  CAS  PubMed  Google Scholar 

  38. Ono A, Suzuki F, Kawamura Y et al (2012) Long-term continuous entecavir therapy in nucleos(t)ide-naïve chronic hepatitis B patients. J Hepatol 57:508–514

    Article  CAS  PubMed  Google Scholar 

  39. Lampertico P, Soffredini R, Facchetti F et al (2012) Tenofovir monotherapy suppressed viral suppression in most field practice, treatment-naïve patients with chronic hepatitis B followed for 3 years in a multicenter European study. Hepatology 56(Suppl 1):Abstract 401

    Google Scholar 

  40. Petersen J, Heyne R, Mauss S et al (2013) Effectiveness of tenofovir for chronic hepatitis B in field practice – 2 year interim results from the prospective German multicenter non-interventional study (GEMINIS). J Hepatol 58(Suppl 1):Abstract 768

    Google Scholar 

  41. Goodman ZD, Afdhal NH, Buti M et al (2013) Morphometric assessment of quantitative collagen and liver fibrosis in patients with Chronic Hepatitis B (CHB) treated for up to five years with Tenofovir Disoproxil Fumarate (TDF). Hepatology 58:596A–p597A

    Google Scholar 

  42. Buti M, Washington MK, Gane E et al (2014) Hepatic steatosis does not predict regression of liver cirrhosis in chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF). J Hepatol 58(Suppl 1):Poster 677

    Google Scholar 

  43. Chen CJ, Yang HI, Su J et al (2006) Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295(1):65–73

    Article  CAS  PubMed  Google Scholar 

  44. Kew MC (2011) Hepatitis B virus x protein in the pathogenesis of hepatitis B virus induced hepatocellular carcinoma. J Gastroenterol Hepatol 26

  45. Arzumanyan A, Reis HM, Feitelson MA (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 13:123–135

    Article  CAS  PubMed  Google Scholar 

  46. Wong GL, Chan HL, Yiu KK et al (2013) Meta-analysis: the association of hepatitis B virus genotypes and hepatocellular carcinoma. Aliment Pharmacol Ther 37:517–526

    Article  CAS  PubMed  Google Scholar 

  47. Papatheodoridis GV, Dalekos GN, Yurdaydin C et al (2015) Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir. J Hepatol 62(2):363–370

    Article  CAS  PubMed  Google Scholar 

  48. Wu CY, Lin JT, Ho HJ et al (2014) Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study. Gastroenterology 147:143–151

    Article  CAS  PubMed  Google Scholar 

  49. Liaw YF, Sung JJ, Chow WC et al (2004) Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 351:1521–1531

    Article  CAS  PubMed  Google Scholar 

  50. Singal AK, Salameh H, Kuo YF, Fontana RJ (2013) Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 38:98–106

    Article  CAS  PubMed  Google Scholar 

  51. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A (2010) Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol 53:348–356

    Article  CAS  PubMed  Google Scholar 

  52. Hosaka T, Suzuki F, Kobayashi M et al (2013) Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 58:98–107

    Article  CAS  PubMed  Google Scholar 

  53. Lim YS, Han S, Heo NY et al (2014) Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine. Gastroenterology 147:152–161

    Article  CAS  PubMed  Google Scholar 

  54. Yang HI, Yuen MF, Chan HL et al (2011) Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol 12:568–574

    Article  PubMed  Google Scholar 

  55. Lee MH, Yang HI, Liu J et al (2013) Prediction models of long-term cirrhosis and HCC risk in chronic hepatitis B patients: risk scores integrating host and virus profiles. Hepatology 58:546–554

    Article  CAS  PubMed  Google Scholar 

  56. Kim WR, Berg T, Loomba R et al (2013) Long term Tenofovir Disoproxil Fumarate (Tdf) therapy and the risk of Hepatocellular Carcinoma. J Hepatol 58:S19–S19

    Article  Google Scholar 

  57. Wong VW, Chan SL, Mo F et al (2010) Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J Clin Oncol 28:1660–1665

    Article  CAS  PubMed  Google Scholar 

  58. Yuen MF, Tanaka Y, Fong DY et al (2009) Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol 50:80–88

    Article  PubMed  Google Scholar 

  59. Wong GL, Chan HL, Chan HY et al (2013) Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment. Gastroenterology 144:933–944

    Article  PubMed  Google Scholar 

  60. Arends P, Sonneveld MJ, Zoutendijk R et al (2014) Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. Gut. doi:10.1136/gutjnl-2014-307023 (Epub ahead of print)

  61. Papatheodoridis G, Dalekos G, Sypsa V et al (2014) PAGE-B: risk score for hepatocellular carcinoma (HCC) development in Caucasian chronic hepatitis B (CHB) patients receiving entecavir (ETV) or tenofovir (TDF). J Hepatol 60:S435

    Article  Google Scholar 

  62. Cho JY, Paik YH, Sohn W et al (2014) Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease. Gut 63:1943–1950

    Article  CAS  PubMed  Google Scholar 

  63. Manns MP, Akarca US, Chang TT et al (2012) Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901. Expert Opin Drug Saf 11:361–368

    Article  CAS  PubMed  Google Scholar 

  64. Viganò M, Brocchieri A, Spinetti A et al (2014) Tenofovir-induced Fanconi syndrome in chronic hepatitis B monoinfected patients that reverted after tenofovir withdrawal. J Clin Virol 61:600–603

    Article  PubMed  Google Scholar 

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Einhaltung ethischer Richtlinien

Interessenkonflikt. T. Berg gibt Tätigkeiten als Berater, Referent und Investigator für die Firmen AbbVie, Bristol-Myers Squibb, Gilead, Novartis, MSO, Janssen und Roche an. F. van Bömmel gibt Beratertätigkeiten für die Firmen Gilead, Bristol-Myers Squibb und Roche sowie Referententätigkeiten für die Firmen Gilead, Bristol-Myers Squibb, Roche, AbbVie und Janssen an.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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  1. Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Liebigstr. 20, 04103, Leipzig, Deutschland

    F. van Bömmel &  T. Berg

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van Bömmel, F., Berg, T. Langzeittherapie der HBV-Infektion mit oralen Polymeraseinhibitoren. Gastroenterologe 10, 268–283 (2015). https://doi.org/10.1007/s11377-015-0998-4

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