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Therapie der Koinfektion mit Hepatitis-B und -D: Mono- oder Kombinationstherapien mit Peginterferon, Nukleos(t)idanaloga und/oder Myrcludex?

Treatment of hepatitis B and D coinfection: mono- or combination treatment with peginterferon, nucleos(t)ide analogs and/or myrcludex?

Zusammenfassung

Die chronische Koinfektion mit dem Hepatitis-B- (HBV) und dem Hepatitis-Delta-Virus (HDV) stellt die schwerste Form der viralen Hepatitiden dar. Die HDV-Infektion führt oft zu einer Leberzirrhose, einer Leberdekompensation und einem hepatozellulären Karzinom (HCC). Bislang stand zur Behandlung der Hepatitis D nur pegyliertes Interferon α‑2a (PEG-IFNα-2a) zur Verfügung, mit dem jedoch Ansprechraten von lediglich 25–40 % erreicht werden konnten. Darüber hinaus ist bekannt, dass es auch noch Jahre nach Beendigung der antiviralen Therapie zu einem späten Relaps der HDV-RNA kommen kann. Erfreulicherweise sind neue Substanzen zur Behandlung der chronischen Hepatitis D in Entwicklung bzw. bereits zugelassen. Der Entry-Inhibitor Bulevirtid und der Prenylierungsinhibitor Lonafarnib werden derzeit bei Patienten mit chronischer Hepatitis D in klinischen Studien der Phase III untersucht. Zusätzlich wurde im Juli 2020 mit Bulevirtid (2 mg/Tag) erstmals ein Entry-Inhibitor zur Behandlung der chronischen Hepatitis D in Europa zugelassen. Die Daten über die Wirksamkeit und Sicherheit dieser neuen antiviralen Medikamente zur Behandlung der Hepatitis D werden hier zusammengefasst.

Abstract

Persistent coinfection with the hepatitis B (HBV) and hepatitis D virus (HDV) represents the most severe form of viral hepatitis. HDV infection often leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). So far, treatment options are limited as the only antiviral treatment with proven efficacy against HDV is based on administration of type 1 interferons, in clinical practice pegylated interferon alfa-2a (PEG-IFNα-2a). However, treatment response is still unsatisfactory with 25–40% HDV-RNA suppression. In addition, late HDV RNA relapse has been described during long-term follow-up. Fortunately, new treatment options for patients with chronic hepatitis D are currently under clinical investigation or even approved already. The hepatocyte entry inhibitor bulevirtide and the prenylation inhibitor lonafarnib are currently being explored in patients with chronic hepatitis D in phase III clinical studies. In addition, in July 2020, bulevirtide (2 mg/day) was approved in the European Union for the treatment of chronic hepatitis D. We provide a summary of data regarding the efficacy of these new antiviral drugs and the existing safety data on treatment of HDV infection.

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Literatur

  1. 1.

    Hughes SA, Wedemeyer H, Harrison PM (2011) Hepatitis delta virus. Lancet 378(9785):73–85

    PubMed  Google Scholar 

  2. 2.

    Stockdale AJ, Kreuels B, Henrion MYR, Giorgi E, Kyomuhangi I, de Martel C et al (2020) The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol 73(3):523–532

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Chen HY, Shen DT, Ji DZ, Han PC, Zhang WM, Ma JF et al (2019) Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut 68(3):512–521. https://doi.org/10.1136/gutjnl-2018-316601

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Fattovich G, Boscaro S, Noventa F, Pornaro E, Stenico D, Alberti A et al (1987) Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B. J Infect Dis 155(5):931–935

    CAS  PubMed  Google Scholar 

  5. 5.

    Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G et al (2000) Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European concerted action on viral hepatitis (Eurohep). Gut 46(3):420–426

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Niro GA, Smedile A, Ippolito AM, Ciancio A, Fontana R, Olivero A et al (2010) Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol 53(5):834–840

    PubMed  Google Scholar 

  7. 7.

    Yurdaydin C, Keskin O, Kalkan C, Karakaya F, Caliskan A, Kabacam G et al (2018) Interferon treatment duration in patients with chronic delta hepatitis and its effect on the natural course of the disease. J Infect Dis 217(8):1184–1192

    CAS  PubMed  Google Scholar 

  8. 8.

    Fernandez-Montero JV, Vispo E, Barreiro P, Sierra-Enguita R, de Mendoza C, Labarga P et al (2014) Hepatitis delta is a major determinant of liver decompensation events and death in HIV-infected patients. Clin Infect Dis 58(11):1549–1553

    CAS  PubMed  Google Scholar 

  9. 9.

    Wedemeyer H, Manns MP (2010) Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol 7(1):31–40

    PubMed  Google Scholar 

  10. 10.

    Yurdaydin C, Abbas Z, Buti M, Cornberg M, Esteban R, Etzion O et al (2019) Treating chronic hepatitis delta: the need for surrogate markers of treatment efficacy. J Hepatol 70(5):1008–1015

    PubMed  Google Scholar 

  11. 11.

    Spaan M, Carey I, Bruce M, Shang D, Horner M, Dusheiko G et al (2020) Hepatitis delta genotype 5 is associated with favourable disease outcome and better response to treatment compared to genotype 1. J Hepatol 72(6):1097–1104

    CAS  PubMed  Google Scholar 

  12. 12.

    Roulot D, Brichler S, Layese R, BenAbdesselam Z, Zoulim F, Thibault V et al (2020) Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta. J Hepatol 73(5):1046–1062

    CAS  PubMed  Google Scholar 

  13. 13.

    Braga WS, de Oliveira CM, de Araujo JR, Castilho Mda C, Rocha JM, Gimaque JB et al (2014) Chronic HDV/HBV co-infection: predictors of disease stage—a case series of HDV-3 patients. J Hepatol 61(6):1205–1211

    PubMed  Google Scholar 

  14. 14.

    Heidrich B, Manns MP, Wedemeyer H (2013) Treatment options for hepatitis delta virus infection. Curr Infect Dis Rep 15(1):31–38

    PubMed  Google Scholar 

  15. 15.

    Erhardt A, Gerlich W, Starke C, Wend U, Donner A, Sagir A et al (2006) Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int 26(7):805–810

    CAS  PubMed  Google Scholar 

  16. 16.

    Wedemeyer H, Yurdaydin C, Dalekos GN, Erhardt A, Cakaloglu Y, Degertekin H et al (2011) Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 364(4):322–331

    CAS  PubMed  Google Scholar 

  17. 17.

    Wedemeyer H, Yurdaydin C, Hardtke S, Caruntu FA, Curescu MG, Yalcin K et al (2019) Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis 19(3):275–286

    CAS  PubMed  Google Scholar 

  18. 18.

    Heidrich B, Serrano BC, Idilman R, Kabacam G, Bremer B, Raupach R et al (2012) HBeAg-positive hepatitis delta: virological patterns and clinical long-term outcome. Liver Int 32(9):1415–1425

    CAS  PubMed  Google Scholar 

  19. 19.

    Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, Lehmann P et al (2017) Antiviral treatment and liver-related complications in hepatitis delta. Hepatology 65(2):414–425

    CAS  PubMed  Google Scholar 

  20. 20.

    Wranke A, Hardtke S, Heidrich B, Dalekos G, Yalcin K, Tabak F et al (2020) Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta. J Viral Hepat 27(12):1359–1368

    CAS  PubMed  Google Scholar 

  21. 21.

    Strassburg CP, Obermayer-Straub P, Alex B, Durazzo M, Rizzetto M, Tukey RH et al (1996) Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis. Gastroenterology 111(6):1576–1586

    CAS  PubMed  Google Scholar 

  22. 22.

    Strassburg CP, Obermayer-Straub P, Manns MP (1996) Autoimmunity in hepatitis C and D virus infection. J Viral Hepat 3(2):49–59

    CAS  PubMed  Google Scholar 

  23. 23.

    Heidrich B, Yurdaydin C, Kabacam G, Ratsch BA, Zachou K, Bremer B et al (2014) Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology 60(1):87–97

    CAS  PubMed  Google Scholar 

  24. 24.

    Bremer B, Anastasiou OE, Hardtke S, Caruntu FA, Curescu MG, Yalcin K et al (2021) Residual low HDV viraemia is associated HDV RNA relapse after PEG-IFna-based antiviral treatment of hepatitis delta: results from the HIDIT-II study. Liver Int 41(2):295–299. https://doi.org/10.1111/liv.14740

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Lazear HM, Schoggins JW, Diamond MS (2019) Shared and distinct functions of type I and type III interferons. Immunity 50(4):907–923

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Hamid SS, Etzion O, Lurie Y, Bader N, Yardeni D, Channa SM et al (2017) A phase 2 randomized clinical trial to evaluate the safety and efficacy of pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection. Interim results from the LIMT HDV study (abstr.). Hepatology 66:496A

    Google Scholar 

  27. 27.

    Etzion O, Hamid S, Lurie Y, Gane E, Bader N, Yardeni D et al (2019) End of study results from LIMT HDV study: 36 % durable virologic response at 24 weeks post-treatment with pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection. J Hepatol 70:e32

    Google Scholar 

  28. 28.

    Koh C, Hercun J, Rahman F, Huang A, Da B, Surana P et al (2020) A phase 2 study of peginterferon lambda, lonafarnib and ritonavir for 24 weeks: end-of-treatment results from the LIFT HDV study. J Hepatol 73:S130

    Google Scholar 

  29. 29.

    Gunsar F, Akarca US, Ersoz G, Kobak AC, Karasu Z, Yuce G et al (2005) Two-year interferon therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther 10(6):721–726

    CAS  PubMed  Google Scholar 

  30. 30.

    Yurdaydin C, Bozkaya H, Onder FO, Senturk H, Karaaslan H, Akdogan M et al (2008) Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J Viral Hepat 15(4):314–321

    CAS  PubMed  Google Scholar 

  31. 31.

    Sheldon J, Ramos B, Toro C, Rios P, Martinez-Alarcon J, Bottecchia M et al (2008) Does treatment of hepatitis B virus (HBV) infection reduce hepatitis delta virus (HDV) replication in HIV-HBV-HDV-coinfected patients? Antivir ther 13(1):97–102

    CAS  PubMed  Google Scholar 

  32. 32.

    Soriano V, Vispo E, Sierra-Enguita R, Mendoza C, Fernandez-Montero JV, Labarga P et al (2014) Efficacy of prolonged tenofovir therapy on hepatitis delta in HIV-infected patients. AIDS 28(16):2389–2394

    CAS  PubMed  Google Scholar 

  33. 33.

    Beguelin C, Friolet N, Moradpour D, Sahli R, Suter-Riniker F, Luthi A et al (2017) Impact of tenofovir on hepatitis delta virus replication in the Swiss human immunodeficiency virus cohort study. Clin Infect Dis 64(9):1275–1278

    PubMed  Google Scholar 

  34. 34.

    European Association for the Study of the Liver (2017) EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 67(2):370–398

    Google Scholar 

  35. 35.

    Wedemeyer H (2010) Re-emerging interest in hepatitis delta: new insights into the dynamic interplay between HBV and HDV. J Hepatol 52(5):627–629

    PubMed  Google Scholar 

  36. 36.

    Urban S, Bartenschlager R, Kubitz R, Zoulim F (2014) Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 147(1):48–64

    CAS  PubMed  Google Scholar 

  37. 37.

    Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M et al (2016) Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol 65(3):490–498

    CAS  PubMed  Google Scholar 

  38. 38.

    Wedemeyer H, Bogomolov P, Blank A, Allweiss L, Dandri-Petersen M, Bremer B et al (2018) Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of myrcludex B in combination with tenofovir in patients with chronic HBV/HDV co-infection. J Hepatol 68:S3

    Google Scholar 

  39. 39.

    Wedemeyer H, Schöneweis K, Bogomolov PO, Voronkova N, Chulanov V, Stepanova T et al (2019) Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in combination with PEG-interferon alpha 2a in patients with chronic HBV/HDV co-infection. J Hepatol 70:GS-13

    Google Scholar 

  40. 40.

    Wedemeyer H, Schöneweis K, Bogomolov PO, Chulanov V, Stepanova T, Viacheslav M et al (2020) 48 weeks of high dose (10 mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV co-infection. J Hepatol 73:S19–S57

    Google Scholar 

  41. 41.

    Wedemeyer H, Aleman S, Andreone P, Blank A, Brunetto M, Bogolomov P et al (2021) Bulevirtide monotherapy at low and high doses in patients with chronic hepatitis delta: 24-week interim data of the phase 3 MYR301 study. J Hepatol 75(2):S294–S803

    Google Scholar 

  42. 42.

    Asselah T, Arama S, Bogomolov P, Bourliere M, Fontaine H, Gherlan G et al (2021) Safety and efficacy of bulevirtide monotherapy and in combination with peginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data of MYR204 phase 2b study. J Hepatol 75(2):S201–S293

    Google Scholar 

  43. 43.

    Koh C, Canini L, Dahari H, Zhao X, Uprichard SL, Haynes-Williams V et al (2015) Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis 15(10):1167–1174

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Yurdaydin C, Keskin O, Kalkan C, Karakaya F, Caliskan A, Karatayli E et al (2018) Optimizing lonafarnib treatment for the management of chronic delta hepatitis: the LOWR HDV‑1 study. Hepatology 67(4):1224–1236

    CAS  PubMed  Google Scholar 

  45. 45.

    Yurdaydin C, Kalkan C, Karakaya F, Caliskan A, Karatayli S, Keskin O et al (2018) Subanalysis of the LOWR HDV‑2 study reveals high response rates to lonafarnib in patients with low viral loads. J Hepatol 68:S89

    Google Scholar 

  46. 46.

    Bazinet MPV, Cebotarescu V, Cojuhari L, Jimbei P, Vaillant A (2018) Establishment of persistent functional remission of HBV and HDV infection following REP 2139 and pegylated interferon alpha 2a therapy in patients with chronic HBV/HDV co-infection: 18 month follow-up results from the REP 301-LTF study. J Hepatol 68:S509

    Google Scholar 

  47. 47.

    Bazinet M, Pantea V, Cebotarescu V, Cojuhari L, Jimbei P, Anderson M et al (2021) Persistent control of hepatitis B virus and hepatitis delta virus infection following REP 2139-ca and pegylated interferon therapy in chronic hepatitis B virus/hepatitis delta virus coinfection. Hepatol Commun 5(2):189–202

    CAS  PubMed  Google Scholar 

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Correspondence to Katja Deterding.

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K. Deterding weist auf folgende Beziehungen hin: Vortragshonorare und Reisekostenerstattung von Gilead, MSD/Merck, Falk, Alnylam, AbbVie.

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

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Stefan Zeuzem, Frankfurt am Main

Heiner Wedemeyer, Hannover

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Deterding, K. Therapie der Koinfektion mit Hepatitis-B und -D: Mono- oder Kombinationstherapien mit Peginterferon, Nukleos(t)idanaloga und/oder Myrcludex?. Gastroenterologe 16, 433–441 (2021). https://doi.org/10.1007/s11377-021-00565-9

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Schlüsselwörter

  • Hepatitisviren
  • Bulevirtid
  • Lonafarnib
  • Peginterferon α-2a
  • Chronische Hepatitis

Keywords

  • Hepatitis viruses
  • Bulevirtide
  • Lonafarnib
  • Peginterferon alfa-2a
  • Chronic hepatitis