Antiviral Therapy of Chronic Hepatitis D Virus Infection – Addendum to the S3 Guideline “Prophylaxis, Diagnosis and Therapy of Hepatitis B Virus Infection” of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS)^[1]

Key words

bulevirtide - liver diseases - liver cirrhosis - co-infections - therapy - HDV infection - HDV - Hepatitis D

¹ We would like to dedicate this Addendum to Mr. Egbert Trowe, a patient representative with heart and soul, who unfortunately left us much too early.

Publikationsverlauf

Eingereicht: 06. September 2023

Angenommen: 24. September 2023

Artikel online veröffentlicht:
11. Dezember 2023

• References

• 1 Cornberg M, Sandmann L, Protzer U. et al. 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 2021; 59: 691-776
• 2 Fattovich G, Boscaro S, Noventa F. et al. Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B. J Infect Dis 1987; 155: 931-935
• 3 Fattovich G, Giustina G, Christensen E. et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut 2000; 46: 420-426
• 4 Miao Z, Zhang S, Ou X. et al. Estimating the Global Prevalence, Disease Progression, and Clinical Outcome of Hepatitis Delta Virus Infection. J Infect Dis 2020; 221: 1677-1687
• 5 Stockdale AJ, Kreuels B, Henrion MYR. et al. The global prevalence of hepatitis D virus infection: Systematic review and meta-analysis. J Hepatol 2020; 73: 523-532
• 6 Béguelin C, Moradpour D, Sahli R. et al. Hepatitis delta-associated mortality in HIV/HBV-coinfected patients. J Hepatol 2017; 66: 297-303
• 7 Kamal H, Westman G, Falconer K. et al. Long-Term Study of Hepatitis Delta Virus Infection at Secondary Care Centers: The Impact of Viremia on Liver-Related Outcomes. Hepatology 2020; 72: 1177-1190
• 8 Alfaiate D, Clément S, Gomes D. et al. Chronic hepatitis D and hepatocellular carcinoma: A systematic review and meta-analysis of observational studies. J Hepatol 2020; 73: 533-539
• 9 Kamal H, Fornes R, Simin J. et al. Risk of hepatocellular carcinoma in hepatitis B and D virus co-infected patients: A systematic review and meta-analysis of longitudinal studies. J Viral Hepat 2021;
• 10 Le Gal F, Brichler S, Sahli R. et al. First international external quality assessment for hepatitis delta virus RNA quantification in plasma. Hepatology 2016; 64: 1483-1494
• 11 Bremer B, Anastasiou OE, Ciesek S. et al. Automated nucleic acid isolation methods for HDV viral load quantification can lead to viral load underestimation. Antivir Ther 2019; 24: 117-123
• 12 Rizzetto M, Verme G, Recchia S. et al. Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med 1983; 98: 437-441
• 13 Yurdaydın C, Idilman R, Bozkaya H. et al. Natural history and treatment of chronic delta hepatitis. J Viral Hepat 2010; 17: 749-756
• 14 Saracco G, Rosina F, Brunetto MR. et al. Rapidly progressive HBsAg-positive hepatitis in Italy. The role of hepatitis delta virus infection. J Hepatol 1987; 5: 274-281
• 15 Gheorghe L, Iacob S, Simionov I. et al. Natural history of compensated viral B and D cirrhosis. Rom J Gastroenterol 2005; 14: 329-335
• 16 Roulot D, Brichler S, Layese R. et al. Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta. J Hepatol 2020; 73: 1046-1062
• 17 Palom A, Rodríguez-Tajes S, Navascués CA. et al. Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia. Aliment Pharmacol Ther 2020; 51: 158-166
• 18 Romeo R, Del Ninno E, Rumi M. et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology 2009; 136: 1629-1638
• 19 Romeo R, Foglieni B, Casazza G. et al. High serum levels of HDV RNA are predictors of cirrhosis and liver cancer in patients with chronic hepatitis delta. PLoS One 2014; 9: e92062
• 20 Ricco G, Popa DC, Cavallone D. et al. Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection. J Viral Hepat 2018; 25: 911-919
• 21 Yurdaydin C, Keskin O, Kalkan Ç. et al. Interferon Treatment Duration in Patients With Chronic Delta Hepatitis and its Effect on the Natural Course of the Disease. J Infect Dis 2018; 217: 1184-1192
• 22 Wranke A, Serrano BC, Heidrich B. et al. Antiviral treatment and liver-related complications in hepatitis delta. Hepatology 2017; 65: 414-425
• 23 Manesis EK, Vourli G, Dalekos G. et al. Prevalence and clinical course of hepatitis delta infection in Greece: a 13-year prospective study. J Hepatol 2013; 59: 949-956
• 24 Niro GA, Smedile A, Ippolito AM. et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol 2010; 53: 834-840
• 25 Wedemeyer H, Yurdaydìn C, Dalekos GN. et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011; 364: 322-331
• 26 Wedemeyer H, Yurdaydin C, Hardtke S. et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis 2019; 19: 275-286
• 27 Cornberg M, Lok AS-F, Terrault NA. et al. Guidance for design and endpoints of clinical trials in chronic hepatitis B – Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡. J Hepatol 2020; 72: 539-557
• 28 Farci P, Roskams T, Chessa L. et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology 2004; 126: 1740-1749
• 29 Yurdaydin C, Abbas Z, Buti M. et al. Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy. J Hepatol 2019; 70: 1008-1015
• 30 Calle Serrano B, Großhennig A, Homs M. et al. Development and evaluation of a baseline-event-anticipation score for hepatitis delta. J Viral Hepat 2014; 21: e154-e163
• 31 Melo Da Silva E, Kay A, Lobato C. et al. Non-F HBV/HDV-3 coinfection is associated with severe liver disease in Western Brazilian Amazon. J Med Virol 2019; 91: 1081-1086
• 32 Zachou K, Yurdaydin C, Drebber U. et al. Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver Int 2010; 30: 430-437
• 33 Wranke A, Hardtke S, Heidrich B. et al. Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta. J Viral Hepat 2020; 27: 1359-1368
• 34 Su C-W, Huang Y-H, Huo T-I. et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology 2006; 130: 1625-1635
• 35 Berzigotti A, Garcia-Tsao G, Bosch J. et al. Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis. Hepatology 2011; 54: 555-561
• 36 El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006; 4: 369-380
• 37 Li W, Urban S. Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications. J Hepatol 2016; 64: S32-S40
• 38 Petersen J, Dandri M, Mier W. et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 2008; 26: 335-341
• 39 Europäische Arzneimittel-Agentur (EMA). https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_de.pdf n.d.
• 40 Wedemeyer H, Schöneweis K, Bogomolov P. et al. Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis 2023; 23: 117-129
• 41 Lampertico P, Roulot D, Wedemeyer H. Bulevirtide with or without pegIFNα for patients with compensated chronic hepatitis delta: From clinical trials to real-world studies. J Hepatol 2022; 77: 1422-1430
• 42 Wedemeyer H, Schöneweis K, Bogomolov PO. et al. Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in cwith PEG-interferon Alpha 2a in patients with chronic HBV/HDV co-infection. Journal of Hepatology 2019; 70: e81
• 43 Asselah T, Arama SS, Bogomolov P. et al. 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. Journal of Hepatology 2021; 75: S291
• 44 Bogomolov P, Alexandrov A, Voronkova N. et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study. J Hepatol 2016; 65: 490-498
• 45 Wedemeyer H, Aleman S, Brunetto M. et al. Efficacy and safety of bulevirtide monotherapy given at 2 mg or 10 mg dose level once daily for treatment of chronic hepatitis delta: week 48 primary end point results from a phase 3 randomized, multicenter, parallel design study. Journal of Hepatology 2022; 77: S4-S5
• 46 Wedemeyer H, Aleman S, Brunetto MR. et al. A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D. N Engl J Med 2023;
• 47 Jachs M, Schwarz C, Panzer M. et al. Response-guided long-term treatment of chronic hepatitis D patients with bulevirtide-results of a “real world” study. Aliment Pharmacol Ther 2022; 56: 144-154
• 48 Degasperi E, Anolli MP, Uceda Renteria SC. et al. Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension. J Hepatol 2022; 77: 1525-1531
• 49 Herta T, Hahn M, Maier M. et al. Efficacy and Safety of Bulevirtide plus Tenofovir Disoproxil Fumarate in Real-World Patients with Chronic Hepatitis B and D Co-Infection. Pathogens 2022; 11: 517
• 50 Zöllner C, Hofmann J, Lutz K. et al. Real-life experiences with bulevirtide for the treatment of hepatitis delta-48 weeks data from a German centre. Liver Int 2022; 42: 2403-2407
• 51 Dietz-Fricke C, Tacke F, Zöllner C. et al. Treating hepatitis D with bulevirtide – Real-world experience from 114 patients. JHEP Rep 2023; 5: 100686
• 52 Europäische Arzneimittel-Agentur (EMA). https://www.ema.europa.eu/en/documents/product-information/pegasys-epar-product-information_de.pdf n.d.
• 53 Zhang Z, Ni Y, Lempp FA. et al. Hepatitis D virus-induced interferon response and administered interferons control cell division-mediated virus spread. J Hepatol 2022; 77: 957-966
• 54 Farci P, Mandas A, Coiana A. et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med 1994; 330: 88-94
• 55 Sandmann L, Wedemeyer H. Interferon-based treatment of chronic hepatitis D. Liver Int 2022;
• 56 Heidrich B, Yurdaydın C, Kabaçam G. et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology 2014; 60: 87-97
• 57 Keskin O, Wedemeyer H, Tüzün A. et al. Association Between Level of Hepatitis D Virus RNA at Week 24 of Pegylated Interferon Therapy and Outcome. Clin Gastroenterol Hepatol 2015; 13: 2342-2349.e1-2
• 58 Sandmann L, Yurdaydin C, Deterding K. et al. HBcrAg Levels Are Associated With Virological Response to Treatment With Interferon in Patients With Hepatitis Delta. Hepatol Commun 2021;
• 59 Yurdaydin C, Bozkaya H, Gürel S. et al. Famciclovir treatment of chronic delta hepatitis. J Hepatol 2002; 37: 266-271
• 60 Niro GA, Ciancio A, Tillman HL. et al. Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment Pharmacol Ther 2005; 22: 227-232
• 61 Kabaçam G, Onder FO, Yakut M. et al. Entecavir treatment of chronic hepatitis D. Clin Infect Dis 2012; 55: 645-650
• 62 Soriano V, Vispo E, Sierra-Enguita R. et al. Efficacy of prolonged tenofovir therapy on hepatitis delta in HIV-infected patients. AIDS 2014; 28: 2389-2394
• 63 Béguelin C, Friolet N, Moradpour D. et al. Impact of Tenofovir on Hepatitis Delta Virus Replication in the Swiss Human Immunodeficiency Virus Cohort Study. Clin Infect Dis 2017; 64: 1275-1278
• 64 Murata K, Asano M, Matsumoto A. 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: 362-371
• 65 Heidrich B, Deterding K, Tillmann HL. et al. Virological and clinical characteristics of delta hepatitis in Central Europe. J Viral Hepat 2009; 16: 883-894
• 66 Sureau C, Negro F. The hepatitis delta virus: Replication and pathogenesis. J Hepatol 2016; 64: S102-S116
• 67 European Association for the Study of the Liver. Electronic address: [e-mail], 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
• 68 Da BL, Surana P, Takyar V. et al. Vibration-controlled transient elastography for the detection of cirrhosis in chronic hepatitis D infection. J Viral Hepat 2020; 27: 428-436
• 69 Da BL, Surana P, Kleiner DE. et al. The Delta-4 fibrosis score (D4FS): A novel fibrosis score in chronic hepatitis D. Antiviral Res 2020; 174: 104691
• 70 Lutterkort GL, Wranke A, Yurdaydin C. et al. Non-invasive fibrosis score for hepatitis delta. Liver Int 2017; 37: 196-204
• 71 Enc F, Ulasoglu C. A case of autoimmune hepatitis following pegylated interferon treatment of chronic hepatitis delta. North Clin Istanb 2020; 7: 407-410
• 72 Stelzl E, Ciesek S, Cornberg M. et al. Reliable quantification of plasma HDV RNA is of paramount importance for treatment monitoring: A European multicenter study. J Clin Virol 2021; 142: 104932
• 73 Heller T, Rotman Y, Koh C. et al. Long-term therapy of chronic delta hepatitis with peginterferon alfa. Aliment Pharmacol Ther 2014; 40: 93-104
• 74 Hercun J, Kim GE, Da BL. et al. Durable virological response and functional cure of chronic hepatitis D after long-term peginterferon therapy. Aliment Pharmacol Ther 2021; 54: 176-182
• 75 Spaan M, Carey I, Bruce M. et al. Hepatitis delta genotype 5 is associated with favourable disease outcome and better response to treatment compared to genotype 1. J Hepatol 2020; 72: 1097-1104
• 76 Wang W, Lempp FA, Schlund F. et al. Assembly and infection efficacy of hepatitis B virus surface protein exchanges in 8 hepatitis D virus genotype isolates. J Hepatol 2021; 75: 311-323
• 77 Fontaine H, Fougerou-Leurent C, Gordien E. et al. Real life study of bulevirtide in chronic hepatitis delta: preliminary results of the ANRS HD EP01 BuleDelta prospective cohort. Journal of Hepatology 2022; 77: S72
• 78 De Ledinghen V, Hermabessière P, Metivier S. et al. Bulevirtide, with or without peg- interferon, in HDV infected patients in a real-life setting. Two-year results from the French multicenter early access program. Hepatology 2022; 76: S26-S28
• 79 Lédinghen de V, Metivier S, Bardou-Jacquet E. et al. Treatment with Bulevirtide in patients with chronic HBV/HDV co-infection. Safety and efficacy at month 18 in real-world settings. Journal of Hepatology 2022; 77: S840
• 80 Asselah T, Loureiro D, Le Gal F. et al. Early virological response in six patients with hepatitis D virus infection and compensated cirrhosis treated with Bulevirtide in real-life. Liver Int 2021; 41: 1509-1517
• 81 Nkongolo S, Hollnberger J, Urban S. [Bulevirtide as the first specific agent against hepatitis D virus infections-mechanism and clinical effect]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2022; 65: 254-263
• 82 Volz T, Allweiss L, Ben M. et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol 2013; 58: 861-867
• 83 Giersch K, Bhadra OD, Volz T. et al. Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo. Gut 2019; 68: 150-157
• 84 Anolli MP, Degasperi E, Allweiss L. et al. A 3-Year Course Of Bulevirtide Monotherapy May Cure Hdv Infection In Cirrhotics. J Hepatol 2023;
• 85 Behrendt P, Traidl S, Böker KHW. et al. T-cell driven allergic cutaneous reaction complicating treatment of hepatitis delta virus infection with bulevirtide. Liver Int 2022; 42: 1770-1771
• 86 Schwarz C, Chromy D, Bangert C. et al. Immediate-type hypersensitivity reaction to bulevirtide and successful desensitization in a patient with HBV/HDV-associated compensated cirrhosis. J Hepatol 2022; 77: 254-255
• 87 Blank A, Meier K, Urban S. et al. Drug-drug interaction potential of the HBV and HDV entry inhibitor myrcludex B assessed in vitro. Antivir Ther 2018; 23: 267-275
• 88 Nkongolo S, Ni Y, Lempp FA. et al. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol 2014; 60: 723-731
• 89 Lempp FA, Urban S. Inhibitors of hepatitis B virus attachment and entry. Intervirology 2014; 57: 151-157
• 90 Donkers JM, Zehnder B, van Westen GJP. et al. Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. Sci Rep 2017; 7: 15307
• 91 Blank A, Eidam A, Haag M. et al. The NTCP-inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics. Clin Pharmacol Ther 2018; 103: 341-348
• 92 Schaper M, Rodriguez-Frias F, Jardi R. et al. Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. J Hepatol 2010; 52: 658-664
• 93 Wedemeyer H. Re-emerging interest in hepatitis delta: new insights into the dynamic interplay between HBV and HDV. J Hepatol 2010; 52: 627-629
• 94 Deterding K, Xu C-J, Port K. et al. Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA. J Viral Hepat 2023;
• 95 Lok AS, Zoulim F, Dusheiko G. et al. Durability of Hepatitis B Surface Antigen Loss With Nucleotide Analogue and Peginterferon Therapy in Patients With Chronic Hepatitis B. Hepatol Commun 2020; 4: 8-20
• 96 Loglio A, Ferenci P, Uceda Renteria SC. et al. Safety and effectiveness of up to 3 years’ bulevirtide monotherapy in patients with HDV-related cirrhosis. J Hepatol 2022; 76: 464-469
• 97 Niro GA, Smedile A, Fontana R. et al. HBsAg kinetics in chronic hepatitis D during interferon therapy: on-treatment prediction of response. Aliment Pharmacol Ther 2016; 44: 620-628
• 98 Kabaçam G, Dalekos GN, Çakaloğlu Y. et al. Pegylated interferon-based treatment in patients with advanced liver disease due to chronic delta hepatitis. Turk J Gastroenterol 2012; 23: 560-568
• 99 Andrade de O LJ, D’Oliveira A, Silva CAC. et al. A meta-analysis of patients with chronic hepatitis C treated with interferon-alpha to determine the risk of autoimmune thyroiditis. Acta Gastroenterol Latinoam 2011; 41: 104-110
• 100 Roche B, Samuel D. Liver transplantation in delta virus infection. Semin Liver Dis 2012; 32: 245-255
• 101 Kim JH, Sinn DH, Kang W. et al. Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment. Hepatology 2017; 66: 335-343
• 102 Sinn DH, Lee J, Goo J. et al. Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load. Hepatology 2015; 62: 694-701
• 103 Zoutendijk R, Reijnders JGP, Zoulim F. et al. Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut 2013; 62: 760-765
• 104 Lok ASF, McMahon BJ, Brown RS. et al. Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta-analysis. Hepatology 2016; 63: 284-306