Skip to main content

Advertisement

Log in

Treatment Options for Hepatitis Delta Virus Infection

  • Intra-abdominal Infections, Hepatitis, and Gastroenteritis (D Bobak, Section Editor)
  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

The hepatitis D virus (HDV), the smallest virus known to infect man, causes the most severe form of chronic viral hepatitis, hepatitis delta. It is estimated that about 15 to 20 million people are suffering from chronic HDV infection. HDV is a defective satellite virus depending on the hepatitis B surface antigen (HBsAg) for transmission. Chronic hepatitis delta is associated with a rapid progression of liver fibrosis and a high prevalence of liver cirrhosis, even in younger patients. Immunization against hepatitis B virus (HBV) protects from HDV infection, but there is no specific vaccine against HDV available for HBsAg-positive individuals. Treatment options for hepatitis delta patients are limited. So far, only interferon-alpha has shown an antiviral efficacy against HDV. Recent trials showed sustained virological response rates concerning HDV in 25 %–30 % of patients treated with pegylated interferons. HDV is dominant over HBV in the majority of cases, but HBV DNA-positive subjects should be treated with HBV polymerase inhibitors. Combination therapy of pegylated interferon-alpha and adefovir showed a more pronounced HBsAg decline, but the exact role of combination therapies in hepatitis delta requires further investigation. Alternative future treatment strategies may include prenylation inhibitors and HBV entry inhibitors, which are in early clinical development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

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

  1. Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet. 2011.

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

    Article  PubMed  Google Scholar 

  3. Arboleda M, Castilho MC, Fonseca JC, Albuquerque BC, Saboia RC, et al. Epidemiological aspects of hepatitis B and D virus infection in the northern region of Amazonas, Brazil. Trans R Soc Trop Med Hyg. 1995;89:481–3.

    Article  PubMed  CAS  Google Scholar 

  4. Gaeta GB, Stroffolini T, Smedile A, Niro G, Mele A. Hepatitis delta in Europe: vanishing or refreshing? Hepatology. 2007;46:1312–3.

    Article  PubMed  Google Scholar 

  5. Wedemeyer H, Heidrich B, Manns MP. Hepatitis D virus infection–not a vanishing disease in Europe! Hepatology. 2007;45:1331–2. author reply 1332–1333.

    Article  PubMed  Google Scholar 

  6. Heidrich B, Deterding K, Tillmann HL, Raupach R, Manns MP, et al. Virological and clinical characteristics of delta hepatitis in Central Europe. J Viral Hepat. 2009;16:883–94.

    Google Scholar 

  7. Cross TJ, Rizzi P, Horner M, Jolly A, Hussain MJ, et al. The increasing prevalence of hepatitis delta virus (HDV) infection in South London. J Med Virol. 2008;80:277–82.

    Article  PubMed  Google Scholar 

  8. Kucirka LM, Farzadegan H, Feld JJ, Mehta SH, Winters M, et al. Prevalence, correlates, and viral dynamics of hepatitis delta among injection drug users. J Infect Dis. 2010;202:845–52.

    Article  PubMed  Google Scholar 

  9. Farci P. Delta hepatitis: an update. J Hepatol. 2003;39 Suppl 1:S212–9.

    Article  PubMed  CAS  Google Scholar 

  10. Gaeta GB, Stroffolini T, Chiaramonte M, Ascione T, Stornaiuolo G, et al. Chronic hepatitis D: a vanishing Disease? An Italian multicenter study. Hepatology. 2000;32:824–7.

    Article  PubMed  CAS  Google Scholar 

  11. Taylor JM. Hepatitis delta virus. Virology. 2006;344:71–6.

    Article  PubMed  CAS  Google Scholar 

  12. Weiner AJ, Choo QL, Wang KS, Govindarajan S, Redeker AG, et al. A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p24 delta and p27 delta. J Virol. 1988;62:594–9.

    PubMed  CAS  Google Scholar 

  13. Lai MM. RNA replication without RNA-dependent RNA polymerase: surprises from hepatitis delta virus. J Virol. 2005;79:7951–8.

    Article  PubMed  CAS  Google Scholar 

  14. Greco-Stewart VS, Schissel E, Pelchat M. The hepatitis delta virus RNA genome interacts with the human RNA polymerases I and III. Virology. 2009;386:12–5.

    Article  PubMed  CAS  Google Scholar 

  15. Radjef N, Gordien E, Ivaniushina V, Gault E, Anais P, et al. Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades. J Virol. 2004;78:2537–44.

    Article  PubMed  CAS  Google Scholar 

  16. Makuwa M, Caron M, Souquiere S, Malonga-Mouelet G, Mahe A, et al. Prevalence and genetic diversity of hepatitis B and delta viruses in pregnant women in Gabon: molecular evidence that hepatitis delta virus clade 8 originates from and is endemic in central Africa. J Clin Microbiol. 2008;46:754–6.

    Article  PubMed  Google Scholar 

  17. Shakil AO, Hadziyannis S, Hoofnagle JH, Di Bisceglie AM, Gerin JL, et al. Geographic distribution and genetic variability of hepatitis delta virus genotype I. Virology. 1997;234:160–7.

    Article  PubMed  CAS  Google Scholar 

  18. Parana R, Kay A, Molinet F, Viana S, Silva LK, et al. HDV genotypes in the Western Brazilian Amazon region: a preliminary report. AmJTrop Med Hyg. 2006;75:475–9.

    CAS  Google Scholar 

  19. Wu JC, Chiang TY, Sheen IJ. Characterization and phylogenetic analysis of a novel hepatitis D virus strain discovered by restriction fragment length polymorphism analysis. J Gen Virol. 1998;79(Pt 5):1105–13.

    PubMed  CAS  Google Scholar 

  20. Su CW, Huang YH, Huo TI, Shih HH, Sheen IJ, et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology. 2006;130:1625–35.

    Article  PubMed  CAS  Google Scholar 

  21. Niro GA, Casey JL, Gravinese E, Garrubba M, Conoscitore P, et al. Intrafamilial transmission of hepatitis delta virus: molecular evidence. J Hepatol. 1999;30:564–9.

    Article  PubMed  CAS  Google Scholar 

  22. Manock SR, Kelley PM, Hyams KC, Douce R, Smalligan RD, et al. An outbreak of fulminant hepatitis delta in the Waorani, an indigenous people of the Amazon basin of Ecuador. AmJTrop Med Hyg. 2000;63:209–13.

    CAS  Google Scholar 

  23. Flodgren E, Bengtsson S, Knutsson M, Strebkova EA, Kidd AH, et al. Recent high incidence of fulminant hepatitis in Samara, Russia: molecular analysis of prevailing hepatitis B and D virus strains. J Clin Microbiol. 2000;38:3311–6.

    PubMed  CAS  Google Scholar 

  24. Heidrich B, Beatriz SC, Idilman R, Kabacam G, Bremer B, et al. HBeAg-positive hepatitis delta: virological patterns and clinical long-term outcome. Liver Int. 2012;32:1415–25.

    Article  PubMed  CAS  Google Scholar 

  25. Niro GA, Smedile A, Ippolito AM, Ciancio A, Fontana R, et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol. 2010;53:834–40.

    Article  PubMed  Google Scholar 

  26. Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009;136:1629–38.

    Article  PubMed  Google Scholar 

  27. Buti M, Homs M, Rodriguez-Frias F, Funalleras G, Jardi R, et al. Clinical outcome of acute and chronic hepatitis delta over time: a long-term follow-up study. J Viral Hepat. 2011;18:434–42.

    Article  PubMed  CAS  Google Scholar 

  28. Calle-Serrano B, Grosshennig A, Heidrich B, Jaroszewicz J, Kirschner J, et al. Comparing the long-term outcome of hepatitis delta and HBV monoinfection: Is HDV-infection really worse? J Hepatol. 2011;54:144.

    Article  Google Scholar 

  29. Ji J, Sundquist K, Sundquist J. A population-based study of hepatitis D virus as potential risk factor for hepatocellular carcinoma. J Natl Cancer Inst. 2012;104:790–2.

    Article  PubMed  Google Scholar 

  30. Williams V, Brichler S, Radjef N, Lebon P, Goffard A, et al. Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene. J Gen Virol. 2009;90:2759–67.

    Article  PubMed  CAS  Google Scholar 

  31. Pollicino T, Raffa G, Santantonio T, Gaeta GB, Iannello G, et al. Replicative and transcriptional activities of hepatitis B virus in patients coinfected with hepatitis B and hepatitis delta viruses. J Virol. 2011;85:432–9.

    Article  PubMed  CAS  Google Scholar 

  32. Schaper M, Rodriguez-Frias F, Jardi R, Tabernero D, Homs M, 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. 52: 658–64.

  33. Wedemeyer H. Re-emerging interest in hepatitis delta: new insights into the dynamic interplay between HBV and HDV. J Hepatol. 2010;52:627–9.

    Article  PubMed  Google Scholar 

  34. Mederacke I, Filmann N, Yurdaydin C, Bremer B, Puls F, et al. Rapid early HDV RNA decline in the peripheral blood but prolonged intrahepatic hepatitis Delta antigen persistence after liver transplantation. J Hepatol. 2011.

  35. Mederacke I, Bremer B, Heidrich B, Kirschner J, Deterding K, et al. Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics. J Clin Microbiol. 2010;48:2022–9.

    Article  PubMed  CAS  Google Scholar 

  36. Soriano V, Puoti M, Bonacini M, Brook G, Cargnel A, et al. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV International Panel. AIDS. 2005;19:221–40.

    Article  PubMed  Google Scholar 

  37. Zachou K, Yurdaydin C, Drebber U, Dalekos GN, Erhardt A, et al. Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver Int. 2010;30:430–7.

    Article  PubMed  CAS  Google Scholar 

  38. Cornberg M, Protzer U, Dollinger MM, Petersen J, Wedemeyer H, et al. Prophylaxis, Diagnosis and Therapy of Hepatitis-B-Virus-(HBV-)Infection: upgrade of the guideline, AWMF-Register 021/011. Z Gastroenterol. 2007;45:525–74.

    Article  PubMed  CAS  Google Scholar 

  39. • EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009; 50: 227–42. The guideline clearly describes the clinical management of patients infected with HBV as well as patients coinfected with HBV and HDV.

  40. Farci P, Mandas A, Coiana A, Lai ME, Desmet V, et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med. 1994;330:88–94.

    Article  PubMed  CAS  Google Scholar 

  41. Rosina F, Saracco G, Lattore V, Quartarone V, Rizzetto M, et al. Alpha 2 recombinant interferon in the treatment of chronic hepatitis delta virus (HDV) hepatitis. Prog Clin Biol Res. 1987;234:299–303.

    PubMed  CAS  Google Scholar 

  42. •• Wedemeyer H, Yurdaydin C, Dalekos GN, Erhardt A, Cakaloglu Y, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364:322–31. This the so far largest clinical trial treating patients chronically infected with HDV with pegylated Interferon. Overall, the SVR rate was 25–30 %.

  43. Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M, et al. Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up. Hepatology. 2006;44:728–35.

    Article  PubMed  CAS  Google Scholar 

  44. Lamers MH, Kirgiz OO, Heidrich B, Wedemeyer H, Drenth JP. Interferon-alpha for patients with chronic hepatitis delta: a systematic review of randomized clinical trials. Antivir Ther. 2012;17:1029–37.

    Article  PubMed  CAS  Google Scholar 

  45. Degertekin H, Yalcin K, Yakut M, Yurdaydin C. Seropositivity for delta hepatitis in patients with chronic hepatitis B and liver cirrhosis in Turkey: a meta-analysis. Liver Int. 2008;28:494–8.

    Article  PubMed  Google Scholar 

  46. Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology. 2004;126:1740–9.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  48. Lau DT, Kleiner DE, Park Y, Di Bisceglie AM, Hoofnagle JH. Resolution of chronic delta hepatitis after 12 years of interferon alfa therapy. Gastroenterology. 1999;117:1229–33.

    Article  PubMed  CAS  Google Scholar 

  49. Niro GA, Ciancio A, Tillman HL, Lagget M, Olivero A, et al. Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment Pharmacol Ther. 2005;22:227–32.

    Article  PubMed  CAS  Google Scholar 

  50. Yurdaydin C, Bozkaya H, Gurel S, Tillmann HL, Aslan N, et al. Famciclovir treatment of chronic delta hepatitis. J Hepatol. 2002;37:266–71.

    Article  PubMed  CAS  Google Scholar 

  51. Yurdaydin C, Bozkaya H, Onder FO, Senturk H, Karaaslan H, et al. Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J Viral Hepat. 2008;15:314–21.

    Article  PubMed  CAS  Google Scholar 

  52. Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology. 2006;44:713–20.

    Article  PubMed  CAS  Google Scholar 

  53. Kabacam G, Onder FO, Yakut M, Seven G, Karatayli SC, et al. Entecavir treatment of chronic hepatitis D. Clin Infect Dis. 2012;55:645–50.

    Article  PubMed  CAS  Google Scholar 

  54. Jaroszewicz J, Ho H, Markova A, Deterding K, Wursthorn K, et al. Hepatitis B surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside/nucleotide analogues. Antivir Ther. 2011;16:915–24.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  56. Martin-Carbonero L, Teixeira T, Poveda E, Plaza Z, Vispo E, et al. Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues. AIDS. 2011;25:73–9.

    Article  PubMed  Google Scholar 

  57. Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet. 2011;378:73–85.

    Article  PubMed  Google Scholar 

  58. Serrano BC, Manns MP, Wedemeyer H. Hepatitis delta and HIV infection. Semin Liver Dis. 2012;32:120–9.

    Article  CAS  Google Scholar 

  59. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–31.

    Article  PubMed  CAS  Google Scholar 

  60. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol. 2010;53:348–56.

    Article  PubMed  CAS  Google Scholar 

  61. Zoutendijk R, Reijnders JG, Zoulim F, Brown A, Mutimer DJ, et al. Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut. 2012.

  62. Vietheer PT, Netter HJ, Sozzi T, Bartholomeusz A. Failure of the lamivudine-resistant rtM204I hepatitis B virus mutants to efficiently support hepatitis delta virus secretion. J Virol. 2005;79:6570–3.

    Article  PubMed  CAS  Google Scholar 

  63. Samuel D, Zignego AL, Reynes M, Feray C, Arulnaden JL, et al. Long-term clinical and virological outcome after liver transplantation for cirrhosis caused by chronic delta hepatitis. Hepatology. 1995;21:333–9.

    Article  PubMed  CAS  Google Scholar 

  64. Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest. 2003;112:407–14.

    PubMed  CAS  Google Scholar 

  65. Petersen J, Dandri M, Mier W, Lutgehetmann M, Volz T, et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol. 2008;26:335–41.

    Article  PubMed  CAS  Google Scholar 

  66. Lutgehetmann M, Mancke LV, Volz T, Helbig M, Allweiss L, et al. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology. 2012;55:685–94.

    Article  PubMed  Google Scholar 

  67. Muir AJ, Shiffman ML, Zaman A, Yoffe B, de la Torre A, et al. Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology. 2010;52:822–32.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Heiner Wedemeyer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heidrich, B., Manns, M.P. & Wedemeyer, H. Treatment Options for Hepatitis Delta Virus Infection. Curr Infect Dis Rep 15, 31–38 (2013). https://doi.org/10.1007/s11908-012-0307-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-012-0307-z

Keywords

Navigation