Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Chronic hepatitis D at a standstill: where do we go from here?

Nature Reviews Gastroenterology & Hepatology volume 11, pages 68–71 (2014)Cite this article

Subjects

Abstract

Immigration is fuelling a new reservoir of hepatitis D virus (HDV) in Europe, and hepatitis D still represents an important medical problem in the USA. The disease continues to be a major medical scourge in the developing world, in particular in countries such as Pakistan, Mongolia and Mauritania. New therapeutic strategies are being developed to disrupt interactions between HDV and its viral partner HBV, or with the host. Blocking or modifying the hepatitis B surface antigen (HBsAg) might interfere with the uptake or release of the hepatitis D virion; interference with host-mediated post-translational changes of proteins that are crucial to the HDV life cycle, such as prenylation, is another potential therapeutic option. At present, however, the only realistic option is to optimize IFN-α therapy. As eradication of HBsAg is the ultimate end point of therapy, long-term interferon administration might be required, raising an issue of tolerance in patients. Treatment with IFN-λ is a potential alternative approach to IFN-α; treatment of hepatitis C with this cytokine seems to cause fewer adverse effects than IFN-α and, therefore, might be more suitable for long-term treatment of HDV.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Treatment algorithm and follow-up in HBsAg-positive patients with anti-HDV antibodies.
Figure 2: Sequential steps directing the biological cycle of HDV and potential therapeutic approaches.

Similar content being viewed by others

References

  1. Rizzetto, M. Hepatitis D: thirty years after. J. Hepatol. 50, 1043–1050 (2009).

    Article  CAS  Google Scholar 

  2. Taylor, J. M. Structure and replication of hepatitis delta virus RNA. Curr. Top. Microbiol. Immunol. 307, 1–23 (2006).

    CAS  PubMed  Google Scholar 

  3. World Health Organization. Weekly epidemiological report. Hepatitis B position. 84, 405–420 (2009).

  4. Rizzetto, M., Ponzetto, A. & Forzani, I. Epidemiology of hepatitis delta virus: overview. Prog. Clin. Biol. Res. 364, 1–20 (1991).

    CAS  PubMed  Google Scholar 

  5. Rizzetto, M. & Ciancio, A. Epidemiology of hepatitis D. Semin. Liver Dis. 32, 211–219 (2012).

    Article  Google Scholar 

  6. Huo, T. I. et al. Decreasing hepatitis D virus infection in Taiwan: an analysis of contributory factors. J. Gastroenterol. Hepatol. 12, 747–751 (1997).

    Article  CAS  Google Scholar 

  7. Kao, J. H., Chen, P. J., Lai, M. Y. & Chen, D. S. Hepatitis D virus genotypes in intravenous drug users in Taiwan: decreasing prevalence and lack of correlation with hepatitis B virus genotypes. J. Clin. Microbiol. 40, 3047–3049 (2002).

    Article  Google Scholar 

  8. Gaeta, G. B. et al. Hepatitis delta in Europe: vanishing or refreshing? Hepatology 46, 1312–1313 (2007).

    Article  Google Scholar 

  9. Stroffolini, T. et al. Evolving clinical landscape of chronic hepatitis B: A multicenter Italian study. J. Med. Virol. 81, 1999–2006 (2009).

    Article  Google Scholar 

  10. Heidrich, B. et al. Virological and clinical characteristics of delta hepatitis in Central Europe. J. Viral Hepat. 16, 883–894 (2009).

    Article  CAS  Google Scholar 

  11. Cross, T. J. et al. The increasing prevalence of hepatitis delta virus (HDV) infection in South London. J. Med. Virol. 80, 277–282 (2008).

    Article  Google Scholar 

  12. Le Gal, F. et al. Hepatitis D virus infection. Not a vanishing disease in Europe. Hepatology 45, 1332–1333 (2007).

    Article  Google Scholar 

  13. Erhardt, A. et al. Socioepidemiological data on hepatitis delta in a German university clinic—increase in patients from Eastern Europe and the former Soviet Union. Z. Gastroenterol. 41, 523–526 (2003).

    Article  CAS  Google Scholar 

  14. Bialek, S. R., Bower, W. A. & Mottram, K. Risk factors for hepatitis B in an outbreak of hepatitis B and D among injection drug users. J. Urban Health 82, 468–478 (2005).

    Article  Google Scholar 

  15. Kucirka, L. M. et al. Prevalence, correlates, and viral dynamics of hepatitis delta among injection drug users. J. Infect. Dis. 202, 845–852 (2010).

    Article  Google Scholar 

  16. Gish, R. G. et al. Coinfection with hepatitis B and D: epidemiology, prevalence and disease in patients in Northern California. J. Gastroenterol. Hepatol. http://dx.doi.org/10.1111/jgh.12217.

  17. Holmberg, S. D. & Ward, J. W. Hepatitis delta: seek and ye shall find. J. Infect. Dis. 202, 822–824 (2010).

    Article  Google Scholar 

  18. Niro, G. A., Rosina, F. & Rizzetto, M. Treatment of hepatitis D. J. Viral Hepat. 12, 2–9 (2005).

    Article  CAS  Google Scholar 

  19. Farci, P. et al. Treatment of chronic hepatitis D with interferon α-2a. N. Engl. J. Med. 330, 88–94 (1994).

    Article  CAS  Google Scholar 

  20. Ciancio, A. & Rizzetto, M. PEG-IFN for the treatment of hepatitis D. Nat. Rev. Gastroenterol. Hepatol. 8, 304–306 (2011).

    Article  CAS  Google Scholar 

  21. Castelnau, C. et al. Efficacy of peginterferon α-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up. Hepatology 44, 728–735 (2006).

    Article  CAS  Google Scholar 

  22. Niro, G. A. et al. Pegylated interferon α-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology 44, 713–720 (2006).

    Article  CAS  Google Scholar 

  23. Erhardt, A. et al. Treatment of chronic hepatitis delta with pegylated interferon-α2b. Liver Int. 26, 805–810 (2006).

    Article  CAS  Google Scholar 

  24. Wedemeyer, H. et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N. Engl. J. Med. 364, 322–331 (2011).

    Article  CAS  Google Scholar 

  25. Heidrich, B. et al. Long-term follow-up after peg-ifna2a based therapy of chronic hepatitis delta [abstract]. J. Hepatol. 58 (Suppl. 1), S20 (2013).

    Article  Google Scholar 

  26. Niro, G. A. et al. Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment. Pharmacol. Ther. 22, 227–232 (2005).

    Article  CAS  Google Scholar 

  27. Yurdaydin, C. et al. Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J. Viral Hepat. 15, 314–321 (2008).

    Article  CAS  Google Scholar 

  28. Kabaçam, G. et al. Entecavir treatment of chronic hepatitis D. Clin. Infect. Dis. 55, 645–650 (2012).

    Article  Google Scholar 

  29. Kao, J. H. Diagnosis of hepatitis B virus infection through serological and virological markers. Expert Rev. Gastroenterol. Hepatol. 2, 553–562 (2008).

    Article  CAS  Google Scholar 

  30. Lai, M. M. RNA replication without RNA-dependent RNA polymerase: surprises from hepatitis delta virus. J. Virol. 79, 7951–7958 (2005).

    Article  CAS  Google Scholar 

  31. Singh, S. et al. Design of potential siRNA molecules for hepatitis delta virus gene silencing. Bioinformation 8, 749–757 (2012).

    Article  Google Scholar 

  32. Chang, J. & Taylor, J. M. Susceptibility of human hepatitis delta virus RNAs to small interfering RNA action. J. Virol. 77, 9728–9731 (2003).

    Article  CAS  Google Scholar 

  33. Sureau, C. The role of the HBV envelope proteins in the HDV replication cycle. Curr. Top. Microbiol. Immunol. 307, 113–131 (2006).

    CAS  PubMed  Google Scholar 

  34. Abou-Jaoudé, G. & Sureau, C. Entry of hepatitis delta virus requires the conserved cysteine residues of the hepatitis B virus envelope protein antigenic loop and is blocked by inhibitors of thiol-disulfide exchange. J. Virol. 81, 13057–13066 (2007).

    Article  Google Scholar 

  35. Lütgehetmann, M. et al. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology 55, 685–694 (2012).

    Article  Google Scholar 

  36. Komla-Soukha, I. & Sureau, C. A tryptophan-rich motif in the carboxyl terminus of the small envelope protein of hepatitis B virus is central to the assembly of hepatitis delta virus particles. J. Virol. 80, 4648–4655 (2006).

    Article  CAS  Google Scholar 

  37. Vietheer, P. T., Netter, H. J., Sozzi, T. & Bartholomeusz, A. Failure of the lamivudine-resistant rtM204I hepatitis B virus mutants to efficiently support hepatitis delta virus secretion. J. Virol. 79, 6570–6573 (2005).

    Article  CAS  Google Scholar 

  38. Andreone, P., Spertini, F. & Negro, F. Lamivudine-associated remission of chronic hepatitis delta. Ann. Intern. Med. 132, 598 (2000).

    Article  CAS  Google Scholar 

  39. Shih, H. H. et al. Hepatitis B surface antigen levels and sequences of natural hepatitis B virus variants influence the assembly and secretion of hepatitis d virus. J. Virol. 82, 2250–2264 (2008).

    Article  CAS  Google Scholar 

  40. Huang, W. H., Chen, C. W., Wu, H. L. & Chen, P. J. Post-translational modification of delta antigen of hepatitis D virus. Curr. Top. Microbiol. Immunol. 307, 91–112 (2006).

    CAS  PubMed  Google Scholar 

  41. Glenn, J. S. Prenylation of HDAg and antiviral drug development. Curr. Top. Microbiol. Immunol. 307, 133–149 (2006).

    CAS  PubMed  Google Scholar 

  42. Bordier, B. B. et al. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. J. Virol. 76, 10465–10472 (2002).

    Article  CAS  Google Scholar 

  43. Bordier, B. B. et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J. Clin. Invest. 112, 407–414 (2003).

    Article  CAS  Google Scholar 

  44. Ouzan, D., Pénaranda, G., Joly, H. & Halfon, P. Optimized HBsAg titer monitoring improves interferon therapy in patients with chronic delta. J. Hepatol. 58, 1258–1259 (2013).

    Article  CAS  Google Scholar 

  45. Muir, A. J. et al. Peginterferon λ-1a (λ) compared with peginterferon α-2a (α) in treatment-naive patients with HCV genotypes 1 or 4: SVR24 results from EMERGE phase 2b [abstract]. J. Hepatology 56, 299A (2012).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, University of Torino, Molinette Hospital, Corso Bramante 88, 10126, Torino, Italy

    Alessia Ciancio & Mario Rizzetto

Authors
  1. Alessia Ciancio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mario Rizzetto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed equally to all aspects of the generation of this article.

Corresponding author

Correspondence to Mario Rizzetto.

Ethics declarations

Competing interests

M. Rizzetto is on an Advisory Board for Bristol–Myers Squibb, Janssen and MSD. A. Ciancio declares no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ciancio, A., Rizzetto, M. Chronic hepatitis D at a standstill: where do we go from here?. Nat Rev Gastroenterol Hepatol 11, 68–71 (2014). https://doi.org/10.1038/nrgastro.2013.164

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2013.164

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing