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.

Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options

Key Points

  • Co-infection with HBV and HDV is considered to be the most severe form of viral hepatitis, affecting 15–20 million individuals worldwide

  • HDV is an RNA virusoid that depends on HBV envelope proteins for its assembly, and host cellular proteins to facilitate its replication

  • Current treatment options for chronic HDV infection are limited to interferon regimes

  • Three novel antivirals targeting virus entry or particle assembly and/or secretion have shown promising results in phase II clinical trials

Abstract

Chronic hepatitis D is the most severe form of viral hepatitis, affecting 20 million HBV-infected people worldwide. The causative agent, hepatitis delta virus (HDV), is a unique human pathogen: it is the smallest known virus; it depends on HBV to disseminate its viroid-like RNA; it encodes only one protein (HDAg), which has both structural and regulatory functions; and it replicates using predominantly host proteins. The failure of HBV-specific nucleoside analogues to suppress the HBV helper function, and the limitations of experimental systems to study the HDV life cycle, have impeded the development of HDV-specific drugs. Thus, the only clinical regimen for HDV is IFNα, which shows some efficacy but long-term virological responses are rare. Insights into the receptor-mediated entry of HDV, and the observation that HDV assembly requires farnesyltransferase, have enabled novel therapeutic strategies to be developed. Interference with entry, for example through blockade of the HBV–HDV-specific receptor sodium/taurocholate cotransporting polypeptide NTCP by Myrcludex B, and inhibition of assembly by blockade of farnesyltransferase using lonafarnib or nucleic acid polymers such as REP 2139-Ca, have shown promising results in phase II studies. In this Review, we summarize our knowledge of HDV epidemiology, pathogenesis and molecular biology, with a particular emphasis on possible future developments.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Structure of hepatitis D virus (HDV).
Figure 2: The replication cycle of HDV.

References

  1. 1

    Rizzetto, M. et al. Immunofluorescence detection of new antigen–antibody system (δ/anti-δ) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 18, 997–1003 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Rizzetto, M. et al. Incidence and significance of antibodies to delta antigen in hepatitis B virus infection. Lancet 2, 986–990 (1979).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Rizzetto, M. et al. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. J. Infect. Dis. 141, 590–602 (1980).

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Rizzetto, M. et al. δ Agent: association of δ antigen with hepatitis B surface antigen and RNA in serum of δ-infected chimpanzees. Proc. Natl Acad. Sci. USA 77, 6124–6128 (1980).

    Article  CAS  PubMed  Google Scholar 

  5. 5

    He, L. F. et al. The size of the hepatitis delta agent. J. Med. Virol. 27, 31–33 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Chen, P. J. et al. Structure and replication of the genome of the hepatitis δ virus. Proc. Natl Acad. Sci. USA 83, 8774–8778 (1986).

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Kos, A., Dijkema, R., Arnberg, A. C., van der Meide, P. H. & Schellekens, H. The hepatitis delta (δ) virus possesses a circular RNA. Nature 323, 558–560 (1986).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Wang, K. S. et al. Structure, sequence and expression of the hepatitis delta (δ) viral genome. Nature 323, 508–514 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Kuo, M. Y. et al. Molecular cloning of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and applications. J. Virol. 62, 1855–1861 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Gudima, S., Chang, J., Moraleda, G., Azvolinsky, A. & Taylor, J. Parameters of human hepatitis delta virus genome replication: the quantity, quality, and intracellular distribution of viral proteins and RNA. J. Virol. 76, 3709–3719 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Ryu, W. S., Netter, H. J., Bayer, M. & Taylor, J. Ribonucleoprotein complexes of hepatitis delta virus. J. Virol. 67, 3281–3287 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Li, W. & Urban, S. Entry of hepatitis B and hepatitis D virus into hepatocytes: basic insights and clinical implications. J. Hepatol. 64, S32–S40 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Verrier, E. R. et al. A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses. Hepatology 63, 35–48 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Lamas Longarela, O. et al. Proteoglycans act as cellular hepatitis delta virus attachment receptors. PLoS ONE 8, e58340 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Leistner, C. M., Gruen-Bernhard, S. & Glebe, D. Role of glycosaminoglycans for binding and infection of hepatitis B virus. Cell. Microbiol. 10, 122–133 (2008).

    CAS  PubMed  Google Scholar 

  16. 16

    Schulze, A., Gripon, P. & Urban, S. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 46, 1759–1768 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Sureau, C. & Salisse, J. A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus A-determinant. Hepatology 57, 985–994 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. 18

    Urban, S. Liver capsule: entry and entry inhibition of hepatitis B virus and hepatitis delta virus into hepatocytes. Hepatology 63, 633 (2016).

    Article  PubMed  Google Scholar 

  19. 19

    Ni, Y. et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146, 1070–1083 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Yan, H. et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1, e00049 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Anwer, M. S. & Stieger, B. Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch. 466, 77–89 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Chou, H. C., Hsieh, T. Y., Sheu, G. T. & Lai, M. M. Hepatitis delta antigen mediates the nuclear import of hepatitis delta virus RNA. J. Virol. 72, 3684–3690 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Tavanez, J. P. et al. Hepatitis delta virus ribonucleoproteins shuttle between the nucleus and the cytoplasm. RNA 8, 637–646 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Chang, J., Nie, X., Chang, H. E., Han, Z. & Taylor, J. Transcription of hepatitis delta virus RNA by RNA polymerase II. J. Virol. 82, 1118–1127 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. 25

    Greco-Stewart, V. S., Miron, P., Abrahem, A. & Pelchat, M. The human RNA polymerase II interacts with the terminal stem-loop regions of the hepatitis delta virus RNA genome. Virology 357, 68–78 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Macnaughton, T. B., Shi, S. T., Modahl, L. E. & Lai, M. M. Rolling circle replication of hepatitis delta virus RNA is carried out by two different cellular RNA polymerases. J. Virol. 76, 3920–3927 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Modahl, L. E., Macnaughton, T. B., Zhu, N., Johnson, D. L. & Lai, M. M. RNA-Dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. Mol. Cell. Biol. 20, 6030–6039 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Flores, R., Owens, R. A. & Taylor, J. Pathogenesis by subviral agents: viroids and hepatitis delta virus. Curr. Opin. Virol. 17, 87–94 (2016).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Modahl, L. E. & Lai, M. M. Transcription of hepatitis delta antigen mRNA continues throughout hepatitis delta virus (HDV) replication: a new model of HDV RNA transcription and replication. J. Virol. 72, 5449–5456 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Kuo, M. Y., Sharmeen, L., Dinter-Gottlieb, G. & Taylor, J. Characterization of self-cleaving RNA sequences on the genome and antigenome of human hepatitis delta virus. J. Virol. 62, 4439–4444 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Wu, H. N. et al. Human hepatitis δ virus RNA subfragments contain an autocleavage activity. Proc. Natl Acad. Sci. USA 86, 1831–1835 (1989).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Macnaughton, T. B., Wang, Y. J. & Lai, M. M. Replication of hepatitis delta virus RNA: effect of mutations of the autocatalytic cleavage sites. J. Virol. 67, 2228–2234 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Reid, C. E. & Lazinski, D. W. A host-specific function is required for ligation of a wide variety of ribozyme-processed RNAs. Proc. Natl Acad. Sci. USA 97, 424–429 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Sharmeen, L., Kuo, M. Y. & Taylor, J. Self-ligating RNA sequences on the antigenome of human hepatitis delta virus. J. Virol. 63, 1428–1430 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Hsieh, S. Y., Chao, M., Coates, L. & Taylor, J. Hepatitis delta virus genome replication: a polyadenylated mRNA for delta antigen. J. Virol. 64, 3192–3198 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Lo, K., Hwang, S. B., Duncan, R., Trousdale, M. & Lai, M. M. Characterization of mRNA for hepatitis delta antigen: exclusion of the full-length antigenomic RNA as an mRNA. Virology 250, 94–105 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Gudima, S., Wu, S. Y., Chiang, C. M., Moraleda, G. & Taylor, J. Origin of hepatitis delta virus mRNA. J. Virol. 74, 7204–7210 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Taylor, J. M. Hepatitis D virus replication. Cold Spring Harb. Perspect. Med. 5, a021568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Sureau, C., Taylor, J., Chao, M., Eichberg, J. W. & Lanford, R. E. Cloned hepatitis delta virus cDNA is infectious in the chimpanzee. J. Virol. 63, 4292–4297 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Bonino, F., Heermann, K. H., Rizzetto, M. & Gerlich, W. H. Hepatitis delta virus: protein composition of delta antigen and its hepatitis B virus-derived envelope. J. Virol. 58, 945–950 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Chao, M., Hsieh, S. Y. & Taylor, J. Role of two forms of hepatitis delta virus antigen: evidence for a mechanism of self-limiting genome replication. J. Virol. 64, 5066–5069 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Luo, G. X. et al. A specific base transition occurs on replicating hepatitis delta virus RNA. J. Virol. 64, 1021–1027 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Polson, A. G., Bass, B. L. & Casey, J. L. RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature 380, 454–456 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Wong, S. K. & Lazinski, D. W. Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1. Proc. Natl Acad. Sci. USA 99, 15118–15123 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Hartwig, D. et al. Interferon-α stimulation of liver cells enhances hepatitis delta virus RNA editing in early infection. J. Hepatol. 41, 667–672 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Hartwig, D. et al. The large form of ADAR 1 is responsible for enhanced hepatitis delta virus RNA editing in interferon-α-stimulated host cells. J. Viral Hepat. 13, 150–157 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Glenn, J. S., Taylor, J. M. & White, J. M. In vitro-synthesized hepatitis delta virus RNA initiates genome replication in cultured cells. J. Virol. 64, 3104–3107 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Kuo, M. Y. P., Chao, M. & Taylor, J. Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J. Virol. 63, 1945–1950 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Alves, C., Freitas, N. & Cunha, C. Characterization of the nuclear localization signal of the hepatitis delta virus antigen. Virology 370, 12–21 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Cao, D., Haussecker, D., Huang, Y. & Kay, M. A. Combined proteomic–RNAi screen for host factors involved in human hepatitis delta virus replication. RNA 15, 1971–1979 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Lee, C. H., Chang, S. C., Wu, C. H. & Chang, M. F. A novel chromosome region maintenance 1-independent nuclear export signal of the large form of hepatitis delta antigen that is required for the viral assembly. J. Biol. Chem. 276, 8142–8148 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    O'Malley, B. & Lazinski, D. W. Roles of carboxyl-terminal and farnesylated residues in the functions of the large hepatitis delta antigen. J. Virol. 79, 1142–1153 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Glenn, J. S., Watson, J. A., Havel, C. M. & White, J. M. Identification of a prenylation site in delta virus large antigen. Science 256, 1331–1333 (1992).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Otto, J. C. & Casey, P. J. The hepatitis delta virus large antigen is farnesylated both in vitro and in animal cells. J. Biol. Chem. 271, 4569–4572 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Hwang, S. B. & Lai, M. M. Isoprenylation masks a conformational epitope and enhances trans-dominant inhibitory function of the large hepatitis delta antigen. J. Virol. 68, 2958–2964 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Hwang, S. B. & Lai, M. M. Isoprenylation mediates direct protein–protein interactions between hepatitis large delta antigen and hepatitis B virus surface antigen. J. Virol. 67, 7659–7662 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    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  PubMed  PubMed Central  Google Scholar 

  58. 58

    Macnaughton, T. B. & Lai, M. M. Genomic but not antigenomic hepatitis delta virus RNA is preferentially exported from the nucleus immediately after synthesis and processing. J. Virol. 76, 3928–3935 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Freitas, N., Cunha, C., Menne, S. & Gudima, S. O. Envelope proteins derived from naturally integrated hepatitis B virus DNA support assembly and release of infectious hepatitis delta virus particles. J. Virol. 88, 5742–5754 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Lempp, F. A. & Urban, S. Generation of a cell line that supports the full lifecycle of hepatitis delta virus [poster P181]. J. Viral Hepat. 22, 109–110 (2015).

    Google Scholar 

  61. 61

    Gudima, S., Meier, A., Dunbrack, R., Taylor, J. & Bruss, V. Two potentially important elements of the hepatitis B virus large envelope protein are dispensable for the infectivity of hepatitis delta virus. J. Virol. 81, 4343–4347 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Sureau, C., Guerra, B. & Lee, H. The middle hepatitis B virus envelope protein is not necessary for infectivity of hepatitis delta virus. J. Virol. 68, 4063–4066 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Sureau, C., Guerra, B. & Lanford, R. E. Role of the large hepatitis B virus envelope protein in infectivity of the hepatitis delta virion. J. Virol. 67, 366–372 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

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

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Watanabe, T. et al. Involvement of host cellular multivesicular body functions in hepatitis B virus budding. Proc. Natl Acad. Sci. USA 104, 10205–10210 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Gripon, P. et al. Infection of a human hepatoma cell line by hepatitis B virus. Proc. Natl Acad. Sci. USA 99, 15655–15660 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Wieland, S. F. The chimpanzee model for hepatitis B virus infection. Cold Spring Harb. Perspect. Med. 5, a021469 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Dandri, M. & Lütgehetmann, M. Mouse models of hepatitis B and delta virus infection. J. Immunol. Methods 410, 39–49 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Bissig, K. D. et al. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J. Clin. Invest. 120, 924–930 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    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  CAS  PubMed  Google Scholar 

  71. 71

    Ponzetto, A. et al. Transmission of the hepatitis B virus-associated δ agent to the eastern woodchuck. Proc. Natl Acad. Sci. USA 81, 2208–2212 (1984).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Netter, H. J., Kajino, K. & Taylor, J. M. Experimental transmission of human hepatitis delta virus to the laboratory mouse. J. Virol. 67, 3357–3362 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Li, H. et al. HBV life cycle is restricted in mouse hepatocytes expressing human NTCP. Cell. Mol. Immunol. 11, 175–183 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Yan, H. et al. Molecular determinants of hepatitis B and D virus entry restriction in mouse sodium taurocholate cotransporting polypeptide. J. Virol. 87, 7977–7991 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Lempp, F. A. et al. Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. J. Hepatol. 64, 556–564 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Giersch, K. et al. Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection. J. Hepatol. 60, 538–544 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    He, W. et al. Hepatitis D virus infection of mice expressing human sodium taurocholate co-transporting polypeptide. PLoS Pathog. 11, e1004840 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Winer, B. Y. & Ploss, A. Determinants of hepatitis B and delta virus host tropism. Curr. Opin. Virol. 13, 109–116 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Giersch, K. et al. Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J. Hepatol. 63, 346–353 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Lutgehetmann, M. et al. In vivo proliferation of hepadnavirus-infected hepatocytes induces loss of covalently closed circular DNA in mice. Hepatology 52, 16–24 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. 81

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

    Article  PubMed  Google Scholar 

  82. 82

    Gaeta, G. B. et al. Chronic hepatitis D: a vanishing disease? An Italian multicenter study. Hepatology 32, 824–827 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. 83

    Smedile, A. et al. Epidemiologic patterns of infection with the hepatitis B virus-associated delta agent in Italy. Am. J. Epidemiol. 117, 223–229 (1983).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    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. 28, 494–498 (2008).

    Article  PubMed  Google Scholar 

  85. 85

    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  PubMed  Google Scholar 

  86. 86

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

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Gish, R. G. et al. Coinfection with hepatitis B and D: epidemiology, prevalence and disease in patients in Northern California. J. Gastroenterol. Hepatol. 28, 1521–1525 (2013).

    Article  PubMed  Google Scholar 

  88. 88

    Kushner, T., Serper, M. & Kaplan, D. E. Delta hepatitis within the Veterans Affairs medical system in the United States: prevalence, risk factors, and outcomes. J. Hepatol. 63, 586–592 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    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  PubMed  PubMed Central  Google Scholar 

  90. 90

    El Bouzidi, K. et al. Hepatitis delta virus testing, epidemiology and management: a multicentre cross-sectional study of patients in London. J. Clin. Virol. 66, 33–37 (2015).

    Article  PubMed  Google Scholar 

  91. 91

    Manesis, E. K. et al. Prevalence and clinical course of hepatitis delta infection in Greece: a 13-year prospective study. J. Hepatol. 59, 949–956 (2013).

    Article  PubMed  Google Scholar 

  92. 92

    Hao, L. J., Li, L., Zhang, Y. Y. & Song, P. H. Hepatitis D virus infection in liver tissues of patients with hepatitis B in China. Chin. Med. J. (Engl.) 105, 204–208 (1992).

    CAS  Google Scholar 

  93. 93

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

    Article  PubMed  Google Scholar 

  94. 94

    Braga, W. S. et al. Hepatitis D virus infection in the Western Brazilian Amazon — far from a vanishing disease. Rev. Soc. Bras. Med. Trop. 45, 691–695 (2012).

    Article  PubMed  Google Scholar 

  95. 95

    Fonseca, J. C. et al. Prevalence of infection with hepatitis delta virus (HDV) among carriers of hepatitis B surface antigen in Amazonas State, Brazil. Trans. R. Soc. Trop. Med. Hyg. 82, 469–471 (1988).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Viana, S., Paraná, R., Moreira, R. C., Compri, A. P. & Macedo, V. High prevalence of hepatitis B virus and hepatitis D virus in the western Brazilian Amazon. Am. J. Trop. Med. Hyg. 73, 808–814 (2005).

    Article  PubMed  Google Scholar 

  97. 97

    Fattovich, G., Bortolotti, F. & Donato, F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J. Hepatol. 48, 335–352 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Fattovich, G. 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 46, 420–426 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Rosenblum, L. et al. Sexual practices in the transmission of hepatitis B virus and prevalence of hepatitis delta virus infection in female prostitutes in the United States. JAMA 267, 2477–2481 (1992).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Wu, J. C. et al. Evidence of transmission of hepatitis D virus to spouses from sequence analysis of the viral genome. Hepatology 22, 1656–1660 (1995).

    CAS  PubMed  Google Scholar 

  101. 101

    François-Souquière, S., Makuwa, M., Bisvigou, U. & Kazanji, M. Epidemiological and molecular features of hepatitis B and hepatitis delta virus transmission in a remote rural community in central Africa. Infect. Genet. Evol. 39, 12–21 (2016).

    Article  PubMed  Google Scholar 

  102. 102

    Niro, G. A. et al. Intrafamilial transmission of hepatitis delta virus: molecular evidence. J. Hepatol. 30, 564–569 (1999).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Ramia, S. & Bahakim, H. Perinatal transmission of hepatitis B virus-associated hepatitis D virus. Ann. Inst. Pasteur Virol. 139, 285–290 (1988).

    Article  CAS  PubMed  Google Scholar 

  104. 104

    Yurdaydin, C., Idilman, R., Bozkaya, H. & Bozdayi, A. M. Natural history and treatment of chronic delta hepatitis. J. Viral Hepat. 17, 749–756 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Negro, F. Hepatitis D virus coinfection and superinfection. Cold Spring Harb. Perspect. Med. 4, a021550 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Guilhot, S. et al. Expression of the hepatitis delta virus large and small antigens in transgenic mice. J. Virol. 68, 1052–1058 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Verme, G. et al. A histological study of hepatitis delta virus liver disease. Hepatology 6, 1303–1307 (1986).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Pugnale, P., Pazienza, V., Guilloux, K. & Negro, F. Hepatitis delta virus inhibits alpha interferon signaling. Hepatology 49, 398–406 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Lunemann, S. et al. Effects of HDV infection and pegylated interferon α treatment on the natural killer cell compartment in chronically infected individuals. Gut 64, 469–482 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. 110

    Lunemann, S. et al. Compromised function of natural killer cells in acute and chronic viral hepatitis. J. Infect. Dis. 209, 1362–1373 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Nisini, R. et al. Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles. J. Virol. 71, 2241–2251 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Grabowski, J. et al. Hepatitis D virus-specific cytokine responses in patients with chronic hepatitis delta before and during interferon alfa-treatment. Liver Int. 31, 1395–1405 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Su, C. W. et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology 130, 1625–1635 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Casey, J. L. et al. Hepatitis B virus (HBV)/hepatitis D virus (HDV) coinfection in outbreaks of acute hepatitis in the Peruvian Amazon basin: the roles of HDV genotype III and HBV genotype F. J. Infect. Dis. 174, 920–926 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Gomes-Gouvea, M. S. et al. Hepatitis B virus and hepatitis delta virus genotypes in outbreaks of fulminant hepatitis (Labrea black fever) in the western Brazilian Amazon region. J. Gen. Virol. 90, 2638–2643 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Lee, C. M., Bih, F. Y., Chao, Y. C., Govindarajan, S. & Lai, M. M. Evolution of hepatitis delta virus RNA during chronic infection. Virology 188, 265–273 (1992).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Rizzetto, M. et al. Treatment of chronic delta hepatitis with alpha-2 recombinant interferon. J. Hepatol. 3, S229–S233 (1986).

    Article  PubMed  Google Scholar 

  118. 118

    Hughes, S. A., Wedemeyer, H. & Harrison, P. M. Hepatitis delta virus. Lancet 378, 73–85 (2011).

    Article  PubMed  Google Scholar 

  119. 119

    Wranke, A., Heidrich, B., Hardtke, S. & Wedemeyer, H. Current management of HBV/HDV coinfection and future perspectives. Curr. Hepatol. Rep. 14, 284–292 (2015).

    Article  Google Scholar 

  120. 120

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

    Article  CAS  PubMed  Google Scholar 

  121. 121

    Heidrich, B. et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology 60, 87–97 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Wedemeyer, H. et al. Prolonged therapy of hepatitis delta for 96 weeks with PEG-IFNa-2a plus tenofovir or placebo does not prevent HDV RNA relapse: the HIDIT-2 study. Presented at the International Liver Congress 2014 http://hepatitis-delta.org/assets/DownloadPage/000000/2014-04-HIDIT-II-EASL-Homepage.pdf (2014).

  123. 123

    Wedemeyer, H. et al. Prolonged therapy of hepatitis delta for 96 weeks with pegylated-interferon-α-2a plus tenofovir or placebo does not prevent HDV RNA relapse: the HIDIT-2 study [abstract]. J. Hepatol. 60, S2–S3 (2014).

    Article  Google Scholar 

  124. 124

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Yen, L., Magnier, M., Weissleder, R., Stockwell, B. R. & Mulligan, R. C. Identification of inhibitors of ribozyme self-cleavage in mammalian cells via high-throughput screening of chemical libraries. RNA 12, 797–806 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    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  PubMed  PubMed Central  Google Scholar 

  127. 127

    Wooddell, C. I. et al. Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection. Mol. Ther. 21, 973–985 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Yuen, M. F. et al. ARC-520 produces deep and durable knockdown of viral antigens and DNA in a phase II study in patients with chronic hepatitis B [abstract LB-9]. Hepatology 62, 1385A (2015).

    Google Scholar 

  129. 129

    Meier, A., Mehrle, S., Weiss, T. S., Mier, W. & Urban, S. Myristoylated PreS1-domain of the hepatitis B virus L-protein mediates specific binding to differentiated hepatocytes. Hepatology 58, 31–42 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. 130

    Schieck, A. et al. Hepatitis B virus hepatotropism is mediated by specific receptor recognition in the liver and not restricted to susceptible hosts. Hepatology 58, 43–53 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Koh, C. et al. 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, 1167–1174 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Yurdaydin, C. et al. Optimizing the prenylation inhibitor lonafarnib using ritonavir boosting in patients with chronic delta hepatitis [oral presentation O118]. J. Hepatol. 62 (Suppl. 2), S252 (2015).

    Article  Google Scholar 

  133. 133

    Koh, C. et al. Prenylation inhibition with lonafarnib decreases hepatitis D levels in humans [poster 1860]. Hepatology 60, 1092A (2014).

    Google Scholar 

  134. 134

    Bazinet, M. et al. REP 2139 monotherapy and combination therapy with pegylated interferon: safety and potent reduction of HBsAg and HDV RNA in Caucasian patients with chronic HBV/HDV co-infection [oral presentation HDV2 O-09]. J. Viral Hepat. 22, 5–6 (2015).

    Google Scholar 

  135. 135

    Poutay, D. et al. Nucleic acid polymers are efficient in blocking hepatitis delta virus entry in vitro [poster P177]. J. Viral Hepat. 22, 107 (2015).

    Google Scholar 

  136. 136

    Bazinet, M. et al. Update on the safety and efficacy of REP 2139 mono-therapy and subsequent combination therapy with pegylated interferon alpha-2a in chronic HBV/HDV co-infection in Caucasian patients [abstract]. Hepatology 62, 222A (2015).

    Article  Google Scholar 

  137. 137

    Bogomolov, P. et al. A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B [abstract]. Hepatology 60, 1279A–1280A (2014).

    Google Scholar 

  138. 138

    Blank, A. et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor Myrcludex B. J. Hepatol. http://dx.doi.org/10.1016/j.jhep.2016.04.013 (2016).

  139. 139

    Bogomolov, P. et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J. Hepatol. http://dx.doi.org/10.1016/j.jhep.2016.04.016 (2016).

  140. 140

    Yust-Katz, S. et al. Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma. Cancer 119, 2747–2753 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Rizzetto, M. & Ciancio, A. The prenylation inhibitor, lonafarnib: a new therapeutic strategy against hepatitis delta. Lancet Infect. Dis. 15, 1119–1120 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. 142

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    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  PubMed  PubMed Central  Google Scholar 

  144. 144

    Berndt, N., Hamilton, A. D. & Sebti, S. M. Targeting protein prenylation for cancer therapy. Nat. Rev. Cancer 11, 775–791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Palsuledesai, C. C. & Distefano, M. D. Protein prenylation: enzymes, therapeutics, and biotechnology applications. ACS Chem. Biol. 10, 51–62 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. 146

    Offensperger, W. B., Offensperger, S., Walter, E., Blum, H. E. & Gerok, W. Suramin prevents duck hepatitis B virus infection in vivo. Antimicrob. Agents Chemother. 37, 1539–1542 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Poutay, D. et al. Nucleic acid polymers are efficient in blocking hepatitis delta virus entry in vitro [abstract LP26]. J. Hepatol. 62 (Suppl. 2), S276 (2015).

    Article  Google Scholar 

  148. 148

    Replicor. Conference presentations http://replicor.com/wp-content/uploads/2016/05/Poster-FRI-105-EASL-2016.pdf (2016).

  149. 149

    Gripon, P., Cannie, I. & Urban, S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J. Virol. 79, 1613–1622 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Petersen, J. et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat. Biotechnol. 26, 335–341 (2008).

    Article  CAS  PubMed  Google Scholar 

  151. 151

    Schulze, A., Schieck, A., Ni, Y., Mier, W. & Urban, S. Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction. J. Virol. 84, 1989–2000 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. 152

    Nkongolo, S. et al. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J. Hepatol. 60, 723–731 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Haag, M. et al. Quantitative bile acid profiling by liquid chromatography quadrupole time-of-flight mass spectrometry: monitoring hepatitis B therapy by a novel Na+-taurocholate cotransporting polypeptide inhibitor. Anal. Bioanal. Chem. 407, 6815–6825 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    Slijepcevic, D. et al. Impaired uptake of conjugated bile acids and hepatitis B virus preS1-binding in Na+-taurocholate cotransporting polypeptide knockout mice. Hepatology 62, 207–219 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Vaz, F. M. et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology 61, 260–267 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. 156

    Makino, S. et al. Molecular cloning and sequencing of a human hepatitis delta (δ) virus RNA. Nature 329, 343–346 (1987).

    Article  CAS  PubMed  Google Scholar 

  157. 157

    Nassal, M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64, 1972–1984 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

F.A.L. has received research grants from the German Center for Infection Research (DZIF) (TTU 05.901, TTU 05.804, TTU 05.904, TTU 05.704), the German Research Foundation (UR72/ 7–1) and the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology. Y.N. has received research grants from the German Center for Infection Research (DZIF) (TTU 05.901, TTU 05.804, TTU 05.904, TTU 05.704). S.U. has received research grants from the German Center for Infection Research (DZIF) (TTU 05.901, TTU 05.804, TTU 05.904, TTU 05.704) and the German Research Foundation (UR72/ 7–1).

Author information

Affiliations

Authors

Contributions

F.A.L. and S.U. researched data for the article. Y.N. prepared the figures. All authors provided substantial contribution to discussion of content and writing of the article. S.U. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Stephan Urban.

Ethics declarations

Competing interests

S.U. is co-applicant and co-inventor of patents protecting Myrcludex B. S.U. is also a consultant for Gilead and Humabs BioMed SA. F.A.L. and Y.N. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lempp, F., Ni, Y. & Urban, S. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol 13, 580–589 (2016). https://doi.org/10.1038/nrgastro.2016.126

Download citation

Further reading

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