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
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.
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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).
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.
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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
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