title: New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus.
abstract: Current therapies of chronic hepatitis B (CHB) remain limited to pegylated-interferon-alpha (PegIFN-α) or any of the five approved nucleos(t)ide analogues (NUC) treatments. While viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of NUC, i.e. entecavir and tenofovir, HBsAg loss is achieved by PegIFN-α and/or NUC in only 10% of patients, after a 5-year follow-up. Attempts to improve the response by administering two different NUC or a combination of NUC and PegIFN-α have not provided a dramatic increase in the rate of functional cure. Because of this and the need of long-term NUC administration, there is a renewed interest regarding the understanding of various steps of the HBV replication cycle, as well as specific virus-host cell interactions, in order to define new targets and develop new antiviral drugs. This includes a direct inhibition of viral replication with entry inhibitors, drugs targeting cccDNA, siRNA targeting viral transcripts, capsid assembly modulators, and approaches targeting the secretion of viral envelope proteins. Restoration of immune responses is a complementary approach. The restoration of innate immunity against HBV can be achieved, with TLR agonists or specific antiviral cytokine delivery. Restoration of adaptive immunity may be achieved with inhibitors of negative checkpoint regulators, therapeutic vaccines, or autologous transfer of engineered HBV-specific T cells. Novel targets and compounds will readily be evaluated using both relevant and novel in vitro and in vivo models of HBV infection. The addition of one or several new drugs to current therapies should offer the prospect of a markedly improved response to treatments and an increased rate of functional cure. This should lead to a reduced risk of antiviral drug resistance, and to a decreased incidence of cirrhosis and hepatocellular carcinoma (HCC).
authors.affiliation: INSERM, U1052, Lyon 69003, France; Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.affiliation: INSERM, U1052, Lyon 69003, France; Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France; Institut Universitaire de France (IUF), 75005 Paris, France. Electronic address: fabien.zoulim@inserm.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D003698:Hepatitis Delta Virus / Q000502:physiology*; D006801:Humans; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents
keywords: Direct acting antivirals (DAA); Hepatitis B virus; Host-targeting antivirals (HTA); Immunotherapy; Viral targets