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New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus

  • Author Footnotes
    † These author contributed equally.
    David Durantel
    Footnotes
    † These author contributed equally.
    Affiliations
    INSERM, U1052, Lyon 69003, France

    Cancer Research Center of Lyon (CRCL), Lyon 69008, France

    University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France
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  • Author Footnotes
    † These author contributed equally.
    Fabien Zoulim
    Correspondence
    Corresponding author. Address: Centre de Recherche en Cancérologie de Lyon (CRCL), UMR INSERM U1052 – CNRS 5286, 151 cours Albert Thomas, 69424 Lyon Cedex 03, France. Tel.: +33 4 72 68 19 70; fax: +33 4 72 68 19 71.
    Footnotes
    † These author contributed equally.
    Affiliations
    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
    Search for articles by this author
  • Author Footnotes
    † These author contributed equally.

      Summary

      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).

      Abbreviations:

      CHB (chronic hepatitis B), NUC (nucleos(t)ide analogues), PegIFN-α (pegylated-interferon-alpha), cccDNA (covalently-closed-circular DNA), siRNA or RNAi (small interfering RNA), HBV (hepatitis B virus), TLR (toll-like receptor, HCC, hepatocellular carcinoma), WHO (world health organization), IFN (interferon), HBsAg (small envelope protein antigen), pgRNA (pregenomic RNA), HDV (hepatitis delta virus), CHD (chronic hepatitis D), DAA (direct acting antiviral), HTA (host-targeting antiviral), HBpol (HBV polymerase), TP (terminal protein domain), RT domain (reverse transcription domain), RNAse H (ribonuclease H), rcDNA (relaxed-circular DNA), TAF (tenofovir alafenamide fumarate), TDF (tenofovir disoproxil fumarate), HBc or Cp (core proteins), CpAM (core protein allosteric modulator), ETV (entecavir), cIAP (cellular inhibitors of apoptosis proteins), NK (natural killer), NKT (natural killer T cell), SVR (sustained virologic response), pDC (plasmacytoid dendritic cell), PRR (pathogen recognition receptor), RLR (RIG-like receptor), NLR (NOD-like receptor), IFN (interferon), TAM (tumor-associated macrophages), TCR (T cell receptor), CAR (chimeric antigen receptor), WHV (Woodchuck hepatitis virus)

      Keywords

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