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The scientific basis of combination therapy for chronic hepatitis B functional cure

Nature Reviews Gastroenterology & Hepatology volume 20, pages 238–253 (2023)Cite this article

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Abstract

Functional cure of chronic hepatitis B (CHB) — or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy — is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available.

Key points

  • Functional cure is defined as loss of hepatitis B surface antigen (HBsAg) and undetectable hepatitis B virus (HBV) DNA after 6 months off therapy; it is associated with improved clinical outcomes and is the optimal goal of therapy for chronic hepatitis B.

  • Novel agents fall into three categories: those that reduce viral replication, those that reduce viral antigen load and immunotherapies; combinations that lead to functional cure are being explored.

  • Profound viral suppression alone is unlikely to lead to functional cure or reduction in quantitative (q)HBsAg levels.

  • Combining replication inhibition with immunotherapy leads to some reduction in qHBsAg levels (<1 log) and HBsAg loss, usually in patients with low baseline qHBsAg levels.

  • Reducing viral antigen production reduces qHBsAg levels by up to 3 log, which might be sustained off therapy, and in combination with replication inhibitors or immunotherapy can achieve HBsAg loss in some instances, although not all are sustained.

  • More than one path to functional cure is likely to exist, and finding the optimal one for each patient is the challenge.

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Fig. 1: Schematic diagram of HBV life cycle showing the two overlapping pathways (secretory and replicative) and potential strategies for antiviral therapy, including reducing viral replication and reducing antigen burden.
Fig. 2: Immune pathways in HBV and strategies to activate host immunity.

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Acknowledgements

The authors thank Y. C. Tan for his assistance in retrieving references and creating tables of the therapeutic agents and G. Ligat for assistance in drafting the figures. S.G.L. acknowledges the following grant support: NMRC grant NMRC/TCR/014-NUHS/2015, NMRC/CIRG/1351/2013, NMRC/CSA-SI/0016/2017, NMRC/CIRG/1479/2017 and NMRC/OFLCG19May-0038. T.F.B. acknowledges the following grant support: European Union (EU H2020-HEPCAR #667273, ERC-AdG-2020-FIBCAN #101021417), the French Cancer Agency (TheraHCC2.0 IHU201901299), the ANRS (ECTZ103701, 131760, 104017, ECTZ75178), Inserm Plan Cancer 2019–2023, IdEx Unistra (ANR-10-IDEX-0002), SFRI-STRAT’US (ANR 20-SFRI-0012) and EUR IMCBio (ANR-17-EURE-0023) under the framework of the French ‘Investments for the Future’ programme. F.Z. and M.L. acknowledge the support of French National Research Agency (ANR) Program Investissements d’Avenir (cirB-RNA project – ANR-17-RHUS-0003); the European Union H2020 grant EU H2020-847939-IP-cure-B.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Seng Gee Lim

  2. Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, Laboratoire d’Excellence HepSYS, Service d’Hépato-gastroénterologie, Pôle Hépato-digestif, IHU Strasbourg, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France

    Thomas F. Baumert

  3. Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

    Carolina Boni

  4. New Zealand Liver Transplant Unit, Auckland City Hospital, University of Auckland, Auckland, New Zealand

    Ed Gane

  5. Epigenetics, Microenvironment and Liver Cancer Laboratory of INSERM Unit 1052, Institute of Hepatology, Hepatology Department, Hospices Civils de Lyon, University of Lyon, Lyon, France

    Massimo Levrero

  6. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    Anna S. Lok

  7. Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK

    Mala K. Maini

  8. Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Norah A. Terrault

  9. Viral Hepatitis Research Laboratory of INSERM Unit 1052, Institute of Hepatology, Hepatology Department, Hospices Civils de Lyon, University of Lyon, Lyon, France

    Fabien Zoulim

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All authors contributed to researching data for the article, discussion of content, writing, and reviewing and editing the manuscript.

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Correspondence to Seng Gee Lim.

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Competing interests

S.G.L. is on the advisory board for Gilead Sciences, Abbott, Roche, Janssen, GlaxoSmithKline (GSK), Grifols, Arbutus, Assembly. He is on the speakers’ bureau for Gilead Sciences, Abbott GSK, Roche and Janssen, and receives educational/research funding from Abbott, Merck Sharpe and Dohme (MSD), Gilead Sciences. T.F.B. is a founder, shareholder and adviser for Alentis Therapeutics. He receives Institutional grant support from Aligos, Janssen, Alentis, Roche. C.B. is a consultant and on the advisory board for Gilead Sciences. E.G. is on the advisory board for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Avalia Immunotherapies, BlueJay Therapeutics, Brii Biosciences, Clear B Therapeutics, Dicerna Pharmaceuticals, Enanta Pharmaceuticals, Finch Therapeutics, Gilead Sciences, GSK, Immunocore, Janssen, Roche, Silverback, Vaccitech, Benatorx, Virion Therapeutics and Vir Biotechnology. He is on the speakers’ bureau for Gilead Sciences, AbbVie, Abbott Diagnostics, Intellia and Roche. M.L. receives educational/research funding from AbbVie, Gilead, MSD, Roche, Bayer, Ipsen. A.L. receives research grants from Gilead, Target. M.K.M. is on the advisory board for Gilead Sciences, Roche, GSK, Vir Biotechnology and receives research funding from Gilead Sciences. N.T. is on the consulting/advisory boards for Moderna; she receives Institutional grant support from Gilead Sciences, GSK, Roche–Genentech and Helio Health. F.Z. acts as a consultant for Aligos, Antios, Arbutus, Assembly, Enanta, Gilead, GSK, Roche, Viravaxx, Zhimeng; he receives research grants from Assembly, Beam, Janssen, Viravaxx.

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Lim, S.G., Baumert, T.F., Boni, C. et al. The scientific basis of combination therapy for chronic hepatitis B functional cure. Nat Rev Gastroenterol Hepatol 20, 238–253 (2023). https://doi.org/10.1038/s41575-022-00724-5

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