Hepatitis B virus (HBV) is a non-cytopathic, hepatotropic virus with the potential to cause a persistent infection, ultimately leading to cirrhosis and hepatocellular carcinoma. Over the past four decades, the basic principles of HBV gene expression and replication as well as the viral and host determinants governing infection outcome have been largely uncovered. Whereas HBV appears to induce little or no innate immune activation, the adaptive immune response mediates both viral clearance as well as liver disease. Here, we review our current knowledge on the immunobiology and pathogenesis of HBV infection, focusing in particular on the role of CD8+ T cells and on several recent breakthroughs that challenge current dogmas. For example, we now trust that HBV integration into the host genome often serves as a relevant source of hepatitis B surface antigen (HBsAg) expression during chronic infection, possibly triggering dysfunctional T cell responses and favouring detrimental immunopathology. Further, the unique haemodynamics and anatomy of the liver - and the changes they frequently endure during disease progression to liver fibrosis and cirrhosis - profoundly influence T cell priming, differentiation and function. We also discuss why therapeutic approaches that limit the intrahepatic inflammatory processes triggered by HBV-specific T cells might be surprisingly beneficial for patients with chronic infection.

Immunobiology and pathogenesis of hepatitis B virus infection.

The global burden of viral hepatitis is substantial; in terms of mortality, hepatitis B virus and hepatitis C virus infections are on a par with HIV, malaria and tuberculosis, among the top four global infectious diseases. In 2016, the 194 Member States of the World Health Organization committed to eliminating viral hepatitis as a public health threat by 2030, with a particular focus on hepatitis B virus and hepatitis C virus infection. With only 10 years to go until the 2030 deadline is reached, and although much progress has been made towards elimination, there are still some important gaps in terms of policy and progress. In this Viewpoint, we asked a selection of scientists and clinicians working in the viral hepatitis field for their opinions on whether elimination of viral hepatitis by 2030 is feasible, what the key areas of progress are and what the focus for the next 10 years and beyond should be for viral hepatitis elimination. Viral hepatitis is a global public health problem. In this Viewpoint, we asked a selection of scientists and clinicians working in the viral hepatitis field to provide their opinions on progress and pitfalls towards the 2030 viral hepatitis elimination goals. Andrea L. Cox is currently a Professor of Medicine, Oncology, and Immunology at The Johns Hopkins University School of Medicine, USA. Her research and clinical interests focus on hepatitis C virus, hepatitis B virus and HIV, including mechanisms through which these chronic viral infections stimulate and evade immune responses. Manal H. El-Sayed is Professor of Paediatrics and director of the Clinical Research Centre at the Faculty of Medicine, Ain Shams University. She is a founding member of the Egyptian National Committee for Control of Viral Hepatitis since 2006. She is the secretary general of the Egyptian Liver Care Society (NGO) and board member of the EASL International Liver Foundation. Jia-Horng Kao is the Chair Professor of the Graduate Institute of Clinical Medicine at the National Taiwan University, Taipei, Taiwan. He has published more than 550 articles on the prevention, natural history, molecular virology, pathogenesis and treatment of chronic viral hepatitis and liver cancer. He is currently the Steering Council member of The Asian Pacific Association for the Study of the Liver (APASL). Jeffrey V. Lazarus is head of the Health Systems and Infectious Diseases team at the Barcelona Institute for Global Health (ISGlobal) and an Associate Professor at the Faculty of Medicine, University of Barcelona, Spain. He is Vice-Chairman of the board of the EASL International Liver Foundation, where he leads the work on the microelimination of hepatitis C. Maud Lemoine is Professor and Honorary Consultant in Hepatology at Imperial College London, UK. Her research interests are mainly related to viral hepatitis in resource-limited countries, where she developed expertise on screening and management of patients with viral hepatitis. She is the head of the PROLIFICA
 (Prevention of Liver Fibrosis and Cancer in Africa) programme and the chief investigator and co-investigator of several studies and interventions on the prevention and management of viral hepatitis B and C in West and East Africa. Anna S. Lok is a Professor of Internal Medicine, Director of Clinical Hepatology, and Assistant Dean for Clinical Research at the University of Michigan, USA. She has published more than 550 articles on viral hepatitis and liver diseases including five editions of the American Association for the Study of Liver Diseases guidelines on hepatitis B and the first edition of the World Health Organization guidelines on hepatitis B. Fabien Zoulim is Professor of Medicine at Lyon University, Head of the Hepatology Department at the Hospices Civils de Lyon, and Head of the Viral Hepatitis Research Laboratory at INSERM U1052, France. He is currently coordinating the ANRS “HBV cure” programme in France and the “IP-cure-B” project funded by the EU H2020 work programme. He co-founded the International Coalition to Eliminate HBV
 (ICE-HBV).

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Progress towards elimination goals for viral hepatitis

Hepatitis B surface antigen seroclearance: Immune mechanisms, clinical impact, importance for drug development.

https://research-information.bris.ac.uk/ws/files/235038973/Impact_of_HBsAg_Gastro_Apr_3_no_mark.pdf

Effects of Hepatitis B Surface Antigen on Virus-Specific and Global T Cells in Patients With Chronic Hepatitis B Virus infection

Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential

Chronic hepatitis B virus (HBV) infection is a common cause of liver disease globally, with a disproportionately high burden in South-East Asia. Vaccines and nucleoside or nucleotide drugs are available and reduce both new infection rates and the development of liver disease in HBV-positive persons who adhere to long-term suppressive treatment. Although there is still considerable value in optimizing access to virus-suppressing regimens, the scientific and medical communities have embarked on a concerted journey to identify new antiviral drugs and immune interventions aimed at curing infection. The mechanisms and drug targets being explored are diverse; however, the field universally recognizes the importance of addressing the persistence of episomal covalently closed circular DNA, the existence of integrated HBV DNA in the host genome and the large antigen load, particularly of hepatitis B surface antigen. Another major challenge is to reinvigorate the exhausted immune response within the liver microenvironment. Ultimately, combinations of new drugs will be required to cure infection. Here we critically review the recent literature that describes the rationale for curative therapies and the resulting compounds that are being tested in clinical trials for hepatitis B.

Therapeutic strategies for hepatitis B virus infection: towards a cure

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

/pdf/author-correction-therapeutic-strategies-for-hepatitis-b-4aanajkvku.pdf

Jinlin Hou

Papers

Therapeutic strategies for hepatitis B virus infection: towards a cure

Author Correction: Therapeutic strategies for hepatitis B virus infection: towards a cure.