A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook

Kramvis, Anna; Chang, Kyong-Mi; Dandri, Maura; Farci, Patrizia; Glebe, Dieter; Hu, Jianming; Janssen, Harry L. A.; Lau, Daryl T.-Y.; Pénicaud, Capucine; Pollicino, Teresa; Testoni, Barbara; van Bömmel, Florian; Andrisani, Ourania M.; Beumont-Mauviel, Maria; Block, Timothy M.; Chan, Henry L Y; Cloherty, Gavin A; Delaney, William E; Geretti, Anna Maria; Gehring, Adam J.; Jackson, Kathy; Lenz, Oliver; Maini, Mala K.; Miller, Veronica; Protzer, Ulrike; Yang, Jenny C.; Yuen, Man-Fung; Zoulim, Fabien; Revill, Peter A

doi:10.1038/s41575-022-00649-z

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A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook

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Author(s): Anna Kramvis ¹ ^, , Kyong-Mi Chang ² , Maura Dandri ³ ^, ⁴ , Patrizia Farci ⁵ , Dieter Glebe ⁶ ^, ⁷ , Jianming Hu ⁸ , Harry L. A. Janssen ⁹ , Daryl T. Y. Lau ¹⁰ , Capucine Penicaud ¹¹ , Teresa Pollicino ¹² , Barbara Testoni ¹³ ^, ¹⁴ , Florian Van Bömmel ¹⁵ , Ourania Andrisani ¹⁶ , Maria Beumont-Mauviel ¹⁷ , Timothy M. Block ¹⁸ , Henry L. Y. Chan ¹⁹ ^, ²⁰ , Gavin A. Cloherty ²¹ , William E. Delaney ²² , Anna Maria Geretti ²³ ^, ²⁴ ^, ²⁵ , Adam Gehring ²⁶ , Kathy Jackson ²⁷ , Oliver Lenz ²⁸ , Mala K. Maini ²⁹ , Veronica Miller ³⁰ , Ulrike Protzer ³¹ , Jenny C. Yang ³² , Man-Fung Yuen ³³ ^, ³⁴ , Fabien Zoulim ³⁵ , Peter A. Revill ²⁷ ^, ³⁶ ^,

Publication date (Electronic): 20 July 2022

Journal: Nature Reviews. Gastroenterology & Hepatology

Publisher: Nature Publishing Group UK

Keywords: Prognostic markers, Diagnostic markers

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Abstract

Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies. Currently, only a few biomarkers are available for monitoring or predicting HBV disease progression and treatment response. As new therapies become available, new biomarkers to monitor viral and host responses are urgently needed. In October 2020, the International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) held a virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. Various stakeholders from academia, clinical practice and the pharmaceutical industry, with complementary expertise, presented and participated in panel discussions. The clinical utility of both classic and emerging viral and immunological serum biomarkers with respect to the course of infection, disease progression, and response to current and emerging treatments was appraised. The latest advances were discussed, and knowledge gaps in understanding and interpretation of HBV biomarkers were identified. This Roadmap summarizes the strengths, weaknesses, opportunities and challenges of HBV biomarkers.

Abstract

Currently, there is no cure for hepatitis B virus (HBV) infection, which can lead to chronic liver disease and liver cancer, and only a few biomarkers are available. This Roadmap provides an overview of HBV serum biomarkers and their challenges.

Key points

As new therapies for hepatitis B virus (HBV) infection become available, new biomarkers to monitor viral and host responses are urgently needed.
This Roadmap summarizes current knowledge on existing and emerging serum biomarkers in the context of chronic HBV infection.
This Roadmap discusses the strengths, weaknesses, opportunities and challenges of serum HBV biomarkers.
This Roadmap provides suggestions of the way forward to advance the biomarkers required to fast-track an HBV cure for all, irrespective of resources, HBV genotype or disease stage.

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Most cited references 215

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Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

Alba Grifoni, Daniela Weiskopf, Sydney Ramirez … (2020)

Summary Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.

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Hepatocellular carcinoma

Josep Llovet, Robin Kate Kelley, Augusto Villanueva … (2021)

Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.

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EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.

Pietro Lampertico, Kosh Agarwal, Thomas Berg … (2017)

Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2,000IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother to child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa treatment can also be considered in mild to moderate chronic hepatitis B patients. Combination therapies are not generally recommended. All treated and untreated patients should be monitored for treatment response and adherence, and the risk of progression and development of complications. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.

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Author and article information

Contributors

Anna Kramvis: Anna.Kramvis@wits.ac.za

Peter A. Revill:

ORCID: http://orcid.org/0000-0003-2715-2541

peter.revill@vidrl.org.au

Journal

Journal ID (nlm-ta): Nat Rev Gastroenterol Hepatol

Journal ID (iso-abbrev): Nat Rev Gastroenterol Hepatol

Title: Nature Reviews. Gastroenterology & Hepatology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1759-5045

ISSN (Electronic): 1759-5053

Publication date (Electronic): 20 July 2022

Pages: 1-19

Affiliations

[1 ]GRID grid.11951.3d, ISNI 0000 0004 1937 1135, Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, , University of the Witwatersrand, ; Johannesburg, South Africa

[2 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, The Corporal Michael J. Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, ; Philadelphia, PA USA

[3 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Internal Medicine, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[4 ]GRID grid.452463.2, German Centre for Infection Research (DZIF), , Hamburg-Lübeck-Borstel-Riems partner site, ; Hamburg, Germany

[5 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

[6 ]GRID grid.8664.c, ISNI 0000 0001 2165 8627, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, , Justus Liebig University Giessen, ; Giessen, Germany

[7 ]GRID grid.452463.2, German Center for Infection Research (DZIF), , Partner Site Giessen-Marburg-Langen, ; Giessen, Germany

[8 ]GRID grid.29857.31, ISNI 0000 0001 2097 4281, Department of Microbiology and Immunology, , The Pennsylvania State University College of Medicine, ; Philadelphia, PA USA

[9 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Toronto Centre for Liver Disease, , University of Toronto, ; Toronto, Canada

[10 ]GRID grid.38142.3c, ISNI 000000041936754X, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, , Harvard Medical School, ; Boston, Massachusetts USA

[11 ]GRID grid.483778.7, Peter Doherty Institute for Infection and Immunity, ; Melbourne, Australia

[12 ]GRID grid.412507.5, ISNI 0000 0004 1773 5724, Laboratory of Molecular Hepatology, Department of Human Pathology, , University Hospital “G. Martino” of Messina, ; Messina, Italy

[13 ]GRID grid.462282.8, ISNI 0000 0004 0384 0005, INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), ; Lyon, France

[14 ]GRID grid.25697.3f, ISNI 0000 0001 2172 4233, University of Lyon, Université Claude-Bernard (UCBL), ; Lyon, France

[15 ]GRID grid.9647.c, ISNI 0000 0004 7669 9786, Department of Hepatology, , Leipzig University Medical Center, ; Leipzig, Germany

[16 ]GRID grid.169077.e, ISNI 0000 0004 1937 2197, Basic Medical Sciences, , Purdue University, ; West Lafayette, Indiana USA

[17 ]GRID grid.497530.c, ISNI 0000 0004 0389 4927, Janssen Infectious Diseases, Janssen, ; Titusville, USA

[18 ]GRID grid.429056.c, Baruch S. Blumberg Institute, ; Doylestown, Pennsylvania USA

[19 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Chinese University of Hong Kong, ; Shatin, Hong Kong

[20 ]GRID grid.460848.6, ISNI 0000 0004 0523 085X, Union Hospital, ; Shatin, Hong Kong

[21 ]GRID grid.417574.4, ISNI 0000 0004 0366 7505, ID Core Research, Abbott Laboratories, ; Abbott Park, IL USA

[22 ]Assembly Bio, South San Francisco, San Francisco, CA USA

[23 ]GRID grid.417570.0, ISNI 0000 0004 0374 1269, Roche Pharma Research & Early Development, ; Basel, Switzerland

[24 ]GRID grid.6530.0, ISNI 0000 0001 2300 0941, Department of Infectious Diseases, Fondazione PTV, Faculty of Medicine, , University of Rome Tor Vergata, ; Rome, Italy

[25 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Infectious Diseases, School of Immunology & Microbial Sciences, , King’s College London, ; London, UK

[26 ]GRID grid.231844.8, ISNI 0000 0004 0474 0428, Toronto Centre for Liver Disease, , University Health Network, ; Toronto, Canada

[27 ]GRID grid.416153.4, ISNI 0000 0004 0624 1200, Victorian Infectious Diseases Reference Laboratory, , Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, ; Melbourne, Australia

[28 ]GRID grid.419619.2, ISNI 0000 0004 0623 0341, Janssen Pharmaceutica, ; Beerse, Belgium

[29 ]GRID grid.83440.3b, ISNI 0000000121901201, Division of Infection & Immunity, Institute of Immunity & Transplantation, , University College London, ; London, UK

[30 ]GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Forum for Collaborative Research, , University of California Berkeley School of Public Health, Washington DC Campus, ; Washington, DC USA

[31 ]Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany

[32 ]GRID grid.418227.a, ISNI 0000 0004 0402 1634, Gilead Sciences, ; Foster City, CA USA

[33 ]GRID grid.194645.b, ISNI 0000000121742757, Department of Medicine, Queen Mary Hospital, , The University of Hong Kong, ; Hong Kong, China

[34 ]GRID grid.194645.b, ISNI 0000000121742757, State Key Laboratory of Liver Research, , The University of Hong Kong, ; Hong Kong, China

[35 ]GRID grid.25697.3f, ISNI 0000 0001 2172 4233, INSERM Unit 1052 – Cancer Research Center of Lyon, Hospices Civils de Lyon, , Lyon University, ; Lyon, France

[36 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Microbiology and Immunology, , University of Melbourne, ; Parkville, Victoria Australia

Author information

Kyong-Mi Chang http://orcid.org/0000-0001-6811-9364

Dieter Glebe http://orcid.org/0000-0001-5039-0252

Capucine Penicaud http://orcid.org/0000-0002-2708-8773

Teresa Pollicino http://orcid.org/0000-0001-6602-3035

Barbara Testoni http://orcid.org/0000-0001-5588-5465

Adam Gehring http://orcid.org/0000-0003-1150-5840

Mala K. Maini http://orcid.org/0000-0001-6384-1462

Ulrike Protzer http://orcid.org/0000-0002-9421-1911

Fabien Zoulim http://orcid.org/0000-0002-2245-0083

Peter A. Revill http://orcid.org/0000-0003-2715-2541

Article

Publisher ID: 649

DOI: 10.1038/s41575-022-00649-z

PMC ID: 9298709

PubMed ID: 35859026

SO-VID: 215c76f7-cc5b-4e0d-8f7b-d2b60fdfc067

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 215

Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

Hepatocellular carcinoma

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.

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