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Review
. 2022 Nov;19(11):727-745.
doi: 10.1038/s41575-022-00649-z. Epub 2022 Jul 20.

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

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  36   37
Affiliations
Review

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

Anna Kramvis et al. Nat Rev Gastroenterol Hepatol. 2022 Nov.

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.

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Conflict of interest statement

A.K. is a recipient of a grant from the Cancer Association of South Africa (CANSA). K.M.C. is supported by the Corporal Michael J. Crescenz VA Medical Center Research Program in Philadelphia, Pennsylvania 19104, USA and has served in the Scientific Advisory Committee for Arbutus Biopharma. M.D. is supported by the German Research Foundation (DFG; SFB841), the German Center for Infection Research (DZIF) and the Dandri lab has received collaborative funding from Gilead Sciences and MYR-GmbH. P.F. has nothing to declare and is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MA, USA. D.G. is supported by the German Research Foundation (DFG; SFB1021), the German Center for Infection Research (DZIF), the Robert Koch Institute, Berlin and the German Federal Ministry of Health. J.H. has been supported by funding from the National Institute of Allergy and Infectious Disease/NIH and Gilead for work relevant here and has consulted for Arbutus, Bristol-Myers-Squibb, Gilead, Janssen, Roche and Sanofi. H.L.A.J. received grants from AbbVie, Gilead Sciences, GlaxoSmithKline, Janssen, Roche, Vir Biotechnology Inc. and is a consultant for Aligos, Antios, Arbutus, Eiger, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, VBI Vaccines, Vir Biotechnology Inc. and Viroclinics. D.T.Y.L. received research grants from GlaxoSmithKline, Janssen and Abbott Laboratories. C.P. is a consultant for Janssen. T.P. has been a speaker for Gilead Science. B.T. has nothing to declare. F.V.B. has received research grants from Gilead Sciences, Roche Diagnostics, Ipsen and Janssen; has been part of speaker’s bureau for Gilead Sciences, Roche, Janssen, Ipsen, Eisai, MSD and GSK; and has received support for conference travels from Gilead, Janssen, Roche, Ibsen, MSD and Bayer. O.A. has nothing to disclose, supported by 5R01DK044533-23. M.B.M. is an employee of Janssen Pharmaceuticals. T.M.B. is on the Board of Hepion Pharma and has received support from Arbutus Biopharma and is a co-founder and equity holder in Glycotest. H.L.Y.C. has served as an adviser of AbbVie, Aligos, Arbutus, Gilead, GSK, Hepion, Janssen, Merck, Roche, Vaccitech, VenatoRx, Vir Biotechnology and Virion Therapeutics, and is a speaker for Gilead, Mylan and Roche. G.C. is an Abbott Employee and shareholder. W.E.D. is an employee of and owns stock in Assembly Bio and owns stock in Gilead Sciences. A.M.G. is an employee of Roche Pharma Research and Early Development and also holds stock units with the company. A.G. receives research funding from Janssen Pharmaceuticals, GSK, and Gilead Sciences and conducts consulting/scientific advising for Janssen Pharmaceuticals, Roche, GSK, Vir Biotech, Finch Therapeutics and SQZ Biotech. O.L. is an employee of Janssen Pharmaceutical NV and owns stock of Johnson and Johnson. K.J. performs contract research for Gilead Sciences and Arrowhead Pharmaceuticals. The M.K.M. lab has received collaborative funding from Gilead Sciences, VIR Biotechnology, Hoffmann-La-Roche and GSK (last 3 years), with no funds taken personally. M.K.M. is supported by Wellcome Investigator Award 21419/Z/18/Z. V.M. and the Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington DC Campus, Washington, DC, USA: the Forum received unrestricted support from multiple companies, but did not receive funding specific to the writing of this manuscript. The companies are: Abbott Diagnostics, Aligos Therapeutics, Inc., Altimmune, Antios, Therapeutics, Assembly Biosciences, Eiger Biopharmaceuticals, ENYO Pharma, Gilead, GSK, Immunocore, Janssen Pharmaceuticals ID&V, Monogram Biosciences Quest Diagnostics, Roche Pharma R&D (pRED), Venatorx Pharmaceuticals, Inc., Vir Biotechnology, Virion Therapeutics, LLC, Viroclinics-DDL Diagnostic Laboratory. U.P. is co-founder and shareholder of SCG Cell Therapy, obtained research support from Abbott, ALIOS, Yhlo and VirBio, and received personal fees from Abbvie, Arbutus, Gilead, GSK, J&J, Roche, Sanofi, Sobi and Vaccitech. J.C.Y. was an employee of Gilead Sciences. M.F.Y. reports being an adviser/consultant for and/or having received grant/research support from AbbVie, Aligos Therapeutics, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Bristol-Myers Squibb, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals, Silverback Therapeutics, Sysmex Corporation, Vir Biotechnology and Roche. F.Z. reports consulting for Aligos, Antios, Arbutus, Assembly, Enochian, Gilead, GSK, Roche Molecular Systems, and Zhimeng and research funding to INSERM from Assembly, Beam and Viravaxx. P.A.R. has previously received research funding from Gilead Sciences and is on the Scientific Advisory Board of Enochian Biosciences.

Figures

Fig. 1
Fig. 1. Course of serum markers in acute resolving hepatitis B virus infection.
The curves in the upper part of the diagram show the relative concentration of the markers in a typical infection. The lines above the curves show the mean lengths of the detection periods of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) as estimated from the numbers of HBV nucleic acid testing (NAT) yields, with and without detectable HBsAg. The lengths of the pre-HBsAg and post-HBsAg window periods (WPs) and pre-NAT and post-NAT WPs as described by Weusten et al.. In a later stage of occult HBV infection, when titres of antibodies against hepatitis B surface antigen (anti-HBs) have declined to below 10–100 mIU/mL, occult persisting HBV DNA in the liver can reappear in plasma. If infection occurs perinatally or in very early childhood, there is no full recovery because of immune system immaturity, and this can lead to chronic infection in 90% of cases. The duration of HBsAg positivity is thus prolonged. The lower panel of the figure depicts the stages of natural infection according to current European Association for the Study of the Liver (EASL) guidelines (hepatitis B e antigen (HBeAg)-positive or HBeAg-negative disease and/or infection). Anti-HBc, hepatitis B c antibody; Anti-HBe, hepatitis B e antibody; HBeAg, hepatitis B e antigen. Adapted with permission from ref., Wiley.
Fig. 2
Fig. 2. Schematic representation of HBcrAg biogenesis.
Hepatitis B core antigen (HBcAg), translated from pre-genomic RNA (pgRNA), forms the icosahedral capsid inside complete and empty virions. The direct translation product from the precore mRNA is the precore precursor protein (p25), from which hepatitis B virus e antigen (HBeAg) and precore (PreC; also known as p22cr) are both derived. Removal of the N-terminal signal peptide of p25, by the signal peptidase during p25 translocation into the endoplasmic reticulum lumen, leads to the production of p22 (ref.), which is further processed at its C-terminal domain (CTD) before being secreted as the dimeric HBeAg (p17),. cccDNA, covalently closed circular DNA; HBc, hepatitis B c; HBcrAg, hepatitis B virus core-related antigen; NTD, N-terminal domain; ORF, open reading frame. Adapted with permission from ref., American Society for Microbiology.
Fig. 3
Fig. 3. Adaptive immune responses against HBV.
Control of hepatitis B virus (HBV) infection requires both cellular (CD4+ and CD8+ T cells) and humoral (antibody production by B cells) arms. Using both cytolytic and cytokine-mediated non-cytolytic mechanisms and major histocompatibility (MHC) class I and class II antigen recognition, CD8+ T cells have a primary effector role to kill and cure HBV-infected hepatocytes,. CD4+ T cells have a key regulatory role,. Neutralizing antibodies to hepatitis B surface antigen (anti-HBsAg) bind circulating virus, thereby reducing viral spread and providing protective immunity. A key role for B cells in protective immunity to HBV has also been suggested by the high rate of HBV reactivation in patients undergoing B cell depletion with anti-CD20 (ref.). IFNγ, interferon-γ.
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