Skip to main content

Advertisement

SpringerLink
Log in

Emerging Biomarkers for HBV Cure: HBsAg and Beyond

  • Hepatitis B (JK Lim, Section Editor)
  • Published:
Current Hepatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Our purpose was to examine current and emerging biomarkers that are being utilized or under study with current therapies and examine the preliminary data with emerging therapies that will likely be combined moving forward to achieve higher rates of functional cure.

Recent Findings

Quantitative HBsAg is the most important biomarker to assess response to current and novel therapies that inhibit viral replication and restore the immune response to those with HBV infection with loss of HBsAg reflecting functional cure. Hepatitis B core-related antigen and serum HBV RNA reflect transcription from cccDNA and declines can be used to predict relapse after discontinuation of hepatitis B therapy.

Summary

Quantitative HBsAg will remain the primary biomarker to assess functional cure. There is need for an assay that measures hepatitis B-specific immune-responses to document restoration of adaptive immunity as we develop novel immunomodulatory therapies to be combined with inhibitors of the hepatitis B viral replication.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Lim JK, Nguyen MH, Kim WR, Gish R, Perumalswami P, Jacobson IM. Prevalence of chronic hepatitis B virus infection in the United States. Am J Gastroenterol. 2020.

  2. Ward JW, Hinman AR. What is needed to eliminate hepatitis B virus and hepatitis C virus as global health threats. Gastroenterology. 2019;156:297–310.

    Article  Google Scholar 

  3. Liver EAFTSOTEASL. Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;2017(67):370–98.

    Google Scholar 

  4. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. J Hepatol. 2017;67:847–61.

    Article  Google Scholar 

  5. Papatheodoridis G, Vlachogiannakos I, Cholongitas E, Wursthorn K, Thomadakis C, Touloumi G, et al. Discontinuation of oral antivirals in chronic hepatitis B: a systematic review. Hepatology. 2016;63:1481–92.

    Article  CAS  Google Scholar 

  6. Chen C, Yang HI, Su J, et al. RIsk of hepatocellular carcinoma across a biological gradient of serum hepatitis b virus dna level. JAMA. 2006;295:65–73.

    Article  CAS  Google Scholar 

  7. Candotti D, Assennato SM, Laperche S, Allain J-P, Levicnik-Stezinar S. Multiple HBV transfusion transmissions from undetected occult infections: revising the minimal infectious dose. Gut. 2019;68:313–21.

    Article  CAS  Google Scholar 

  8. Sulkowski MS, Agarwal K, Fung S, Yuen M, Ma X, Lalezari J, et al. Continued therapy with ABI-H0731+ NrtI results in sequential reduction/loss of HBV DNA, HBV RNA, HBeAg, HBcrAg and HBsAg in HBeAg-positive patients. National AIDS Treatment Advocacy Project. Abstr Am Assoc Study Liver Dis Annu Meet 2019.

  9. Hong T-C, Yang H-C, Kao J-H. Role of HBsAg testing in the management of patients with chronic HBV. Current Hepatology Reports. 2019;18:331–41.

    Article  Google Scholar 

  10. Charre C, Levrero M, Zoulim F, Scholtès C. Non-invasive biomarkers for chronic hepatitis B virus infection management. Antiviral Res. 2019;169:104553.

    Article  CAS  Google Scholar 

  11. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63:261–83.

    Article  Google Scholar 

  12. Chen CH, Lu SN, Hung CH, Wang JH, Hu TH, Changchien CS, et al. The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment. J Hepatol. 2014.

  13. Ma H, Yang RF, Wei L. Quantitative serum HBsAg and HBeAg are strong predictors of sustained HBeAg seroconversion to pegylated interferon alfa-2b in HBeAg-positive patients. J Gastroenterol Hepatol. 2010;25:1498–506.

    Article  CAS  Google Scholar 

  14. Moucari R, Mackiewicz V, Lada O, Ripault MP, Castelnau C, Martinot-Peignoux M, et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology. 2009;49:1151–7.

    Article  CAS  Google Scholar 

  15. Brunetto MR, Moriconi F, Bonino F, Lau GK, Farci P, Yurdaydin C, et al. Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology. 2009;49:1141–50.

    Article  CAS  Google Scholar 

  16. Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky J-M. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol. 2013;58:676–83.

    Article  CAS  Google Scholar 

  17. Marcellin P, Buti M, Krastev Z, Robert A, Zeuzem S, Lou L, et al. Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate. J Hepatol. 2014;61:1228–37.

    Article  CAS  Google Scholar 

  18. van Bömmel F, Berg T. Stopping long-term treatment with nucleos (t) ide analogues is a favourable option for selected patients with HB eAg-negative chronic hepatitis B. Liver Int. 2018;38:90–6.

    Article  Google Scholar 

  19. Liem KS, Fung S, Wong DK, Yim C, Noureldin S, Chen J, et al. Limited sustained response after stopping nucleos (t) ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study). Gut. 2019;68:2206–13.

    Article  CAS  Google Scholar 

  20. Lopatin U. Drugs in the pipeline for HBV. Clin Liver Dis. 2019;23:535–55.

    Article  Google Scholar 

  21. Zoulim F, Lenz O, Vandenbossche JJ, Talloen W, Verbinnen T, Moscalu I, et al. JNJ-56136379, an HBV capsid assembly modulator, is well-tolerated and has antiviral activity in a phase 1 study of patients with chronic infection. Gastroenterology. 2020.

  22. Gane EJ, Locarnini S, Lim TH, Strasser S, Sievert W, Cheng W, et al. First results with rna interference (rnai) in chronic hepatitis b (chb) using ARO-HBV. Hepatology 2018; 68 (6): 1463A-1463A. Hepatology. 2018.

  23. Yuen MF, Gane EJ, Kim DJ, Weilert F, Chan HLY, Lalezari J, et al. Antiviral activity, safety, and pharmacokinetics of capsid assembly modulator NVR 3–778 in patients with chronic HBV infection. Gastroenterology. 2019;156:1392-1403.e7.

    Article  CAS  Google Scholar 

  24. Kimura T, Rokuhara A, Sakamoto Y, Yagi S, Tanaka E, Kiyosawa K, et al. Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load. J Clin Microbiol. 2002;40:439–45.

    Article  CAS  Google Scholar 

  25. Heck JA, Meng X, Frick DN. Cyclophilin B stimulates RNA synthesis by the HCV RNA dependent RNA polymerase. Biochem Pharmacol. 2009;77:1173–80.

    Article  CAS  Google Scholar 

  26. Testoni B, Lebossé F, Scholtes C, Berby F, Miaglia C, Subic M, et al. Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients. J Hepatol. 2019;70:615–25.

    Article  CAS  Google Scholar 

  27. Yoshida K, Desbiolles A, Feldman SF, Ahn SH, Alidjinou EK, Atsukawa M, et al. Assay for Hepatitis B Core-related Antigen Identify Patients With High Viral Load: Systematic Review and Meta-analysis of Individual Participant Data. Clin Gastroenterol Hepatol. 2020.

  28. van Campenhout MJ, Rijckborst V, Brouwer WP, van Oord GW, Ferenci P, Tabak F, et al. Hepatitis B core-related antigen monitoring during peginterferon alfa treatment for HBeAg-negative chronic hepatitis B. J Viral Hepatitis. 2019;26:1156–63.

    Article  Google Scholar 

  29. Tseng T-C, Liu C-J, Hsu C-Y, Hong C-M, Su T-H, Yang W-T, et al. High level of hepatitis B core–related antigen associated with increased risk of hepatocellular carcinoma in patients with chronic HBV infection of intermediate viral load. Gastroenterology. 2019;157:1518-1529.e3.

    Article  CAS  Google Scholar 

  30. Asahina Y, Hayashi N, Hiramatsu N, Izumi N, Koike K, Kumada H, et al. JSH guidelines for the management of hepatitis B virus infection. Hepatol Res. 2014;44:1–58.

    Google Scholar 

  31. Carey I, Gersch J, Wang B, Moigboi C, Kuhns M, Cloherty G, et al. Pregenomic HBV RNA and hepatitis B core-related antigen predict outcomes in hepatitis B e antigen–negative chronic hepatitis B patients suppressed on nucleos(T)ide analogue therapy. Hepatology. 2020;72:42–57.

    Article  CAS  Google Scholar 

  32. Jansen L, Kootstra NA, van Dort KA, Takkenberg RB, Reesink HW, Zaaijer HL. Hepatitis B virus pregenomic RNA is present in virions in plasma and is associated with a response to pegylated interferon alfa-2a and nucleos (t) ide analogues. J Infect Dis. 2016;213:224–32.

    Article  CAS  Google Scholar 

  33. Bai L, Zhang X, Kozlowski M, Li W, Wu M, Liu J, et al. Extracellular hepatitis B virus RNAs are heterogeneous in length and circulate as capsid-antibody complexes in addition to virions in chronic hepatitis B patients. J Virol. 2018;92.

  34. Liu S, Zhou B, Valdes JD, Sun J, Guo H. Serum hepatitis B virus RNA: a new potential biomarker for chronic hepatitis B virus infection. Hepatology. 2019;69:1816–27.

    Article  Google Scholar 

  35. van Bömmel F, Bartens A, Mysickova A, Hofmann J, Krüger DH, Berg T, et al. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology. 2015;61:66–76.

    Article  Google Scholar 

  36. Farag MS, van Campenhout MJH, Pfefferkorn M, Fischer J, Deichsel D, Boonstra A, et al. Hepatitis B virus RNA as early predictor for response to pegylated interferon alpha in HBeAg-negative chronic hepatitis B. Clin Infect Dis. 2020.

  37. Wang J, Shen T, Huang X, Kumar GR, Chen X, Zeng Z, et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol. 2016;65:700–10.

    Article  CAS  Google Scholar 

  38. Yuen M-F, Agarwal K, Gane EJ, Schwabe C, Ahn SH, Kim DJ, et al. Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial. Lancet Gastroenterol Hepatol. 2020;5:152–66.

    Article  Google Scholar 

  39. Sulkowski MS, Agarwal K, Fung S, Yuen M-F, Ma X, Lalezari J, et al. Continued therapy with ABI-H0731+ NrtI results in sequential reduction/loss of HBV DNA, HBV RNA, HBeAg, HBcrAg and HBsAg in HBeAg-positive patients. Hepatology. 2019;70:1486A-1487A.

    Google Scholar 

  40. Cornberg M, Wiegand SB. ImPortance of IP-10 in hepatitis B. Antivir Ther. 2016;21:93–6.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stanford University School of Medicine, 430 Broadway, Pavilion C, 3rd Floor, Redwood City, CA, 94063, USA

    Paul Y. Kwo

Authors
  1. Paul Y. Kwo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul Y. Kwo.

Ethics declarations

Conflict of Interest

Disclosures: TRIO Network, BMS, Assembly Grant Support.

Advisory Board: Gilead, Aligos.

DSMB Janssen.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Hepatitis B

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kwo, P.Y. Emerging Biomarkers for HBV Cure: HBsAg and Beyond. Curr Hepatology Rep 20, 151–157 (2021). https://doi.org/10.1007/s11901-021-00573-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-021-00573-x

Keywords

Search

Navigation