Conventional and emerging biomarkers in hepatitis B
DOI:
https://doi.org/10.59093/27112322.173Keywords:
hepatitis B, hepatitis B virus, biomarkers, viral markers, HBsAg, HBeAg, HBcAg, hepatitis B antibodies.Abstract
Globally, 300 million people are infected with hepatitis B virus (HBV). Although there is a vaccine that prevents infection and antiviral treatment that suppresses the replication of the virus, there is still no cure. The main problem that prevents the total recovery of the patient, even for those who receive treatment, is the persistence of two forms of the viral genome in hepatocytes: covalently closed circular DNA (cccDNA), which is in the form of an episome that has the ability to replicate, and linear subgenomic sequences that are integrated into the human genome, with oncogenic potential. Few biomarkers are currently available to monitor or predict disease progression and response to treatment. These biomarkers are detected during infection and are the basis for monitoring the disease and making a diagnosis of the clinical phase of the infection. New biomarkers have recently emerged, such as hepatitis B core-related antigen (HBcrAg) and HBV RNA detection, which seem to correlate with cccDNA transcriptional levels while during treatment seem to help predict response, and could identify those for whom therapy can be discontinued without risk of relapse. In this review, the usefulness of the main conventional biomarkers in hepatitis B is described, and the two most studied emerging biomarkers are mentioned, which promise to evaluate the course of the infection, as well as to determine disease progression and treatment response.
Downloads
References
World Health Organization (WHO). Hepatitis B. Ginebra, Suiza: WHO; 2022. Acceso 27 de septiembre de 2022. Disponible en https://www.who.int/news-room/fact-sheets/detail/hepatitis-b.
Hayashi S, Nagaoka K, Tanaka Y. Blood-based biomarkers in hepatitis B virus-related hepatocellular carcinoma, including the viral genome and glycosylated proteins. Int J Mol Sci 2021;22. https://doi.org/10.3390/ijms222011051.
Buti M, Riveiro-Barciela M, Rodríguez-Frías F, Tabernero D, Esteban R. Role of biomarkers in guiding cure of viral hepatitis B. Semin Liver Dis 2020;40:49-60. https://doi.org/10.1055/s-0039-3401031.
de Almeida-Pondé RA. Dynamic profile of the HBeAg-anti-HBe system in acute and chronic hepatitis B virus infection: A clinical-laboratory approach. Mol Biol Rep 2021;48:843-854. https://doi.org/10.1007/s11033-020-06056-4.
Kotha S, Neong S, Patel K. Serum biomarkers for diagnosis and monitoring viral hepatitis and hepatocellular carcinoma. Expert Rev Mol Diagn 2018;18:713-722. https://doi.org/10.1080/14737159.2018.1496020.
Baudi I, Inoue T, Tanaka Y. Novel biomarkers of hepatitis B and hepatocellular carcinoma: Clinical significance of HBcrAg and M2BPGi. Int J Mol Sci 2020;21:949. https://doi.org/10.3390/ijms21030949.
Malik GF, Zakaria N, Majeed MI, Ismail FW. Viral hepatitis - The road traveled and the journey remaining. Hepat Med 2022;14:13-26. https://doi.org/10.2147/hmer.S352568.
Yuen MF, Chen DS, Dusheiko GM, Janssen HLA, Lau DTY, Locarnini SA, et al. Hepatitis B virus infection. Nat Rev Dis Primers 2018;4:18035. https://doi.org/10.1038/nrdp.2018.35.
Toro-Montoya AI, Restrepo-Gutiérrez JC. Hepatitis B. Med Lab 2011;17:311-329.
Fanning GC, Zoulim F, Hou J, Bertoletti A. Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat Rev Drug Discov 2019;18:827-844. https://doi.org/10.1038/s41573-019-0037-0.
Kramvis A, Chang KM, Dandri M, Farci P, Glebe D, Hu J, et al. A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol 2022:1-19. https://doi.org/10.1038/s41575-022-00649-z.
Otero-Regino WA, Parga J, Gastelbondo J. Serología del virus de la hepatitis B: para múltiples escenarios, múltiples exámenes. Rev Colomb Gastroenterol 2018;33:411-422. https://doi.org/10.22516/25007440.327.
de Almeida-Pondé RA. Detection of the serological markers hepatitis B virus surface antigen (HBsAg) and hepatitis B core IgM antibody (anti-HBcIgM) in the diagnosis of acute hepatitis B virus infection after recent exposure. Microbiol Immunol 2022;66:1-9. https://doi.org/10.1111/1348-0421.12943.
Alves-Araujo de Almeida N, Salete-de Paula V. Occult hepatitis B virus (HBV) infection and challenges for hepatitis elimination: A literature review. J Appl Microbiol 2022;132:1616-1635. https://doi.org/10.1111/jam.15351.
Inoue T, Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. Clin Mol Hepatol 2020;26:261-279. https://doi.org/10.3350/cmh.2020.0032.
Lee JH, Kim HS. Current laboratory tests for diagnosis of hepatitis B virus infection. Int J Clin Pract 2021;75:e14812. https://doi.org/10.1111/ijcp.14812.
Charre C, Levrero M, Zoulim F, Scholtès C. Non-invasive biomarkers for chronic hepatitis B virus infection management. Antiviral Res 2019;169:104553. https://doi.org/10.1016/j.antiviral.2019.104553.
Riveiro-Barciela M, Pericàs JM, Buti M. How to interpret viral markers in the management of chronic hepatitis B infection. Clin Microbiol Infect 2022;28:355-361. https://doi.org/10.1016/j.cmi.2021.10.020.
Liu Y, Jiang M, Xue J, Yan H, Liang X. Serum HBV RNA quantification: useful for monitoring natural history of chronic hepatitis B infection. BMC Gastroenterol 2019;19:53. https://doi.org/10.1186/s12876-019-0966-4.
Cornberg M, Wong VW, Locarnini S, Brunetto M, Janssen HLA, Chan HL. The role of quantitative hepatitis B surface antigen revisited. J Hepatol 2017;66:398-411. https://doi.org/10.1016/j.jhep.2016.08.009.
Mak LY, Seto WK, Fung J, Yuen MF. Use of HBsAg quantification in the natural history and treatment of chronic hepatitis B. Hepatol Int 2020;14:35-46. https://doi.org/10.1007/s12072-019-09998-5.
Gozlan Y, Aaron D, Davidov Y, Likhter M, Ben Yakov G, Cohen-Ezra O, et al. HBV-RNA, quantitative HBsAg, levels of hbv in peripheral lymphocytes and HBV mutation profiles in chronic hepatitis B. Viruses 2022;14. https://doi.org/10.3390/v14030584.
Svicher V, Salpini R, Malagnino V, Piermatteo L, Alkhatib M, Cerva C, et al. New markers in monitoring the reactivation of hepatitis B virus infection in immunocompromised hosts. Viruses 2019;11:783. https://doi.org/10.3390/v11090783.
European Association for the Study of the Liver (EASL). EASL 2017 Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-398. https://doi.org/10.1016/j.jhep.2017.03.021.
Coffin CS, Zhou K, Terrault NA. New and old biomarkers for diagnosis and management of chronic hepatitis B virus infection. Gastroenterology 2019;156:355-368. https://doi.org/10.1053/j.gastro.2018.11.037.
Vachon A, Osiowy C. Novel biomarkers of hepatitis B virus and their use in chronic hepatitis B patient management. Viruses 2021;13:951. https://doi.org/10.3390/v13060951.
Mak LY, Seto WK, Fung J, Yuen MF. New biomarkers of chronic hepatitis B. Gut Liver 2019;13:589-595. https://doi.org/10.5009/gnl18425.
Rybicka M, Bielawski KP. Recent advances in understanding, diagnosing, and treating hepatitis B virus infection. Microorganisms 2020;8:1416. https://doi.org/10.3390/microorganisms8091416.
Ou Q, Guo J, Zeng Y, Chen H. Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection. J Viral Hepat 2020;27:224-232. https://doi.org/10.1111/jvh.13260.
Butler EK, Gersch J, McNamara A, Luk KC, Holzmayer V, de Medina M, et al. Hepatitis B virus serum DNA and RNA levels in nucleos(t)ide analog-treated or untreated patients during chronic and acute infection. Hepatology 2018;68:2106-2117. https://doi.org/10.1002/hep.30082.
van Bömmel F, van Bömmel A, Krauel A, Wat C, Pavlovic V, Yang L, et al. Serum HBV RNA as a predictor of peginterferon alfa-2a response in patients with HBeAg-positive chronic hepatitis B. J Infect Dis 2018;218:1066-1074. https://doi.org/10.1093/infdis/jiy270.
Liao H, Liu Y, Li X, Wang J, Chen X, Zou J, et al. Monitoring of serum HBV RNA, HBcrAg, HBsAg and anti-HBc levels in patients during long-term nucleoside/nucleotide analogue therapy. Antivir Ther 2019;24:105-115. https://doi.org/10.3851/imp3280.
van Campenhout MJ, van Bömmel F, Pfefferkorn M, Fischer J, Deichsel D, Boonstra A, et al. Host and viral factors associated with serum hepatitis B virus RNA levels among patients in need for treatment. Hepatology 2018;68:839-847. https://doi.org/10.1002/hep.29872.
Höner-Zu Siederdissen C, Maasoumy B, Cornberg M. New viral biomarkers for hepatitis B: Are we able to change practice? J Viral Hepat 2018;25:1226-1235. https://doi.org/10.1111/jvh.12993.
Breitkreutz R, Zhang W, Lee M, Hoffmann A, Tokus M, Su Q, et al. Hepatitis B virus nucleic acids circulating in the blood: distinct patterns in HBs carriers with hepatocellular carcinoma. Ann N Y Acad Sci 2001;945:195-206. https://doi.org/10.1111/j.1749-6632.2001.tb03886.x.
Cortese MF, Riveiro-Barciela M, Tabernero D, Rodriguez-Algarra F, Palom A, Sopena S, et al. Standardized hepatitis B virus RNA quantification in untreated and treated chronic patients: A promising marker of infection follow-up. Microbiol Spectr 2022;10:e0214921. https://doi.org/10.1128/spectrum.02149-21.
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. https://doi.org/10.1002/hep.31026.
Inoue T, Tanaka Y. The role of hepatitis B core-related antigen. Genes (Basel) 2019;10:357. https://doi.org/10.3390/genes10050357.
Mak LY, Wong DK, Cheung KS, Seto WK, Lai CL, Yuen MF. Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection. Aliment Pharmacol Ther 2018;47:43-54. https://doi.org/10.1111/apt.14376.
Tseng TC, Liu CJ, Hsu CY, Hong CM, Su TH, Yang WT, 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.e1513. https://doi.org/10.1053/j.gastro.2019.08.028.
Chi XM, Wang XM, Wang ZF, Wu RH, Gao XZ, Xu HQ, et al. Serum hepatitis B core-related antigen as a surrogate marker of hepatitis B e antigen seroconversion in chronic hepatitis B. World J Gastroenterol 2021;27:6927-6938. https://doi.org/10.3748/wjg.v27.i40.6927.
Chang XJ, Sun C, Chen Y, Li XD, Yu ZJ, Dong Z, et al. On-treatment monitoring of liver fibrosis with serum hepatitis B core-related antigen in chronic hepatitis B. World J Gastroenterol 2019;25:4764-4778. https://doi.org/10.3748/wjg.v25.i32.4764.
Huang SC, Yang HC, Kao JH. Hepatitis B reactivation: diagnosis and management. Expert Rev Gastroenterol Hepatol 2020;14:565-578. https://doi.org/10.1080/17474124.2020.1774364.
Wu JW, Kao JH, Tseng TC. Three heads are better than two: Hepatitis B core-related antigen as a new predictor of hepatitis B virus-related hepatocellular carcinoma. Clin Mol Hepatol 2021;27:524-534. https://doi.org/10.3350/cmh.2021.0012.
Hou J, Wang G, Wang F, Cheng J, Ren H, Zhuang H, et al. Guideline of prevention and treatment for chronic hepatitis B (2015 update). J Clin Transl Hepatol 2017;5:297-318. https://doi.org/10.14218/jcth.2016.00019.
Papatheodoridi M, Papatheodoridis G. Emerging diagnostic tools to decide when to discontinue nucleos(t)ide analogues in chronic hepatitis B. Cells 2020;9:493. https://doi.org/10.3390/cells9020493.
Raimondo G, Locarnini S, Pollicino T, Levrero M, Zoulim F, Lok AS. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J Hepatol 2019;71:397-408. https://doi.org/10.1016/j.jhep.2019.03.034.
Liu Y, Veeraraghavan V, Pinkerton M, Fu J, Douglas MW, George J, et al. Viral biomarkers for hepatitis B virus-related hepatocellular carcinoma occurrence and recurrence. Front Microbiol 2021;12:665201. https://doi.org/10.3389/fmicb.2021.665201.
Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: A meta-analysis. Gastroenterology 2018;154:1706-1718. https://doi.org/10.1053/j.gastro.2018.01.064.
Tada T, Kumada T, Toyoda H, Kiriyama S, Tanikawa M, Hisanaga Y, et al. HBcrAg predicts hepatocellular carcinoma development: An analysis using time-dependent receiver operating characteristics. J Hepatol 2016;65:48-56. https://doi.org/10.1016/j.jhep.2016.03.013.
Seto WK, Liu KS, Mak LY, Cloherty G, Wong DK, Gersch J, et al. Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation. Gut 2021;70:775-783. https://doi.org/10.1136/gutjnl-2020-321116.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Hepatología’s authorship policy is based on the criteria established by the International Committee of Medical Journal Editors (ICMJE) to credit a person for their work while assigning them responsibility for its publication.
| Article metrics | |
|---|---|
| Abstract views | |
| Galley vies | |
| PDF Views | |
| HTML views | |
| Other views | |
