Association between quantitative HBsAg and serum HBV DNA in occult HBV infection
Keywords:
Occult hepatitis B infection, quantitative HBsAg, hepatitis B virus DNA, HBsAg-negative, indonesiaAbstract
Background and aim: Negative hepatitis B surface antigen (HBsAg) testing does not necessarily exclude hepatitis B virus (HBV) persistence, particularly in endemic regions where occult hepatitis B infection (OBI) may remain undetected. Because HBV DNA testing may be limited by cost and laboratory capacity, quantitative HBsAg (qHBsAg) has been proposed as a potential surrogate marker. However, its diagnostic utility in OBI remains uncertain due to suppressed antigen expression. This study aimed to evaluate the association between qHBsAg and serum HBV DNA among adults with OBI.
Methods: An observational cross-sectional study was conducted at a tertiary referral hospital in Makassar, Indonesia. Adults (≥18 years) with non-reactive HBsAg and detectable serum HBV DNA were included. HBV DNA was quantified using real-time polymerase chain reaction, and qHBsAg was measured using an automated chemiluminescent immunoassay.
Results: Fifty-five participants were included (mean age 54.69 ± 11.79 years; 67.3% male), including 30.9% with hepatic malignancy. qHBsAg values were uniformly non-reactive and narrowly distributed (0.00074–0.01958 IU/mL), whereas HBV DNA remained detectable across the cohort (1.0000–1.9400 IU/mL). qHBsAg showed no significant correlation with HBV DNA (r = −0.160; p = 0.242), and the association remained non-significant after adjustment (r = −0.098; p = 0.490).
Conclusion: In individuals with OBI, qHBsAg within the non-reactive range does not reflect inter-individual variability in circulating HBV DNA and therefore has limited utility as a surrogate marker of viraemia. These findings support the continued need for HBV DNA testing for accurate molecular confirmation of occult HBV infection. (www.actabiomedica.it)
References
1. Guvenir M, Arikan A. Hepatitis B virus: from diagnosis to treatment. Pol J Microbiol. 2020;69(4):391-9. doi:10.33073/pjm-2020-044.
2. Soriano V, González R, Barea L, et al. Occult hepatitis B infection: unveiling clinical burden and new diagnostic strategies. Expert Rev Gastroenterol Hepatol. 2026:1-10. doi:10.1080/17474124.2025.2611857.
3. Raimondo G, Allain JP, Brunetto MR, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008;49(4):652-7. doi:10.1016/j.jhep.2008.07.014.
4. Mak L-Y, Wong DK-H, Pollicino T, Raimondo G, Hollinger FB, Yuen M-F. Occult hepatitis B infection and hepatocellular carcinoma: epidemiology, virology, hepatocarcinogenesis and clinical significance. Journal of Hepatology. 2020;73(4):952-64. doi:10.1016/j.jhep.2020.05.042.
5. Wang C, Xue R, Wang X, Xiao L, Xian J. High-sensitivity HBV DNA test for the diagnosis of occult HBV infection: commonly used but not reliable. Front Cell Infect Microbiol. 2023;13:1186877. doi:10.3389/fcimb.2023.1186877.
6. Yang Y, Xing H, Wu G, Zhao Y. Global prevalence of occult hepatitis B virus infection in HBcAb-positive individuals: a systematic review and meta-analysis. Scientific Reports. 2025;15(1):44244. doi:10.1038/s41598-025-23207-4.
7. Saitta C, Pollicino T, Raimondo G. Occult hepatitis B virus infection: an update. Viruses. 2022;14(7). doi:10.3390/v14071504.
8. Testoni B, Scholtès C, Plissonnier ML, et al. Quantification of circulating HBV RNA expressed from intrahepatic cccDNA in untreated and NUC-treated patients with chronic hepatitis B. Gut. 2024;73(4):659-67. doi:10.1136/gutjnl-2023-330644.
9. Islam S, Shahera U, Jahan M, Tabassum S. Evaluation and determination of quantitative hepatitis B surface antigen diagnostic performance in chronic hepatitis B virus-infected patients. Cureus. 2023;15(6):e41202. doi:10.7759/cureus.41202.
10. Yılmaz T, Özdemir E, Düzenci D, Bahçecioğlu İH. Clinical and histopathological correlation of quantitative HBsAg levels in chronic hepatitis B. International Journal of Hepatology. 2025;2025(1):9096871. doi:10.1155/ijh/9096871.
11. Kuhns MC, Holzmayer V, Anderson M, et al. Molecular and serological characterization of Hepatitis B virus (HBV)-positive samples with very low or undetectable levels of HBV surface antigen. Viruses. 2021;13(10):2053.
12. Bubonja-Šonje M, Peruč D, Abram M, Mohar-Vitezić B. Prevalence of occult hepatitis B virus infection and characterisation of hepatitis B surface antigen mutants among adults in western Croatia. Ann Hepatol. 2024;29(1):101156. doi:10.1016/j.aohep.2023.101156.
13. Zhong G, Jiang Z-H, Wang X-Y, et al. Increasing prevalence of occult HBV infection in adults vaccinated against hepatitis B at birth. Vaccines. 2025;13(2):174.
14. Lusida MI, Juniastuti, Yano Y. Current hepatitis B virus infection situation in Indonesia and its genetic diversity. World J Gastroenterol. 2016;22(32):7264-74. doi:10.3748/wjg.v22.i32.7264.
15. Yamani LN, Triani E, Amin M, et al. Prevalence and genotype distribution of hepatitis B virus among migrant workers in Lombok Island, Indonesia. Asian Pacific Journal of Tropical Medicine. 2020;13(1).
16. Jaroszewicz J, Serrano BC, Wursthorn K, et al. Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV) infection: a European perspective. Journal of Hepatology. 2010;52(4):514-22. doi:10.1016/j.jhep.2010.01.014.
17. Nwokediuko SC, Osuala PC, Uduma UV, Alaneme AK, Onwuka CC, Mesigo C. Pattern of liver disease admissions in a Nigerian tertiary hospital. Niger J Clin Pract. 2013;16(3):339-42. doi:10.4103/1119-3077.113458.
18. Loho IM, Hasan I, Lesmana CRA, Dewiasty E, Gani RA. Hepatocellular carcinoma in a tertiary referral hospital in Indonesia: lack of improvement of one-year survival rates between 1998-1999 and 2013-2014. Asian Pacific Journal of Cancer Prevention. 2016;17(4):2165-70.
19. Wang H, Wang J, Zhang S, et al. Clinical features and transition of acute hepatitis B virus infection. Journal of Viral Hepatitis. 2025;32(2):e14048. doi:10.1111/jvh.14048.
20. Ali H, Buenning C, Daghfal D. Advancing HBV diagnostics: the role of ultrasensitive HBsAg testing. Diagnostics (Basel). 2025;15(21). doi:10.3390/diagnostics15212744.
21. Posuwan N, Wasitthankasem R, Pimsing N, et al. Hepatitis B prevalence in an endemic area of hepatitis C virus: a population-based study implicated in hepatitis elimination in Thailand. Journal of Virus Eradication. 2024;10(4):100577. doi:10.1016/j.jve.2024.100577.
22. Delghandi S, Raoufinia R, Shahtahmasbi S, Meshkat Z, Gouklani H, Gholoobi A. An overview of occult hepatitis B infection (OBI) with emphasis on HBV vaccination. Heliyon. 2024;10(17):e37097. doi:10.1016/j.heliyon.2024.e37097.
23. Nishikawa H, Osaki Y. Clinical significance of occult hepatitis B infection in progression of liver disease and carcinogenesis. J Cancer. 2013;4(6):473-80. doi:10.7150/jca.6609.
24. Mirian M, Taghizadeh R, Khanahmad H, et al. Exposition of hepatitis B surface antigen (HBsAg) on the surface of HEK293T cell and evaluation of its expression. Res Pharm Sci. 2016;11(5):366-73. doi:10.4103/1735-5362.192485.
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