{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:26:01Z","timestamp":1787199961375,"version":"build-2736575974"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Previous research has identified that Hepatitis B surface antigen glycan isomer (HBsAgGi) specifically marks O-glycosylated M-HBsAg exclusively present on infectious Dane particles (unlike total HBsAg, which is dominated by non-infectious subviral particles), it offers a more specific association with infectious viral burden and cccDNA activity. Accordingly, the present study aims to assess the potential of HBsAgGi as a circulating biomarker to reflect intrahepatic covalently closed circular DNA (cccDNA) and transcriptional activity, and for monitoring antiviral response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 73 individuals diagnosed with chronic genotype C HBV infection were recruited for this study. Serum concentrations of HBsAgGi, HBsAg, HBeAg, HBV DNA, and HBV RNA were measured. Intrahepatic cccDNA and HBV RNA loads were determined in liver biopsy specimens obtained from 16 patients. Correlations between serum HBsAgGi and intrahepatic markers were analyzed. We measured serum Hepatitis B core-related antigen (HBcrAg) levels in 28 patients. 18 patients received nucleos(t)ide analogue therapy for 48 weeks and we evaluated levels of HBsAgGi after therapy. Additionally, receiver operating characteristic (ROC) curve analysis was conducted to assess the discriminative ability of the candidate biomarkers in predicting virological response (VR).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Serum HBsAgGi demonstrated significant positive correlations with intrahepatic cccDNA (r = 0.7172,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01), HBV RNA (r = 0.7879,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01), and the RNA\/cccDNA ratio (r = 0.5840,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), showing stronger correlations than conventional serum markers (HBcrAg, HBV RNA, DNA, HBsAg). HBsAgGi also showed the strongest correlation with serum HBcrAg (r = 0.5361,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01) in 28 patients. During treatment, HBsAgGi levels declined and baseline HBsAgGi predicted VR with superior accuracy (AUC\u00a0=\u00a00.9538) versus other markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Serum HBsAgGi represents an emerging, minimally invasive serum indicator for assessing intrahepatic cccDNA loads and viral transcriptional activity, demonstrating stronger correlations with intrahepatic markers compared to conventional serum markers in this cohort. It also shows promising utility for predicting treatment response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1818958","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:16:03Z","timestamp":1787199363000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["HBsAg glycan isomer: a potential circulating biomarker for monitoring cccDNA and predicting virologic response in chronic hepatitis B"],"prefix":"10.3389","volume":"16","author":[{"given":"Jin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanlan","family":"Ji","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Technical University of Munich","place":["Freising, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaonan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunxun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cailin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanwu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2021.130020","article-title":"O-glycosylated HBsAg peptide can induce specific antibody neutralizing HBV infection","volume":"1866","author":"Angata","year":"2022","journal-title":"Biochim. Biophys. Acta Gen. Subj"},{"key":"B2","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3748\/wjg.v13.i1.65","article-title":"Hepatitis B virus morphogenesis","volume":"13","author":"Bruss","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/diagnostics11020187","article-title":"Hepatitis B core-related antigen as surrogate biomarker of intrahepatic hepatitis B virus covalently-closed-circular DNA in patients with chronic hepatitis B: A meta-analysis","volume":"11","author":"Caviglia","year":"2021","journal-title":"Diagnostics (Basel Switzerland)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2019.104553","article-title":"Non-invasive biomarkers for chronic hepatitis B virus infection management","volume":"169","author":"Charre","year":"2019","journal-title":"Antiviral Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1111\/jvh.13061","article-title":"Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA","volume":"26","author":"Chen","year":"2019","journal-title":"J. Viral Hepatitis"},{"key":"B6","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.antiviral.2013.11.015","article-title":"Amino acid similarities and divergences in the small surface proteins of genotype C hepatitis B viruses between nucleos(t)ide analogue-na\u00efve and lamivudine-treated patients with chronic hepatitis B","volume":"102","author":"Ding","year":"2014","journal-title":"Antiviral Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1097\/hep.0000000000001549","article-title":"AASLD ISDA Practice Guideline on treatment of chronic hepatitis B","volume":"83","author":"Ghany","year":"2026","journal-title":"Hepatol. (Baltimore Md)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1111\/hepr.14076","article-title":"Hepatitis B surface antigen (HBsAg) glycan isomer is predictive of HBsAg seroclearance in patients with chronic hepatitis B","volume":"54","author":"Ikeda","year":"2024","journal-title":"Hepatol. Res. Off. J. Japan Soc. Hepatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1111\/hepr.14016","article-title":"Hepatitis B surface antigen glycan isomer is a predictor of the development of hepatocellular carcinoma during nucleoside\/nucleotide analog therapy","volume":"54","author":"Kozuka","year":"2024","journal-title":"Hepatol. Res. Off. J. Japan Soc. Hepatol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.jhep.2017.03.021","article-title":"EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection","volume":"67","author":"Lampertico","year":"2017","journal-title":"J. Hepatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"S84","DOI":"10.1016\/j.jhep.2016.02.021","article-title":"Mechanisms of HBV-induced hepatocellular carcinoma","volume":"64","author":"Levrero","year":"2016","journal-title":"J. Hepatol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"270","DOI":"10.21203\/rs.3.rs-1180233\/v1","article-title":"Serum O-glycosylated hepatitis B surface antigen levels in patients with chronic hepatitis B during nucleos(t)ide analog therapy","volume":"22","author":"Murata","year":"2022","journal-title":"BMC Gastroenterol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1128\/jcm.39.4.1686-1686.2001","article-title":"Rapid and specific genotyping system for hepatitis B virus corresponding to six major genotypes by PCR using type-specific primers","volume":"39","author":"Naito","year":"2001","journal-title":"J. Clin. Microbiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.1136\/gutjnl-2015-309809","article-title":"HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B","volume":"64","author":"Nassal","year":"2015","journal-title":"Gut"},{"key":"B15","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1111\/jvh.13869","article-title":"Kinetics of serum O-glycosylated M-hepatitis B surface antigen with hepatocellular carcinoma history and nucleos(t)ide analogue therapy in hepatitis B patients","volume":"30","author":"Okumura","year":"2023","journal-title":"J. Viral Hepatitis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3390\/v1020185","article-title":"HBV life cycle: entry and morphogenesis","volume":"1","author":"Sch\u00e4dler","year":"2009","journal-title":"Viruses"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1016\/s0140-6736(18)31865-8","article-title":"Chronic hepatitis B virus infection","volume":"392","author":"Seto","year":"2018","journal-title":"Lancet (London England)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/hep.28156","article-title":"AASLD guidelines for treatment of chronic hepatitis B","volume":"63","author":"Terrault","year":"2016","journal-title":"Hepatol. (Baltimore Md)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1002\/cld.728","article-title":"Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance","volume":"67","author":"Terrault","year":"2018","journal-title":"Hepatol. (Baltimore Md)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1136\/gutjnl-2023-330644","article-title":"Quantification of circulating HBV RNA expressed from intrahepatic cccDNA in untreated and NUC treated patients with chronic hepatitis B","volume":"73","author":"Testoni","year":"2024","journal-title":"Gut"},{"key":"B21","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1055\/a-1830-2741","article-title":"Surrogate markers for hepatitis B virus covalently closed circular DNA","volume":"42","author":"Tu","year":"2022","journal-title":"Semin. Liver Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/v13020180","article-title":"Hepatitis B virus DNA integration: In vitro models for investigating viral pathogenesis and persistence","volume":"13","author":"Tu","year":"2021","journal-title":"Viruses"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1021\/acsinfecdis.0c00638","article-title":"HBsAg, subviral particles, and their clearance in establishing a functional cure of chronic hepatitis B virus infection","volume":"7","author":"Vaillant","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1002\/hep4.1708","article-title":"Risks and benefits of discontinuation of nucleos(t)ide analogue treatment: A treatment concept for patients with HBeAg-negative chronic hepatitis B","volume":"5","author":"van B\u00f6mmel","year":"2021","journal-title":"Hepatol. Commun."},{"key":"B25","doi-asserted-by":"publisher","first-page":"10196","DOI":"10.1021\/acs.analchem.8b01030","article-title":"Highly sensitive glycan profiling of hepatitis B viral particles and a simple method for Dane particle enrichment","volume":"90","author":"Wagatsuma","year":"2018","journal-title":"Anal. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/v16040529","article-title":"Quantitative measurement of serum HBcrAg can be used to assess the feasibility of safe discontinuation of antiviral therapy for chronic hepatitis B","volume":"16","author":"Wang","year":"2024","journal-title":"Viruses"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/scitranslmed.aan0241","article-title":"RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg","volume":"9","author":"Wooddell","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2025.106077","article-title":"Serum O-glycosylated HBsAg levels correlate with HBV RNA in HBeAg positive CHB patients during antiviral therapy","volume":"234","author":"Yao","year":"2025","journal-title":"Antiviral Res."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01950-22","article-title":"Sera of individuals chronically infected with hepatitis B virus (HBV) contain diverse RNA types produced by HBV replication or derived from integrated HBV DNA","volume":"97","author":"Zaiets","year":"2023","journal-title":"J. Virol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1818958\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:16:04Z","timestamp":1787199364000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1818958\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":29,"alternative-id":["10.3389\/fcimb.2026.1818958"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2026.1818958","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"article-number":"1818958"}}