{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T19:00:38Z","timestamp":1783018838016,"version":"3.54.6"},"reference-count":27,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Even after long-term nucleos(t)ide analogue (NA) therapy achieves hepatitis B virus (HBV) DNA suppression in patients with chronic hepatitis B (CHB), serum HBV RNA may remain detectable. HBV RNA reflects intrahepatic viral transcriptional activity. This study identified baseline traits and predictors of persistent HBV RNA positivity during NA therapy after sustained HBV DNA suppression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective study included 155 CHB patients who underwent liver biopsy before initiating NA therapy, subsequently achieved sustained HBV DNA suppression on continuous NA therapy. Patients were classified into two groups according to HBV RNA status during therapy. Baseline clinical, virological and histological variables were assessed by multivariate logistic regression. Correlations between HBV RNA and serological markers were also assessed. The diagnostic performance of the model was analyzed using area under the receiver operating characteristic (AUC) and boostrap internal validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Overall, 47.7% achieved undetectable serum HBV RNA. Higher baseline HBV DNA and absence of intrahepatic hepatitis B core antigen (HBcAg) independently predicted persistent HBV RNA positivity (both P\u2009&lt;\u20090.001). The combined assessment of HBcAg with HBV DNA improved predictive accuracy (AUC\u2009=\u20090.780), outperforming either marker alone. The AUC value of bootstrap internal validation was 0.756. Across the cohort, HBV RNA showed moderate correlation with hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B e antibody (HBeAb). Correlations were minimal in HBeAg-negative patients and most evident in HBeAg-positive patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Incorporating HBcAg histology with baseline HBV DNA may enable more individualized treatment strategies during antiviral therapy. Correlations between HBV RNA and traditional markers are primarily observed in HBeAg-positive patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0352870","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:53:52Z","timestamp":1783014832000},"page":"e0352870","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of baseline HBcAg and HBV DNA with persistent detectability of HBV RNA during NA therapy"],"prefix":"10.1371","volume":"21","author":[{"given":"Lanjie","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixiang","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianli","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xitan","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuntao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiye","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3911-6150","authenticated-orcid":true,"given":"Hongying","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"issue":"11","key":"pone.0352870.ref001","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41575-022-00649-z","article-title":"A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook","volume":"19","author":"A Kramvis","year":"2022","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"4","key":"pone.0352870.ref002","doi-asserted-by":"crossref","first-page":"427","DOI":"10.7150\/ijms.5472","article-title":"Efficacy of entecavir treatment for up to 5 years in nucleos(t)ide-na\u00efve chronic hepatitis B patients in real life","volume":"10","author":"J Luo","year":"2013","journal-title":"Int J Med Sci"},{"issue":"9","key":"pone.0352870.ref003","article-title":"High rates of viral suppression after long-term entecavir treatment of Asian patients with hepatitis B e antigen-positive chronic hepatitis B","volume":"10","author":"CQ Pan","year":"2012","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"1","key":"pone.0352870.ref004","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jhep.2013.08.023","article-title":"Changes of HBsAg and interferon-inducible protein 10 serum levels in naive HBeAg-negative chronic hepatitis B patients under 4-year entecavir therapy","volume":"60","author":"G Papatheodoridis","year":"2014","journal-title":"J Hepatol"},{"key":"pone.0352870.ref005","article-title":"Hepatitis B virus persistence and reactivation","volume":"370","author":"Y Shi","year":"2020","journal-title":"BMJ"},{"issue":"12","key":"pone.0352870.ref006","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1093\/jac\/dkr388","article-title":"Nucleoside\/nucleotide analogues in the treatment of chronic hepatitis B","volume":"66","author":"J Fung","year":"2011","journal-title":"J Antimicrob Chemother"},{"issue":"409","key":"pone.0352870.ref007","doi-asserted-by":"crossref","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":"CI Wooddell","year":"2017","journal-title":"Sci Transl Med"},{"issue":"2","key":"pone.0352870.ref008","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.jhep.2016.09.028","article-title":"Serum HBV pgRNA as a clinical marker for cccDNA activity","volume":"66","author":"K Giersch","year":"2017","journal-title":"J Hepatol"},{"issue":"3","key":"pone.0352870.ref009","article-title":"Association between negative results from tests for HBV DNA and RNA and durability of response after discontinuation of nucles(t)ide analogue therapy","volume":"18","author":"R Fan","year":"2020","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"8","key":"pone.0352870.ref010","doi-asserted-by":"crossref","DOI":"10.1097\/HC9.0000000000000188","article-title":"Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants","volume":"7","author":"AJ Thompson","year":"2023","journal-title":"Hepatol Commun"},{"key":"pone.0352870.ref011","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.ijid.2020.07.031","article-title":"Efficacy of a combination of HBV RNA and HBeAg in predicting HBeAg seroconversion in patients treated with entecavir for 144 weeks","volume":"99","author":"X Wang","year":"2020","journal-title":"Int J Infect Dis"},{"issue":"6","key":"pone.0352870.ref012","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/jvh.13671","article-title":"Serum HBV RNA predicts HBeAg clearance and seroconversion in patients with chronic hepatitis B treated with nucleos(t)ide analogues","volume":"29","author":"Y Wang","year":"2022","journal-title":"J Viral Hepat"},{"issue":"4","key":"pone.0352870.ref013","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/apt.15890","article-title":"Factors associated with the biphasic kinetics of serum HBV RNA in patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues","volume":"52","author":"S Liu","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"issue":"4","key":"pone.0352870.ref014","doi-asserted-by":"crossref","first-page":"462","DOI":"10.5009\/gnl.2013.7.4.462","article-title":"Hepatitis B core antigen expression in hepatocytes reflects viral response to entecavir in chronic hepatitis B patients","volume":"7","author":"JG Lee","year":"2013","journal-title":"Gut Liver"},{"issue":"17","key":"pone.0352870.ref015","doi-asserted-by":"crossref","first-page":"9266","DOI":"10.1128\/JVI.00608-12","article-title":"Hepatitis B virus nucleocapsid but not free core antigen controls viral clearance in mice","volume":"86","author":"Y-J Lin","year":"2012","journal-title":"J Virol"},{"issue":"3","key":"pone.0352870.ref016","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.jhep.2021.05.025","article-title":"EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update","volume":"75","author":"European Association for the Study of the Liver","year":"2021","journal-title":"J Hepatol"},{"issue":"11","key":"pone.0352870.ref017","doi-asserted-by":"crossref","first-page":"940","DOI":"10.3390\/diagnostics10110940","article-title":"Diagnostic accuracy of fibroscan and factors affecting measurements","volume":"10","author":"S Oeda","year":"2020","journal-title":"Diagnostics (Basel)"},{"key":"pone.0352870.ref018","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jcv.2017.12.016","article-title":"Serum HBV DNA plus RNA shows superiority in reflecting the activity of intrahepatic cccDNA in treatment-na\u00efve HBV-infected individuals","author":"H Huang","year":"2018","journal-title":"J Clin Virol"},{"issue":"4","key":"pone.0352870.ref019","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1002\/hep.30325","article-title":"Serum hepatitis B virus RNA: a new potential biomarker for chronic hepatitis B virus infection","volume":"69","author":"S Liu","year":"2019","journal-title":"Hepatology"},{"issue":"4","key":"pone.0352870.ref020","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1136\/gutjnl-2023-330225","article-title":"Non-linear association of baseline viral load with on-treatment hepatocellular carcinoma risk in chronic hepatitis B","volume":"73","author":"W-M Choi","year":"2024","journal-title":"Gut"},{"issue":"1","key":"pone.0352870.ref021","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41577-021-00549-4","article-title":"Immunobiology and pathogenesis of hepatitis B virus infection","volume":"22","author":"M Iannacone","year":"2022","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"pone.0352870.ref022","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/hep.32634","article-title":"HBV transcription and translation persist despite viral suppression in HBV-HIV co-infected patients on antiretroviral therapy","volume":"77","author":"M Lisker-Melman","year":"2023","journal-title":"Hepatology"},{"issue":"6","key":"pone.0352870.ref023","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1002\/hep.23571","article-title":"Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers","volume":"51","author":"AJV Thompson","year":"2010","journal-title":"Hepatology"},{"issue":"1","key":"pone.0352870.ref024","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13027-022-00473-9","article-title":"Levels of HBV RNA in chronic HBV infected patients during first-line nucleos(t)ide analogues therapy","volume":"17","author":"B Jiang","year":"2022","journal-title":"Infect Agent Cancer"},{"issue":"3","key":"pone.0352870.ref025","doi-asserted-by":"crossref","first-page":"390","DOI":"10.14218\/JCTH.2021.00160","article-title":"Change of cytokines in chronic hepatitis B patients and HBeAg are positively correlated with HBV RNA, based on real-world study","volume":"10","author":"Q Zhang","year":"2022","journal-title":"J Clin Transl Hepatol"},{"issue":"5","key":"pone.0352870.ref026","article-title":"Hepatitis B core antibody level: a surrogate marker for host antiviral immunity in chronic Hepatitis B virus infections","volume":"15","author":"Y Shi","year":"2023","journal-title":"Viruses"},{"issue":"4","key":"pone.0352870.ref027","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s00535-025-02211-5","article-title":"Usefulness of serum HBV RNA levels for predicting antiviral response to entecavir treatment in patients with chronic hepatitis B","volume":"60","author":"M Kosaka","year":"2025","journal-title":"J Gastroenterol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0352870","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:53:57Z","timestamp":1783014837000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0352870"}},"subtitle":[],"editor":[{"given":"Jason T.","family":"Blackard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":27,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0352870","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]}}}