{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T02:04:22Z","timestamp":1773367462246,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NovoMu Research Funding, Chinese Foudation For Hepatitis Prevention and Control","award":["MX202508"],"award-info":[{"award-number":["MX202508"]}]},{"name":"Tianjin Key Medical Discipline Construction Project","award":["TJYXZDXK-3-019B"],"award-info":[{"award-number":["TJYXZDXK-3-019B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: HBeAg-positive chronic hepatitis B (CHB) patients with very high viral replication are often clinically considered a homogeneous, low-risk population. However, substantial biochemical, virological, and fibrosis-related heterogeneity may exist. This study aimed to characterize this heterogeneity in treatment-naive, HBeAg-positive CHB patients with ultra-high viral loads (HBV DNA \u2265 7.0 log10 IU\/mL). Furthermore, we sought to identify predictors of significant fibrosis and detect clinically relevant discordant phenotypes, such as silent disease progression despite normal alanine aminotransferase (ALT) levels. Methods: This single-center, retrospective, cross-sectional study analyzed consecutively screened eligible patients. A liver stiffness measurement (LSM, kPa) and controlled attenuation parameter (CAP, dB\/m) were obtained via transient elastography. Significant fibrosis was defined as an LSM \u2265 7.0 kPa. Statistical evaluations included Spearman\u2019s correlation, multivariable regression, ALT-LSM stratification, and K-means clustering. Results: Among 413 included patients, age and aspartate aminotransferase (AST) emerged as independent risk factors for significant fibrosis, whereas log10 HBV DNA and log10 HBsAg were independent negative predictors. Patients with HBsAg \u2265 25,000 IU\/mL exhibited significantly lower LSM values than those with lower HBsAg levels. Notably, 18.4% of patients with strictly normal ALT (\u226440 U\/L) presented with an LSM \u2265 7.0 kPa, indicating silent progression. Cluster analysis further identified two distinct patient phenotypes characterized by differing age, ALT, viral load, and fibrosis profiles. Conclusions: An ultra-high viral load in HBeAg-positive CHB does not guarantee a uniformly benign clinical state. By quantifying biochemical, virological, and fibrotic heterogeneity, this study highlights a critical subgroup with silent fibrosis progression that risks being overlooked by ALT-based assessments alone.<\/jats:p>","DOI":"10.3390\/jcm15062164","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T13:12:24Z","timestamp":1773321144000},"page":"2164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heterogeneity Analysis of HBeAg-Positive Chronic Hepatitis B Patients with Ultra-High Viral Load (HBV DNA \u2265 7.0 log10 IU\/mL)"],"prefix":"10.3390","volume":"15","author":[{"given":"Guifeng","family":"Li","sequence":"first","affiliation":[{"name":"The Second People\u2019s Hospital Affiliated to Tianjin Medical University, Tianjin 300211, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Ren","sequence":"additional","affiliation":[{"name":"The Second People\u2019s Hospital Affiliated to Tianjin Medical University, Tianjin 300211, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Second People\u2019s Hospital, Tianjin 300192, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"The Second People\u2019s Hospital Affiliated to Tianjin Medical University, Tianjin 300211, China"},{"name":"Tianjin Second People\u2019s Hospital, Tianjin 300192, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","first-page":"107735","article-title":"Gray Zone and the Need for Expansion in Chronic Hepatitis B: From Theory to Clinical Practice","volume":"17","author":"Nguyen","year":"2025","journal-title":"World J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ejim.2020.10.022","article-title":"Negligible HCC Risk during Stringently Defined Untreated Immune-Tolerant Phase of Chronic Hepatitis B","volume":"84","author":"Lee","year":"2021","journal-title":"Eur. J. Intern. Med."},{"key":"ref_3","unstructured":"European Association for the Study of the Liver (2025). EASL Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection. J. Hepatol., 83, 502\u2013583."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/S2468-1253(24)00437-0","article-title":"Staging Liver Fibrosis and Cirrhosis Using Non-Invasive Tests in People with Chronic Hepatitis B to Inform WHO 2024 Guidelines: A Systematic Review and Meta-Analysis","volume":"10","author":"Liguori","year":"2025","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"273","DOI":"10.3350\/cmh.2021.0019","article-title":"Negligible Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Patients in Immune-Tolerant Phase: Myth or Fact","volume":"27","author":"Yip","year":"2021","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e0011","DOI":"10.1097\/HC9.0000000000000011","article-title":"Comparable Outcomes between Immune-Tolerant and Active Phases in Noncirrhotic Chronic Hepatitis B: A Meta-Analysis","volume":"7","author":"Lee","year":"2023","journal-title":"Hepatol. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3350\/cmh.2022.0322","article-title":"Long-Term Prognosis and the Need for Histologic Assessment of Chronic Hepatitis B in the Serological Immune-Tolerant Phase","volume":"29","author":"Yoo","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cai, C., Shang, W.-X., Lin, E.-H., Jiang, Y.-C., Chen, H., Xu, K., Chen, L., Chen, R.-C., Cai, Y.-J., and Lin, J. (2024). High Normal Alanine Aminotransferase Is an Indicator for Better Response to Antiviral Therapy in Chronic Hepatitis B. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1367265"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.3748\/wjg.v29.i16.2479","article-title":"Liver Histopathological Lesions Is Severe in Patients with Normal Alanine Transaminase and Low to Moderate Hepatitis B Virus DNA Replication","volume":"29","author":"Jiang","year":"2023","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e0357","DOI":"10.1097\/HC9.0000000000000357","article-title":"Histological Features of Chronic Hepatitis B Patients with Normal Alanine Aminotransferase According to Different Criteria","volume":"8","author":"Huang","year":"2024","journal-title":"Hepatol. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wei, S., Xie, Q., Liao, G., Chen, H., Hu, M., Lin, X., Li, H., and Peng, J. (2024). Patients with Chronic Hepatitis B Who Have Persistently Normal Alanine Aminotransferase or Aged < 30 Years May Exhibit Significant Histologic Damage. BMC Gastroenterol., 24.","DOI":"10.1186\/s12876-024-03208-9"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e0084","DOI":"10.1097\/HC9.0000000000000084","article-title":"What Will It Take to Cure Hepatitis B?","volume":"7","author":"Jeng","year":"2023","journal-title":"Hepatol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/hep4.1859","article-title":"Presence of Liver Inflammation in Asian Patients with Chronic Hepatitis B with Normal ALT and Detectable HBV DNA in Absence of Liver Fibrosis","volume":"6","author":"Liu","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1111\/apt.17272","article-title":"Significant Histological Disease of Patients with Chronic Hepatitis B Virus Infection in the Grey Zone","volume":"57","author":"Wang","year":"2023","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1038\/s41590-024-01928-4","article-title":"Attenuated Effector T Cells Are Linked to Control of Chronic HBV Infection","volume":"25","author":"Heim","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chen, X., Liu, X., Jiang, Y., Xia, N., Liu, C., and Luo, W. (2023). Abnormally Primed CD8 T Cells: The Achilles\u2019 Heel of CHB. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1106700"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ferrando-Martinez, S., Snell Bennett, A., Lino, E., Gehring, A.J., Feld, J., Janssen, H.L.A., and Robbins, S.H. (2021). Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.648420"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1136\/gutjnl-2022-327202","article-title":"Phenotypic CD8 T Cell Profiling in Chronic Hepatitis B to Predict HBV-Specific CD8 T Cell Susceptibility to Functional Restoration in Vitro","volume":"72","author":"Rossi","year":"2023","journal-title":"Gut"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tang, S., Huang, T., Tang, R., Lin, K., Luo, C., Shen, Y., Zhang, K., Tang, Y., Kong, J., and Chen, Z. (2025). EASL 2025 Indications Revisited: Phase-Specific Outcomes with and without Nucleos(t)Ide Analogue Therapy in Chronic Hepatitis B Virus Infection. Gut.","DOI":"10.1136\/gutjnl-2025-335449"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4591","DOI":"10.1038\/s41467-025-59985-8","article-title":"Hepatitis B Virus Surface Antigen Drives T Cell Immunity through Non-Canonical Antigen Presentation in Mice","volume":"16","author":"Li","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/s41586-024-07630-7","article-title":"A Liver Immune Rheostat Regulates CD8 T Cell Immunity in Chronic HBV Infection","volume":"631","author":"Bosch","year":"2024","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1097\/HEP.0000000000000752","article-title":"Chronic Hepatitis B Baseline Viral Load and On-Treatment Liver Cancer Risk: A Multinational Cohort Study of HBeAg-Positive Patients","volume":"80","author":"Choi","year":"2024","journal-title":"Hepatol. Baltim. Md"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.cgh.2024.07.031","article-title":"Baseline Viral Load and On-Treatment Hepatocellular Carcinoma Risk in Chronic Hepatitis B: A Multinational Cohort Study","volume":"23","author":"Choi","year":"2025","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1002\/hep.29800","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":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12072-015-9675-4","article-title":"Asian-Pacific Clinical Practice Guidelines on the Management of Hepatitis B: A 2015 Update","volume":"10","author":"Sarin","year":"2016","journal-title":"Hepatol. Int."},{"key":"ref_26","doi-asserted-by":"crossref","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":"ref_27","first-page":"1425","article-title":"Guidelines for the Prevention and Treatment of Chronic Hepatitis B (Version 2022)","volume":"11","author":"You","year":"2023","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1002\/jmv.22048","article-title":"High Prevalence of Significant Liver Fibrosis and Cirrhosis in Chronic Hepatitis B Patients with Normal ALT in Central Europe","volume":"83","author":"Erhardt","year":"2011","journal-title":"J. Med. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.jhep.2007.07.022","article-title":"The Clinical Significance of Persistently Normal ALT in Chronic Hepatitis B Infection","volume":"47","author":"Lai","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.cgh.2008.10.023","article-title":"Clinical Factors Associated with Liver Stiffness in Hepatitis B e Antigen\u2013Positive Chronic Hepatitis B Patients","volume":"7","author":"Wong","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ijid.2022.08.017","article-title":"Liver Histology of Treatment-Na\u00efve Children with Chronic Hepatitis B Virus Infection in Shanghai China","volume":"123","author":"Hu","year":"2022","journal-title":"Int. J. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Huang, C., Guo, X., Wang, Z., Pan, Y., Jiang, Q., Li, J., Fan, P., Fu, J., Zhang, M., and Wang, F.-S. (2025). Significant Histologic Alterations in Untreated Chronic Hepatitis B Children: A Meta-Analysis. BMC Infect. Dis., 25.","DOI":"10.1186\/s12879-025-11876-5"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"European Association for Study of Liver (2015). Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: Non-Invasive Tests for Evaluation of Liver Disease Severity and Prognosis. J. Hepatol., 63, 237\u2013264.","DOI":"10.1016\/j.jhep.2015.04.006"},{"key":"ref_34","first-page":"105","article-title":"The Role of HBsAg Levels in the Current Management of Chronic HBV Infection","volume":"27","author":"Siederdissen","year":"2014","journal-title":"Ann. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Seto, W.-K., Wong, D.K.-H., Fung, J., Ip, P.P.C., Yuen, J.C.-H., Hung, I.F.-N., Lai, C.-L., and Yuen, M.-F. (2012). High Hepatitis B Surface Antigen Levels Predict Insignificant Fibrosis in Hepatitis B e Antigen Positive Chronic Hepatitis B. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043087"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/6\/2164\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T14:03:10Z","timestamp":1773324190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/6\/2164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,12]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["jcm15062164"],"URL":"https:\/\/doi.org\/10.3390\/jcm15062164","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,12]]}}}