{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:59:01Z","timestamp":1792807141017,"version":"4.5.0"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T00:00:00Z","timestamp":1684713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"High-level Public Health Technical Talents of the Beijing Municipal Health Commission","award":["XUEKEGUGAN-010-018"],"award-info":[{"award-number":["XUEKEGUGAN-010-018"]}],"id":[{"id":"https:\/\/ror.org\/0374a5s68","id-type":"ROR","asserted-by":"crossref"}]},{"name":"High-level Public Health Technical Talents of the Beijing Municipal Health Commission","award":["PX2023005"],"award-info":[{"award-number":["PX2023005"]}],"id":[{"id":"https:\/\/ror.org\/0374a5s68","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Beijing Municipal Administration of Hospitals Incubating Program","award":["XUEKEGUGAN-010-018"],"award-info":[{"award-number":["XUEKEGUGAN-010-018"]}],"id":[{"id":"https:\/\/ror.org\/04baakq55","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Beijing Municipal Administration of Hospitals Incubating Program","award":["PX2023005"],"award-info":[{"award-number":["PX2023005"]}],"id":[{"id":"https:\/\/ror.org\/04baakq55","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>We aim to investigate the impact of different clinical phases\u2019 definitions of chronic hepatitis B (CHB) infection on the profiles of grey zone, based on HBV guidelines set by the Chinese Society of Hepatology and Chinese Society of Infectious Diseases (CSH\/CSID, 2022 version) and guidelines set by the American Association for the Study of Liver Diseases (AASLD, 2018 version). We retrospectively examined untreated CHB patients enrolled in the China Registry of Hepatitis B database. Patients\u2019 clinical phases were determined as per CSH\/CSID and AASLD. Liver fibrosis was estimated by FIB-4 and\/or APRI. Among 3462 CHB patients, 56.9% and 41.7% fell into the grey zone based on AASLD and CSH\/CSID. Compared with grey zone patients as per AASLD, those under CSH\/CSID guidelines showed lower levels of median ALT (26.0 vs. 37.0 U\/L, p &lt; 0.001), AST (25.0 vs. 29.4 U\/L, p &lt; 0.001) and APRI (0.3 vs. 0.4, p &lt; 0.001), and lower rates of advanced fibrosis estimated by APRI (7.9% vs. 11.4% p = 0.001), but comparable rates by FIB-4 (13.0% vs. 14.1%, p = 0.389). With the stepwise lowering of ALT upper limits of normal (ULN) values from 50\/40 U\/L for males\/females to 40\/40 U\/L, 35\/25 U\/L and 30\/19 U\/L, the proportions of grey zone patients as per CSH\/CSID declined from 46.7% to 41.7%, 34.3% and 28.8%, respectively, whereas they remained stable (55.7%, 56.2%, 56.9% and 57.0%) as per AASLD. Compared with the AASLD guidelines, CSH\/CSID guidelines leave fewer and less severe patients in the grey zone. Lowering ALT ULN values reduces the number of grey zone patients as per CSH\/CSID, but not under AASLD guidelines.<\/jats:p>","DOI":"10.3390\/v15051212","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T01:31:46Z","timestamp":1684719106000},"page":"1212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Impact of the Definitions of Clinical Phases on the Profiles of Grey-Zone Patients with Chronic Hepatitis B Virus Infection"],"prefix":"10.3390","volume":"15","author":[{"given":"Xiaoqian","family":"Xu","sequence":"first","affiliation":[{"name":"Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing Clinical Research Institute, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9131-0199","authenticated-orcid":false,"given":"Hao","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing Clinical Research Institute, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Shan","sequence":"additional","affiliation":[{"name":"Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yameng","family":"Sun","sequence":"additional","affiliation":[{"name":"Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"You","sequence":"additional","affiliation":[{"name":"Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jidong","family":"Jia","sequence":"additional","affiliation":[{"name":"Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Disease Center, Peking University Health Science Center, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Kong","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing Clinical Research Institute, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the China Registry of Hepatitis B (CR-HepB) Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,22]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2017). EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol., 67, 370\u2013398.","DOI":"10.1016\/j.jhep.2017.03.021"},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1111\/jgh.15856","article-title":"Precision medicine in the era of potent antiviral therapy for chronic hepatitis B","volume":"37","author":"Yoon","year":"2022","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_5","unstructured":"Chinese Society of Hepatology, Chinese Medical Association, Chinese Society of Infectious Diseases, and Chinese Medical Association (2022). Guidelines for the prevention and treatment of chronic hepatitis B (version 2022). Zhonghua Gan Zang Bing Za Zhi, 30, 1309\u20131331."},{"key":"ref_6","unstructured":"Chinese Society of Hepatology, Chinese Medical Association, Chinese Society of Infectious Diseases, and Chinese Medical Association (2023). Guidelines for the prevention and treatment of chronic hepatitis B (version 2022). J. Clin. Transl. Hepatol., submitted."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ren, S., Wang, W., Lu, J., Wang, K., Ma, L., Zheng, Y., Zheng, S., and Chen, X. (2022). Effect of the change in antiviral therapy indication on identifying significant liver injury among chronic hepatitis B virus infections in the grey zone. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1035923"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1177\/1403494818772188","article-title":"China Registry of Hepatitis B (CR-HepB): Protocol and implementation of a nationwide hospital-based registry of hepatitis B","volume":"48","author":"Shan","year":"2018","journal-title":"Scand. J. Public Health"},{"key":"ref_9","first-page":"322","article-title":"Baseline Characteristics and Treatment Patterns of the Patients Recruited to the China Registry of Hepatitis B","volume":"7","author":"Shan","year":"2019","journal-title":"J Clin Transl Hepatol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.21178","article-title":"Development of a simple noninvasive index to predict significant fibrosis in patients with HIV\/HCV coinfection","volume":"43","author":"Sterling","year":"2006","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1053\/jhep.2003.50346","article-title":"A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C","volume":"38","author":"Wai","year":"2003","journal-title":"Hepatology"},{"key":"ref_12","first-page":"17","article-title":"Establishment of reference intervals for commonly used clinical tests in Chinese population","volume":"4","author":"Shang","year":"2013","journal-title":"Zhong Guo Wei Sheng Biao Zhun Guan Li"},{"key":"ref_13","unstructured":"Chinese Society of Hepatology, and Chinese Medical Association (2022). Expert opinion on expanding anti-HBV treatment for chronic hepatitis B. Zhonghua Gan Zang Bing Za Zhi, 30, 131\u2013136."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1111\/apt.16097","article-title":"East Asia expert opinion on treatment initiation for chronic hepatitis B","volume":"52","author":"Kao","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sarri, G., Westby, M., Bermingham, S., Hill-Cawthorne, G., and Thomas, H. (2013). Diagnosis and management of chronic hepatitis B in children, young people, and adults: Summary of NICE guidance. BMJ, 346.","DOI":"10.1136\/bmj.f3893"},{"key":"ref_16","doi-asserted-by":"crossref","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":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/j.cgh.2021.01.019","article-title":"Natural History and Hepatocellular Carcinoma Risk in Untreated Chronic Hepatitis B Patients With Indeterminate Phase","volume":"20","author":"Huang","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1111\/apt.13802","article-title":"Distribution of disease phase, treatment prescription and severe liver disease among 1598 patients with chronic hepatitis B in the Chronic Hepatitis Cohort Study, 2006-2013","volume":"44","author":"Spradling","year":"2016","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1111\/jvh.13511","article-title":"Distribution and clinical characteristics of patients with chronic hepatitis B virus infection in the grey zone","volume":"28","author":"Yao","year":"2021","journal-title":"J. Viral Hepat."},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1365-2893.2009.01168.x","article-title":"Hepatitis B viral load and risk for liver cirrhosis and hepatocellular carcinoma in The Gambia, West Africa","volume":"17","author":"Mendy","year":"2010","journal-title":"J. Viral Hepat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e50","DOI":"10.1097\/MCG.0b013e3182a9a2e1","article-title":"Predictors of significant fibrosis in chronic hepatitis B patients with low viremia","volume":"48","author":"Abdo","year":"2014","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/liv.13489","article-title":"Non-invasive tests for liver disease severity and the hepatocellular carcinoma risk in chronic hepatitis B patients with low-level viremia","volume":"38","author":"Paik","year":"2018","journal-title":"Liver Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e791","DOI":"10.1093\/cid\/ciac385","article-title":"Simplifying Treatment Criteria in Chronic Hepatitis B: Reducing Barriers to Elimination","volume":"76","author":"Wong","year":"2023","journal-title":"Clin. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Vu, V.D., Do, A., Nguyen, N.H., Kim, L.H., Trinh, H.N., Nguyen, H.A., Nguyen, K.K., Nguyen, M., Huynh, A., and Nguyen, M.H. (2015). Long-term follow-up and suboptimal treatment rates of treatment-eligible chronic hepatitis B patients in diverse practice settings: A gap in linkage to care. BMJ Open Gastroenterol., 2.","DOI":"10.1136\/bmjgast-2015-000060"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1007\/s12072-021-10153-2","article-title":"High-normal alanine aminotransferase is an indicator for liver histopathology in HBeAg-negative chronic hepatitis B","volume":"15","author":"Duan","year":"2021","journal-title":"Hepatol. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1111\/apt.14613","article-title":"Anti-viral therapy can be delayed or avoided in a significant proportion of HBeAg-negative Caucasian patients in the Grey Zone","volume":"47","author":"Bonacci","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1007\/s12072-021-10263-x","article-title":"Risk scores to predict HCC and the benefits of antiviral therapy for CHB patients in gray zone of treatment guidelines","volume":"15","author":"Teng","year":"2021","journal-title":"Hepatol. Int."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Feng, M., Liu, K., Zhao, G., Lou, S., An, B., Lin, L., Ding, Y., Bao, S., and Wang, H. (2022). A novel model based on qAnti-HBc and conventional biomarkers for identifying significant liver injury among CHB patients with ALT \u2264 ULN. Antivir. Res., 202.","DOI":"10.1016\/j.antiviral.2022.105315"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1002\/hep4.1875","article-title":"Aiming for Functional Cure With Established and Novel Therapies for Chronic Hepatitis B","volume":"6","author":"Choi","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1111\/apt.14577","article-title":"An expert consensus for the management of chronic hepatitis B in Asian Americans","volume":"47","author":"Tong","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wu, Z., Ma, A.L., Xie, Q., Zhang, X.Q., Cheng, J., Zhang, D.Z., Wang, G.Q., and Zhao, H. (2021). Significant histological changes and satisfying antiviral efficacy in chronic hepatitis B virus infection patients with normal alanine aminotransferase. Antiviral therapy decision in chronic HBV patients with normal ALT. Clin. Res. Hepatol. Gastroenterol., 45.","DOI":"10.1016\/j.clinre.2020.05.011"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/hep.26385","article-title":"Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: Risk scores integrating host and virus profiles","volume":"58","author":"Lee","year":"2013","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1080\/14787210.2019.1694906","article-title":"Emerging tools in the changing landscape of chronic hepatitis B management","volume":"17","author":"Gill","year":"2019","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jhep.2019.03.004","article-title":"Global liver disease burdens and research trends: Analysis from a Chinese perspective","volume":"71","author":"Xiao","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"420","DOI":"10.14218\/JCTH.2022.00167","article-title":"Impact of National Centralized Drug Procurement Policy on Antiviral Utilization and Expenditure for Hepatitis B in China","volume":"10","author":"Zhao","year":"2022","journal-title":"J. Clin. Transl. Hepatol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/5\/1212\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:39:34Z","timestamp":1760125174000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/5\/1212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,22]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["v15051212"],"URL":"https:\/\/doi.org\/10.3390\/v15051212","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,22]]}}}