Natural History and Clinical Outcomes of HBeAg-Negative Chronic Hepatitis B Patients in the “Grey Zone”: A Longitudinal Cohort Study
- 1The Key Laboratory of Molecular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, 76# Linjiang Road, Yuzhong District, Chongqing 400010, China
Abstract
Introduction and Objectives: Up to one-third of treatment-naïve, HBeAg-negative chronic hepatitis B (CHB) patients with normal ALT do not meet the strict criteria for the inactive carrier (IC) phase, falling into a “Grey Zone” (GZIC). We aimed to delineate the longitudinal outcomes of GZIC patients compared with strictly defined IC patients. Patients and Methods: This retrospective cohort study included 386 HBeAg-negative, ALT-normal CHB patients (125 GZIC, 261 IC). Endpoints included phase transition to immune-active stages, antiviral initiation, and end-stage liver disease (cirrhosis or hepatocellular carcinoma (HCC)). Cumulative incidence was assessed using Kaplan–Meier analysis. Results: Over a median follow-up of 4.5 years, the GZIC cohort exhibited significantly higher cumulative incidence of phase transition (36.8% vs. 13.8%, p < 0.001), antiviral initiation (37.6% vs. 18.8%, p = 0.00014), and end-stage liver disease (4.8% vs. 1.5%, p = 0.049) compared with the IC cohort. All incident HCC cases occurred exclusively in the GZIC group. Multivariate analysis identified baseline GZIC status, male sex, and elevated AFP as independent risk factors. A lower ALT cutoff of 24.5 U/L was superior to 40 U/L in predicting phase transition (p < 0.01). Sex-stratified analyses confirmed that GZIC remained an independent risk factor for phase transition in both male and female patients (both p < 0.05). Conclusions: The GZIC phase is not a benign state. Compared with true inactive carriers, GZIC patients face a significantly elevated risk of progression and liver-related complications, supporting proactive surveillance and timely antiviral intervention.
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BibTeX
@article{xue2026natural,
title = {{Natural History and Clinical Outcomes of HBeAg-Negative Chronic Hepatitis B Patients in the “Grey Zone”: A Longitudinal Cohort Study}},
author = {Yunling Xue and Mengyuan Liu and Guorui Wang and Qiao Tang and Jingsong Wang and Jing Zhang and Yi Zeng and Mingli Peng and Xiaoqing Liu and Peng Hu},
journal = {Journal of Clinical Medicine},
year = {2026},
month = oct,
doi = {10.3390/jcm15207832},
url = {https://www.mdpi.com/2077-0383/15/20/7832},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Natural History and Clinical Outcomes of HBeAg-Negative Chronic Hepatitis B Patients in the “Grey Zone”: A Longitudinal Cohort Study
AU - Yunling Xue
AU - Mengyuan Liu
AU - Guorui Wang
AU - Qiao Tang
AU - Jingsong Wang
AU - Jing Zhang
AU - Yi Zeng
AU - Mingli Peng
AU - Xiaoqing Liu
AU - Peng Hu
PY - 2026
DA - 2026/10/10
JO - Journal of Clinical Medicine
DO - 10.3390/jcm15207832
UR - https://www.mdpi.com/2077-0383/15/20/7832
AB - Introduction and Objectives: Up to one-third of treatment-naïve, HBeAg-negative chronic hepatitis B (CHB) patients with normal ALT do not meet the strict criteria for the inactive carrier (IC) phase, falling into a “Grey Zone” (GZIC). We aimed to delineate the longitudinal outcomes of GZIC patients compared with strictly defined IC patients. Patients and Methods: This retrospective cohort study included 386 HBeAg-negative, ALT-normal CHB patients (125 GZIC, 261 IC). Endpoints included phase transition to immune-active stages, antiviral initiation, and end-stage liver disease (cirrhosis or hepatocellular carcinoma (HCC)). Cumulative incidence was assessed using Kaplan–Meier analysis. Results: Over a median follow-up of 4.5 years, the GZIC cohort exhibited significantly higher cumulative incidence of phase transition (36.8% vs. 13.8%, p < 0.001), antiviral initiation (37.6% vs. 18.8%, p = 0.00014), and end-stage liver disease (4.8% vs. 1.5%, p = 0.049) compared with the IC cohort. All incident HCC cases occurred exclusively in the GZIC group. Multivariate analysis identified baseline GZIC status, male sex, and elevated AFP as independent risk factors. A lower ALT cutoff of 24.5 U/L was superior to 40 U/L in predicting phase transition (p < 0.01). Sex-stratified analyses confirmed that GZIC remained an independent risk factor for phase transition in both male and female patients (both p < 0.05). Conclusions: The GZIC phase is not a benign state. Compared with true inactive carriers, GZIC patients face a significantly elevated risk of progression and liver-related complications, supporting proactive surveillance and timely antiviral intervention.
SN - 2077-0383
ER -