Natural History and Clinical Outcomes of HBeAg-Negative Chronic Hepatitis B Patients in the “Grey Zone”: A Longitudinal Cohort Study

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.