Importance of CHB's grey zone: analysis of patients with HBeAg negative chronic hepatitis B virus infection.

Introduction: HBeAg-negative chronic HBV infection is defined by viremia < 2,000 IU/ml (or < 20,000 IU/ml), normal ALT activity and minimal liver fibrosis. Some patients do not meet all the criteria and belong to the so-called grey zone. The aim of the work was to analyse a group of patients with asymptomatic chronic HBV infection, divide them according to the levels of HBV DNA during follow-up and to compare the clinical and laboratory parameters of the patients within the groups.

Methods: We retrospectively analysed patients with HBeAg-negative chronic HBV infection examined in the Centre for Viral Hepatitis of the Department of Infectology in Košice, Slovakia, from September 2018 to December 2021. Patients were divided into three groups based on HBV DNA levels ​​during long-term follow-up ( 2,000 IU/ ml). We evaluated selected demographic, anamnestic and laboratory data (HBV DNA, ALT, fibrosis stage).

Results: Of the 280 enrolled patients, 160 were men (57.1 %), the average age was 48.0 years, and the mean length of follow-up was 4.7 years. HBV DNA levels ​​were consistently 2,000 IU/ml in 62 patients. 165 patients had normal ALT activity, 74 had fluctuating ALT activity, and permanently increased ALT in 41 patients. 139 patients underwent transient elastography examination, 16 of them had stage F2 fibrosis, two stage F3 and 1 had cirrhosis. When comparing the three groups divided according to HBV DNA, patients with fluctuating HBV DNA had the longest follow-up, but patients with HBV DNA permanently over 2,000 IU/ml were the youngest and the highest proportion of them had elevated ALT activity. 165 patients (58.9%) met the extended criteria of asymptomatic carriers, 115 were in the grey zone.

Conclusion: Patients with HBeAg-negative chronic HBV infection often have fluctuating HBV DNA and ALT values ​​during follow-ups. Statistically significantly higher proportion of abnormal ALT activity in patients with HBV DNA > 2,000 IU/ml may suggest higher risk of adverse outcomes. Initiation of treatment in such patients is not always necessary unless they also meet the other indication criteria for treatment. The exact definition of the grey zone is currently absent (Tab. 2, Fig. 2, Ref. 16).