Indeterminate Phase/Grey Zone of Chronic Hepatitis B: Clinical Features, Outcomes and Molecular Insights

ABSTRACT Chronic hepatitis B virus (HBV) infection remains a global public health challenge, with a high risk of complications such as cirrhosis, hepatocellular carcinoma (HCC) and death. As outlined in current international society guidelines, antiviral therapies are aimed at preventing progression of liver disease to life‐threatening complications and viral transmission. However, the proportion of patients currently treated remains low. Four phases have been identified in the natural history of chronic HBV infection. Because these phases evolve dynamically, serial assessments of alanine aminotransferase (ALT), HBV DNA and liver histology are crucial to optimise treatment strategies. However, 28% to 55% of patients with chronic HBV infection do not fit into any of the four clinical phases precisely defined by international guidelines. These patients fall into the so‐called indeterminate phase or grey zone . Patients in the grey zone generally have no indication for treatment, despite being at risk for progression to liver fibrosis, cirrhosis and HCC. The latest EASL Clinical Practice Guidelines have moved away from rigid phase‐based classifications for therapeutic decisions, adopting instead a personalised, risk‐based approach that integrates HBV DNA, ALT, liver fibrosis, age, family history of HCC and comorbidities. Nevertheless, the concept of the grey zone remains relevant in research, as it highlights a heterogeneous group of patients whose prognosis and management remain challenging. Emerging data suggest that antiviral therapy can improve long‐term outcomes in selected patients previously considered ineligible for treatment, but clinical outcomes are variable and influenced by factors such as age, gender, viral load and histological findings. Further research is needed to refine the management strategies for these patients with grey zone HBV infection and to evaluate the long‐term benefits of antiviral treatment indications. This review article summarises the current knowledge on the clinical features, management approaches and outcomes of patients with chronic HBV infection in the indeterminate phase/grey zone.