Gray zone and the need for expansion in chronic hepatitis B: From theory to clinical practice

Chronic hepatitis B (CHB) remains a significant global health challenge. The natural course of CHB is traditionally divided into four phases: (1) Immune tolerance; (2) Immune activation; (3) Immune control; and (4) Immune escape. However, approximately 20%-30% of patients referred to as the "gray zone" (GZ) do not fit neatly into these categories. These patients often exhibit elevated hepatitis B virus DNA levels alongside normal or mildly elevated alanine aminotransferase levels, placing them at significant risk for liver fibrosis, cirrhosis, and hepatocellular carcinoma. However, current clinical guidelines generally do not recommend antiviral therapy for GZ patients, increasing their vulnerability to adverse outcomes. This mini-review explores the challenges and gaps in CHB management, focusing on GZ patients. It also highlights recent advancements in therapeutic strategies and updates in clinical guidelines, emphasizing the need for a more inclusive, risk-adapted approach to treatment. By leveraging novel biomarkers, noninvasive fibrosis assessment tools, and artificial intelligence-driven predictive models, this article advocates for early intervention to mitigate disease progression and improve clinical outcomes in this overlooked population.