Toward a Precision Cure for Chronic Hepatitis B: Convergence of RNA Silencing, Gene Editing, Immune-Reset Therapies, and Artificial Intelligence-Guided Diagnostics

Abstract

Chronic hepatitis B virus (HBV) infection remains a major global health challenge, affecting over 250 million individuals and causing more than one million deaths annually from cirrhosis and hepatocellular carcinoma. Although current antiviral therapies effectively suppress viral replication, they rarely achieve a functional cure because covalently closed circular DNA (cccDNA) and integrated HBV DNA persist within hepatocytes. Consequently, lifelong treatment is often required, highlighting the urgent need for curative therapeutic strategies. Recent advances in molecular therapeutics, immunotherapy, and artificial intelligence (AI) have created new opportunities for precision HBV management. This narrative review critically evaluates emerging therapeutic approaches, including RNA interference, antisense oligonucleotides, gene-editing technologies, immune-reset therapies, rational combination regimens, biomarker-guided treatment, and AI-enabled precision diagnostics, with emphasis on their potential to achieve a durable functional cure. A comprehensive review of peer-reviewed literature published between 2015 and 2026 was conducted using PubMed, the Cochrane Library, and ClinicalTrials.gov. Clinical trials, mechanistic studies, and expert consensus guidelines focusing on novel HBV therapeutics, biomarkers, and AI applications were systematically evaluated, while non-peer-reviewed reports were excluded. Recent Phase III evidence demonstrates that the RNA-targeting agent bepirovirsen significantly improves sustained hepatitis B surface antigen (HBsAg) loss and functional cure rates compared with current standard therapy. Gene-editing platforms, including PBGENE-HBV, represent promising strategies for directly targeting cccDNA and integrated HBV DNA, although their long-term safety and efficacy remain under investigation. Immune-reset therapies involving therapeutic vaccines, Toll-like receptor agonists, immune checkpoint inhibitors, and engineered T-cell therapies have shown encouraging potential to restore antiviral immunity, particularly when combined with direct-acting antiviral agents. Furthermore, emerging biomarkers such as quantitative HBsAg, hepatitis B core-related antigen (HBcrAg), and serum HBV RNA, integrated with AI-based predictive models, facilitate personalized treatment selection, response monitoring, and prognostic assessment. Collectively, current evidence suggests that the future of chronic HBV management lies in precision combination therapy integrating deep viral suppression, targeted gene editing, immune restoration, and AI-guided clinical decision-making. Although important challenges related to delivery systems, long-term safety, affordability, and global accessibility remain, these multidisciplinary advances provide a realistic pathway toward scalable functional cure strategies and support progress toward achieving the World Health Organization’s hepatitis elimination goals.