Clinical Prospect of Novel Therapies for Functional Cure in Chronic Hepatitis B

Chronic hepatitis B (CHB) remains a major global health problem. Functional cure is defined as sustained hepatitis B surface antigen (HBsAg) seroclearance with undetectable HBV DNA 24 weeks after cessation of therapy. It has emerged as a clinically meaningful endpoint, associated with regression of liver fibrosis, reduced hepatocellular carcinoma (HCC) risk, and a lower treatment burden. However, current CHB therapies, including nucleos(t)ide analogues (NUCs) and pegylated interferon-α (Peg-IFNα), rarely lead to functional cure despite adequate viral suppression, leading to a notable portion of patients remaining at risk for adverse liver-related outcomes, including hepatic decompensation and HCC. Hence, novel therapeutic agents are aimed at accelerating towards functional cure. They are categorized as virus-targeting and immunomodulatory therapies.

This review summarizes the clinical evidence for emerging therapies aimed at acheiving functional cure, with a particular focus on RNA-targeting therapies. It also discusses practical considerations relevant to treatment selection.

Among these novel therapies, RNA-targeting therapies are currently the most promising, with bepirovirsen (an unconjugated antisense oligonucleotide) standing out as the only agent completed in Phase III study showing efficacious results. Combination regimens that use RNA-targeting therapies as backbone are increasingly pursued, leveraging potential synergistic effects to achieve higher rates of HBsAg seroclearance.

RNA-targetting therapies and combination regimens offer promising approaches in attaining functional cure in CHB. Further research should emphasize on the long-term efficacy and safety for these novel agents.