Evaluating the potential of treatment options for chronic hepatitis B

Chronic hepatitis B (CHB) remains a leading cause of cirrhosis and hepatocellular carcinoma worldwide, but long-term or even lifelong viral suppression with nucleos(t)ide analogues (NAs) seldom clears hepatitis B surface antigen (HBsAg), so-called 'functional cure.' In recent years, a shift in treatment strategy from viral suppression toward cure has emerged, catalyzed by three revised international hepatitis B guidelines (2025-2026) and the first-in-class phase 3 evidence that a finite antiviral therapy, the antisense oligonucleotide bepirovirsen, can achieve a functional cure in about one in five NA-suppressed CHB patients with baseline HBsAg below 3000 IU/mL.

We evaluated the spectrum of established and emerging treatment options for CHB, organized around quantitative HBsAg (qHBsAg) as the axis for selecting and sequencing therapy. Coverage spans backbone NAs and pegylated interferon-α, an HBsAg-guided roadmap, finite NA therapy and off-treatment outcomes, bepirovirsen, other virus-targeting and immunomodulatory agents, and genome-directed covalently closed circular DNA silencing and editing.

Bepirovirsen's approaching approval is an inflection point. qHBsAg should guide personalized, sequential therapy, with partial cure (HBsAg < 100 IU/mL) as a potential intermediate target when functional cure is unlikely. Durability, standardized biomarkers, rational combination design, metabolic co-management and equitable access are the priorities; a sterilizing cure remains distant.