Moving Beyond Viral Suppression in Chronic Hepatitis B
Review by Dr. Andrés Gutiérrez (Uruguay)
Study Summary
Current therapies for chronic hepatitis B (CHB), namely nucleos(t)ide analogues (NAs) and pegylated interferon, effectively suppress hepatitis B virus (HBV) replication but rarely achieve hepatitis B surface antigen (HBsAg) loss, the accepted surrogate of functional cure. Consequently, most patients require lifelong antiviral therapy because HBsAg clearance is seldom achieved despite sustained virological suppression. The B-Well program investigated whether a finite course of bepirovirsen, an antisense oligonucleotide targeting all HBV transcripts, could achieve functional cure in patients already receiving effective NA therapy. In two identical international phase 3, randomized, double-blind, placebo-controlled trials conducted across 29 countries, 1,834 adults with noncirrhotic CHB receiving stable NA therapy, HBV DNA <90 IU/mL, ALT ≤2× the upper limit of normal, and HBsAg levels between 100 and 3000 IU/mL were randomized (2:1) to receive weekly subcutaneous bepirovirsen (300 mg) or placebo for 24 weeks. Patients meeting predefined virological criteria discontinued NA therapy at week 48 and the primary endpoint was functional cure at week 72, defined as sustained HBsAg loss together with HBV DNA below the lower limit of quantification without rescue therapy. Functional cure was achieved in 20% of patients in B-Well 1 and 19% in B-Well 2 receiving bepirovirsen, whereas no patient receiving placebo achieved the primary endpoint. Responses were more frequent among patients with baseline HBsAg ≤1000 IU/mL. Approximately one-quarter of treated patients successfully discontinued NA therapy while maintaining virological suppression through week 72. Injection-site reactions and transient alanine aminotransferase elevations were common but generally manageable, and no cases fulfilled criteria for drug-induced liver injury.
Commentary
Current antiviral therapy has dramatically transformed the prognosis of chronic hepatitis B, yet its greatest limitation remains unchanged: most patients continue lifelong treatment because HBsAg loss is rarely achieved. This study provides the strongest evidence to date that finite therapy can move selected patients beyond viral suppression toward functional cure. This distinction is clinically important. While current NAs effectively suppress viral replication and substantially reduce the risk of disease progression, they rarely eliminate HBsAg and therefore seldom allow treatment discontinuation. Pegylated interferon can induce HBsAg loss in a minority of carefully selected patients but its use is limited by modest efficacy, tolerability, and contraindications. Achieving HBsAg clearance is associated with improved long-term clinical outcomes, including lower risks of hepatocellular carcinoma, hepatic decompensation, and the possibility of safely discontinuing lifelong antiviral therapy. Major strengths of this study include its large sample size, two replicate phase 3 trials, broad international participation, and the use of a clinically meaningful endpoint assessed after treatment discontinuation. However, the findings should be interpreted within the context of the selected study population. Only patients without cirrhosis, already well controlled on NA therapy, and with HBsAg levels ≤3000 IU/mL were included. Consequently, these results cannot yet be extrapolated to patients with cirrhosis, uncontrolled HBV replication, higher HBsAg levels, or treatment-naïve disease. Future studies will likely evaluate bepirovirsen as part of combination strategies incorporating siRNA therapies, therapeutic vaccines, and immune modulators to further improve functional cure rates. Nevertheless, this landmark study demonstrates that functional cure is no longer merely an aspirational goal but an achievable therapeutic target for a selected group of patients with chronic hepatitis B.
Citation
Hou J, Lim SG, Buti M, et al. Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection. N Engl J Med. 2026;394:2395-2406. doi:10.1056/NEJMoa2515131.
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