Therapeutic advances in chronic hepatitis B and Delta: where are we now and where are we headed?

Chronic hepatitis B (HBV) and delta (HDV) infections remain major global health challenges. Nucleos(t)ide analogues (NUCs) and bulevirtide, a recently approved entry inhibitor, effectively suppress HBV and HDV replication, respectively, thereby reducing the risk of liver-related complications. However, they rarely induce functional cure, defined as sustained HBsAg loss, and generally require long-term administration. This limitation is primarily driven by the persistence of covalently closed circular DNA (cccDNA) and integrated HBV DNA, which are not targeted by existing treatments. A broad range of novel therapeutic strategies is currently under investigation. Virus-directing agents, including small interfering RNAs, antisense oligonucleotides, nucleic acid polymers, and capsid assembly modulators, have shown promising antiviral activity. However, their efficacy as monotherapy remains modest, with HBsAg loss observed at moderate rates and mainly among patients with a favorable baseline profile. Combination strategies integrating direct antivirals with immune modulation (therapeutic vaccines, toll-like receptor agonists or monoclonal antibodies) may represent a promising pathway to increase the rates of functional cure. In HDV infection, emerging phase 3 combination strategies are also showing promising results, supporting a shift toward more effective, multi-targeted treatment approaches. Building on these advances, the convergence of novel antivirals and immune-modulating strategies, together with precision biomarkers, makes functional cure a realistic long-term objective in HBV and HDV infection.