Emerging therapies for HBsAg seroclearance: spotlight on novel combination strategies

Abstract

Introduction: Functional cure is a favorable endpoint in chronic hepatitis B (CHB), yet it is rarely achieved with currently approved drugs (nucleos[t]ide analogues and pegylated interferon alpha). A range of novel agents, broadly classified into virus-targeting agents and immunomodulators, are hence developed with functional cure as the treatment target. As the data on individual novel agents are maturing, the field has gradually shifted to novel combination strategies. Methods: This article comprehensively reviewed the data on novel combination strategies against CHB. Potential mechanisms and future developmental directions are also discussed Results: RNA silencers (including antisense oligonucleotides and small-interfering RNAs) form the backbone of most combination strategies. Synergistic effects are observable with the combination of RNA silencers + single or dual immunomodulators, primarily through enhancing the magnitude and rate of hepatitis B surface antigen (HBsAg) decline, prolonging RNA silencer effects, and reducing HBsAg rebound after end-of-treatment. Accumulating data also demonstrate immune dysfunction recovery among patients with significant HBsAg reduction on RNA silencer-based or immune checkpoint inhibitor-based combination therapies. Conclusion: Functional cure is now an attainable endpoint with novel combination treatment. Research is warranted to optimize combination regimens, and personalization of treatment strategies will be necessary. With further development, novel combination strategies have the potential to transform future CHB management.