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Current treatment options for chronic hepatitis B virus (HBV) infection cannot achieve functional cure [hepatitis B surface antigen (HBsAg) loss]; therefore, new approaches are under investigation. This review summarizes the most promising approaches in emerging antivirals against HBV, after search in Medline (2016–2022) and European and American liver meetings (2019–2022). Classes of antivirals include entry inhibitors (bulevirtide), capsid assembly modulators (CAMs), translation inhibitors [small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs)], and HBsAg secretion inhibitors [nucleic acid polymers (NAPs)]. Bulevirtide has good efficacy in hepatitis B and D coinfection, but there is limited data in HBV monoinfection. CAMs profoundly reduce serum HBV DNA/RNA levels, but have minimal effects on antigen levels. siRNAs and ASOs mostly reduce HBsAg levels, but small proportions of patients reach HBsAg seroclearance. NAPs reduce serum HBV DNA and especially HBsAg levels offering substantial HBsAg seroconversion rates, but having limited data over a long period. Combinations of agents of different classes are starting to be evaluated. Continued efforts are required in order to address many unanswered questions about the optimal combined regimens of finite duration which will be safe and well tolerated achieving functional cure in a substantial proportion of chronic HBV patients.

State-of-the-art and emerging antivirals for chronic hepatitis B infection