LAUSR

ABSTRACT Introduction Functional cure, defined as sustained HBsAg seroclearance, is associated with favorable outcomes in chronic hepatitis B (CHB). While nucleos(t)ide analogues (NAs) are effective in suppressing HBV replication, NAs are unable to induce functional cure at high rates. A range of novel HBV antivirals, aiming to induce functional cure, are currently under development. Areas covered This article covered novel hepatitis B virus (HBV) antivirals that have entered phase II trials. Virus-directing agents covered include entry inhibitors, transcription inhibitors, RNA silencers, core protein allosteric modulators, noncompetitive polymerase inhibitors, and viral protein export inhibitors. Immunomodulators covered include innate immune stimulators, T-cell modulators, therapeutic vaccines, and monoclonal antibodies. Upcoming developmental directions would also be discussed. Expert opinion Among novel HBV antivirals, RNA silencers, viral protein export inhibitors (with pegylated interferon), and entry inhibitors (with pegylated interferon) appear to be effective in suppressing HBsAg and may even induce functional cure. The other virus-targeting agents have variable effects on HBV DNA, HBsAg, HBeAg, and HBcrAg. Immunomodulators have modest effects on HBsAg but may have important roles in combination therapy. Upcoming trials will answer important questions on ideal dosing, long-term drug effects, and efficacy of combination regimens.