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Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen (HBsAg) loss and suppression of HBV DNA. Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B, including core\/capsid inhibitors, entry inhibitors, RNA interference (siRNA\/ASO), HBsAg inhibitors, Toll-like receptor agonists, checkpoint inhibitors, and therapeutic vaccines.<\/jats:p>","DOI":"10.4254\/wjh.v16.i3.331","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T02:15:56Z","timestamp":1711505756000},"page":"331-343","source":"Crossref","is-referenced-by-count":12,"title":["Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B: A comprehensive review of phases II and III therapeutic agents"],"prefix":"10.4254","volume":"16","author":[{"given":"Robert","family":"Lam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph K","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2060","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000000651"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(22)00386-7"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23190"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22898"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(18)30056-6"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3851\/IMP1497"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2005.02.033"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-305785"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S0399-8320(10)70031-2"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.07.008"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20240"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2017.00073"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.5009\/gnl.2011.5.3.278"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2003.08.015"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-010-9208-0"},{"key":"B16","unstructured":"Ryu SH, Chung YH. 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