Chen J.Ji D.Jia J.Zhuang H.Zhang X.Wang F.S.Zhang W.Dou X.Tanwandee T.Sarin S.K.Maiwall R.Kumar M.Goh G.B.B.Ghazinyan H.Chutaputti A.Chen P.J.You H.Yu M.L.George J.Omata M.Wang G.Q.Lau G.APASL Viral Elimination TaskforceMahidol University2025-06-232025-06-232025-01-01Hepatology International (2025)19360533https://repository.li.mahidol.ac.th/handle/20.500.14594/110867Background: Achieving a “functional” cure for chronic hepatitis B (HBV) is primary goal for novel antiviral treatments. We sought to evaluate efficacy and safety of these novel treatments and identified emerging barriers to achieving a functional cure. Approach: We systematically reviewed clinical trials from 2018 to 2023, identifying 244 trials from clinicaltrials.gov records on HBV. The primary outcome was functional cure rate at the end of follow-up (EOF). Secondary outcomes included changes in HBsAg levels, HBsAg loss rates, HBV DNA rebound, and adverse events. Meta-analysis was performed. Results: Our meta-analysis of 19 studies involving 1789 non-cirrhotic HBV patients found a minimal functional cure rate (0.0%, 95%CI 0.0–0.4%) and low HBsAg loss rates (0.9% at the end of treatment [EOT] and 0.1% at EOF). HBsAg levels declined at EOT (−0.41 log10 IU/mL, 95%CI −0.45 to −0.37, p < 0.001) but this reduction was not sustained to EOF. Virological relapse occurred in 20.5% of cases off-treatment. Although novel treatments were well-tolerated, they had higher adverse event rates (OR = 1.77, 95%CI 1.26–2.48). Challenges to achieving a functional cure include complex trial designs and unknown confounding factors. Conclusion: Novel antiviral treatments showed limited effectiveness in achieving HBsAg loss and reduction, highlighting the need to address identified barriers in future research.MedicineArticleSCOPUS10.1007/s12072-025-10823-52-s2.0-10500823546019360541