Copyright ©The Author(s) 2023.
World J Gastroenterol. Jul 7, 2023; 29(25): 3964-3983
Published online Jul 7, 2023. doi: 10.3748/wjg.v29.i25.3964
Table 1 Efficacy of available antiviral treatments and nucleos(t)ide analogues withdrawal to achieve hepatitis B virus surface antigen loss
Treatment (duration)
HBsAg loss (%)
Current antiviral treatments
Lau et al[84], 2005Peg-IFNα (1 yr)+Mainly Asian6 mo2.9
Marcellin et al[85], 2013Peg-IFNα (1 yr)-Asian60 mo12.0
Chang et al[48], 2010ETV (5 yr)+Asian-1.4
Ahn et al[32], 2016ETV (5 yr)-Mixed-4.6
Marcellin et al[33], 2019TDF (10 yr)+Mixed-4.9
Marcellin et al[33], 2019TDF (10 yr)-Mixed-3.4
Chan et al[30], 2016TAF (3 yr)+Mixed-4.0
Buti et al[31], 2016TAF (3 yr)-Mixed-3.0
Combined treatments
Marcellin et al[86], 2016Peg-IFN + TDF (1 yr)+/-Mixed18 mo9.1
Bourlière et al[87], 2017ETV, TDF, ADV, and LAM (1 yr)-Caucasian12 mo7.8
Lim et al[88], 2022NA add-on Peg-IFN (1 yr)+/-Asian6 mo12.1
Mo et al[89], 2022NAs (HBsAg < 1500 IU/mL, 1 yr)-Asian48 mo33.2
Lim et al[88], 2022NA switch to Peg-IFN (1 yr)+/-Asian6 mo9.7
NA discontinuation
Chen et al[90], 20182.7 yr+Asian96 mo19.6
Song et al[91], 20212.9 yr+Asian73 mo9.5
Kuo et al[92], 20193.1 yr+Asian24 mo4.7 (ETV); 0 (TDF)
Jeng et al[72], 20182.9 yr-Asian36 mo13
Chen et al[90], 20182.9 yr-Asian96 mo33.1
Kuo et al[92], 20193.1 yr-Asian36 mo10 (ETV); 15 (TDF)
Chen et al[93], 20203.2 yr-Asian58 mo20.8
Song et al[91], 20212.7 yr-Asian73 mo14.6
Hirode et al[47], 20223.0 yr-Mixed17 mo15.0
Table 2 Mechanisms of action of the new drugs under development
Treatment class
Mechanism of action
Drugs targeting HBV life cycle
Entry inhibitorsBlockage of liver-specific bile acid transporter (NTCP)Inhibitors of NTCP[124]; NMAb[125]
Capsid assembly modulatorsInterfere with capsid formation and disrupt the encapsidation of pgRNACAMs[126]
Post-transcriptional control inhibitorsPost-transcriptional gene silencing by inhibition of the translation of viral proteinsSiRNA[127-129]; ASOs[130,131]
HBsAg release inhibitorsIntracellular degradation of HBsAg via proteasomal and lysosomal degradationNAPs[132,133]
Innate immune activatorStimulation of innate immunity through TLRs and RIG-ITLRs agonist[134-137]; RIG-I agonists[138,139]
Adaptive immune activatorBlocking the PD-1/PD-L1 pathway to reverse T-cell exhaustion; stimulation of host’s immune response to generate CD4 and CD8 HBV-specific T cellsCheckpoint inhibitors[140,141]; therapeutic vaccines[142,143]
Table 3 Efficacy of drug combinations to achieve sustained hepatitis B virus surface antigen loss
Drug class
Time therapy (wk)
NA +/- CAMNA vs NA + JNJ-6379 (bersacapavir)23224-48HBsAg decline 0.25 log IU/mL vs 0.41 log IU/mLNo major AE
SiRNA +/- NAAB-729 vs NA + AB-729438HBsAg decline 2.03 log IU/mL monotherapy vs 2.16 log IU/mL combinationInjection site reactions; ALT flares
ASO + NAASO-GSK3228836 (bepirovirsen) ± NA45712-24HBsAg < LoQ in 28%-29% and HBsAg loss in 9%-10% after 24 wk of EoTInjection site reactions; few cases of grade 3-4 ALT flares
Inhibitor of NTCP + Peg-IFNBulevirtide + Peg-IFN in HDV-HBV co-infection9048HBsAg loss 26.7% in one arm vs 0% in the otherRelated to Peg-IFN; injection site reactions
NA + TLR agonistsNA + TLR7 agonist (vesatolimod, GS-9620)16224No changes in HBsAgSome grade 3 AE with higher doses (few treatment discontinuations)
NA + TLR agonistsNA + TLR8 agonist (selgantolimod)4824HBsAg loss 5% at week 48Mild and transient gastrointestinal AE
NA + checkpoint inhibitorsNA + PD-1 inhibitor (nivolumab)121 dose (24 follow-up)HBsAg reduction 0.48 log IU/mL (HBsAg loss in 5%)No major AE
NA + checkpoint inhibitorsNA + PD-L1 inhibitor (ASC22, Menvafolimab)4824HBsAg decline 0.38 log IU/mL (HBsAg loss in 19%)Grade 1 and 2 ALT flares
NA + SiRNA +/- CAMNA + JNJ-3989 (siRNA) + NA ± JNJ-6379 (CAM)11748HBsAg decline 2.1 log IU/mL in double vs 1.8 log IU/mL in triple combinationNo major AE
NAP + NA + Peg-IFNREP2139 or REP 2165 + NA + Peg-IFN4048HBsAg loss in 35% and HBsAg < 100 IU/mL in 75%Related to Peg-IFN
SiRNA + NA +/- Peg-IFNVIR 2218 (siRNA) + NA +/- Peg-IFN8024HBsAg decline 2.03 log IU/mL in dual arm vs 2.55 log IU/mL in triple arm (HBsAg < 100 IU/mL in 95% and HBsAg < 10 IU/mL in 55%)Related to Peg-IFN