Past, present, and future of long-term treatment for hepatitis B virus

Table 1 Efficacy of available antiviral treatments and nucleos(t)ide analogues withdrawal to achieve hepatitis B virus surface antigen loss

Ref.	Treatment (duration)	HBeAg	Ethnicity	Follow-up	HBsAg loss (%)
Current antiviral treatments
Lau et al[84], 2005	Peg-IFNα (1 yr)	+	Mainly Asian	6 mo	2.9
Marcellin et al[85], 2013	Peg-IFNα (1 yr)	-	Asian	60 mo	12.0
Chang et al[48], 2010	ETV (5 yr)	+	Asian	-	1.4
Ahn et al[32], 2016	ETV (5 yr)	-	Mixed	-	4.6
Marcellin et al[33], 2019	TDF (10 yr)	+	Mixed	-	4.9
Marcellin et al[33], 2019	TDF (10 yr)	-	Mixed	-	3.4
Chan et al[30], 2016	TAF (3 yr)	+	Mixed	-	4.0
Buti et al[31], 2016	TAF (3 yr)	-	Mixed	-	3.0
Combined treatments
Marcellin et al[86], 2016	Peg-IFN + TDF (1 yr)	+/-	Mixed	18 mo	9.1
Bourlière et al[87], 2017	ETV, TDF, ADV, and LAM (1 yr)	-	Caucasian	12 mo	7.8
Lim et al[88], 2022	NA add-on Peg-IFN (1 yr)	+/-	Asian	6 mo	12.1
Mo et al[89], 2022	NAs (HBsAg < 1500 IU/mL, 1 yr)	-	Asian	48 mo	33.2
Lim et al[88], 2022	NA switch to Peg-IFN (1 yr)	+/-	Asian	6 mo	9.7
NA discontinuation
Chen et al[90], 2018	2.7 yr	+	Asian	96 mo	19.6
Song et al[91], 2021	2.9 yr	+	Asian	73 mo	9.5
Kuo et al[92], 2019	3.1 yr	+	Asian	24 mo	4.7 (ETV); 0 (TDF)
Jeng et al[72], 2018	2.9 yr	-	Asian	36 mo	13
Chen et al[90], 2018	2.9 yr	-	Asian	96 mo	33.1
Kuo et al[92], 2019	3.1 yr	-	Asian	36 mo	10 (ETV); 15 (TDF)
Chen et al[93], 2020	3.2 yr	-	Asian	58 mo	20.8
Song et al[91], 2021	2.7 yr	-	Asian	73 mo	14.6
Hirode et al[47], 2022	3.0 yr	-	Mixed	17 mo	15.0

Only studies with more than 100 patients have been included. HBsAg: Hepatitis B virus surface antigen; HBeAg: Hepatitis B e antigen; Peg-IFN: Pegylated interferon; LAM: Lamivudine; ADV: Adefovir; TDF: Tenofovir; ETV: Entecavir; TAF: Tenofovir alafenamide.

Table 2 Mechanisms of action of the new drugs under development

Treatment class	Mechanism of action	Types
Drugs targeting HBV life cycle
Entry inhibitors	Blockage of liver-specific bile acid transporter (NTCP)	Inhibitors of NTCP[124]; NMAb[125]
Capsid assembly modulators	Interfere with capsid formation and disrupt the encapsidation of pgRNA	CAMs[126]
Post-transcriptional control inhibitors	Post-transcriptional gene silencing by inhibition of the translation of viral proteins	SiRNA[127-129]; ASOs[130,131]
HBsAg release inhibitors	Intracellular degradation of HBsAg via proteasomal and lysosomal degradation	NAPs[132,133]
Immunomodulators
Innate immune activator	Stimulation of innate immunity through TLRs and RIG-I	TLRs agonist[134-137]; RIG-I agonists[138,139]
Adaptive immune activator	Blocking 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 cells	Checkpoint inhibitors[140,141]; therapeutic vaccines[142,143]

HBV: Hepatitis B virus; NTCP: Sodium taurocholate co-transporting polypeptide; NMAb: Neutralizing monoclonal antibodies; CAMs: Nucleocapsid assembly modulators; SiRNA: Small interfering RNA; ASO: Antisense oligonucleotides; NAP: Nucleic acid polymers; TLRs: Toll-like receptors; RIG-I: Retinoic acid-inducible gene-1; PD-1: Programmed death receptor 1; PD-L1: Programmed cell death ligand 1; HBsAg: Hepatitis B virus surface antigen; HBeAg: Hepatitis B e antigen.

Table 3 Efficacy of drug combinations to achieve sustained hepatitis B virus surface antigen loss

Drug class	Drug	Patients	Time therapy (wk)	Efficacy	Safety
NA +/- CAM	NA vs NA + JNJ-6379 (bersacapavir)	232	24-48	HBsAg decline 0.25 log IU/mL vs 0.41 log IU/mL	No major AE
SiRNA +/- NA	AB-729 vs NA + AB-729	43	8	HBsAg decline 2.03 log IU/mL monotherapy vs 2.16 log IU/mL combination	Injection site reactions; ALT flares
ASO + NA	ASO-GSK3228836 (bepirovirsen) ± NA	457	12-24	HBsAg < LoQ in 28%-29% and HBsAg loss in 9%-10% after 24 wk of EoT	Injection site reactions; few cases of grade 3-4 ALT flares
Inhibitor of NTCP + Peg-IFN	Bulevirtide + Peg-IFN in HDV-HBV co-infection	90	48	HBsAg loss 26.7% in one arm vs 0% in the other	Related to Peg-IFN; injection site reactions
NA + TLR agonists	NA + TLR7 agonist (vesatolimod, GS-9620)	162	24	No changes in HBsAg	Some grade 3 AE with higher doses (few treatment discontinuations)
NA + TLR agonists	NA + TLR8 agonist (selgantolimod)	48	24	HBsAg loss 5% at week 48	Mild and transient gastrointestinal AE
NA + checkpoint inhibitors	NA + PD-1 inhibitor (nivolumab)	12	1 dose (24 follow-up)	HBsAg reduction 0.48 log IU/mL (HBsAg loss in 5%)	No major AE
NA + checkpoint inhibitors	NA + PD-L1 inhibitor (ASC22, Menvafolimab)	48	24	HBsAg decline 0.38 log IU/mL (HBsAg loss in 19%)	Grade 1 and 2 ALT flares
NA + SiRNA +/- CAM	NA + JNJ-3989 (siRNA) + NA ± JNJ-6379 (CAM)	117	48	HBsAg decline 2.1 log IU/mL in double vs 1.8 log IU/mL in triple combination	No major AE
NAP + NA + Peg-IFN	REP2139 or REP 2165 + NA + Peg-IFN	40	48	HBsAg loss in 35% and HBsAg < 100 IU/mL in 75%	Related to Peg-IFN
SiRNA + NA +/- Peg-IFN	VIR 2218 (siRNA) + NA +/- Peg-IFN	80	24	HBsAg 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

CAM: Nucleocapsid assembly modulator; HBV: Hepatitis B virus; SiRNA: Small interfering RNA; NTCP: Sodium taurocholate co-transporting polypeptide; ASO: Antisense oligonucleotides; NAP: Nucleic acid polymers; TLRs: Toll-like receptors; RIG-I: Retinoic acid-inducible gene-1; PD-1: Programmed death receptor 1; PD-L1: Programmed cell death ligand 1; HBsAg: Hepatitis B virus surface antigen; HBeAg: Hepatitis B e antigen; ALT: Alanine aminotransferase; LoQ: Limit of quantification; EoT: End of therapy; AE: Adverse events.