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

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.