Current and novel modalities for management of chronic hepatitis B infection

Table 2 New hepatitis B virus treatment modalities and clinical trial phases

Class	Drug name	Mechanism
HBV entry inhibitors	Hepcludex (Bulevirtid, formerly known as Myrcludex B)	Block HBV binding to NTCP receptor; clinical trial phase II
	Betulin derivatives and cyclosporin derivatives
	IFN-α, γ	Decreases cccDNA transcription via epigenetic modifications
	ZFNs	Site-specific cleavage of DNA creates DSBs to target the viral cccDNA; Pre-clinical phase
Agents targeting cccDNA	TALENs
	CRISPR and CRISPR-Cas9 as EBT106 HBV CRISPR Cas9 lipid nanoparticle	Target and reduce the viral cccDNA reservoir; destroy the intrahepatic HBV genome and reduce HBsAg levels; reduction of intracellular pgRNA; preclinical phase
	Arginine methyltransferase 5 (PRMT5)	Restriction of HBV transcription and replication through cccDNA transcription suppression and pgRNA encapsidation inhibition
Targeting HBx	SMC5/6 complex	Block all HBV mRNA transcription except HBx mRNA transcription
	Nitazoxanide	Restore SMC5/6 protein levels and block HBV transcription by inhibiting the HBx-DDB1 binding; clinical trial phase II
	CRV-431	Pan-cyclophilin inhibitor that inhibits liver HBV DNA and HBsAg; clinical trial phase I
Agents targeting viral transcripts	ASO: IONIS-HBVRx (GSK3228836) IONIS-HBVLRx (GSK33389404) RG6004 RO7062931	HBV RNA degradation, inhibit the expression of the corresponding gene, and bind viral mRNA to prevent viral protein production; clinical trial phase II
	siRNAs: AB-729, ARB-1467, ARB-1740, Lunar-HB Vir-2218 (also known as ALN HBV02), JNJ-3989 (ARO-HBV), RG6346 (DCR-HBVS), GSK3228836 (IONIS-HBVRx), and Hepbarna (BB-HB-331)	HBV RNA degradation and reduce viremia, antigenemia, core, and HBx protein inside the hepatocyte; clinical trial phase I and II
	asRNA agent	Block HBV translation; clinical trial phase II
Capsid assembly modulators (core protein assembly modulators)	HAPS as Morphothiadin (GLS4)	Core protein binding that inhibits encapsidation of pgRNA or nucleocapsid assembly, to an extent that the HBV pgRNA could not enter inside the capsid resulting in morphologically normal capsids with no nucleic acid content and therefore the virus will be noninfectious; clinical trial phase I and II
	Phenylpropenamides derivatives as 3711, AT-61, and AT-130
	Sulfamoylbenzamide derivatives as AB-423, AB 506, JNJ-6379, JNJ-0440, NVR 3-778
	Morphothiadin, JNJ 56136379, and ABI-H0731	Core protein binding led to a significant decrease in HBV DNA, but with smaller reductions of HBV RNA and HBsAg; clinical trial phase II
	RO7049389, ABI-H2158, GLS4JHS, ABI-H0731, ABI-H3733, RG7907, QL-007, EDP-514, CB-HBV-001	Core protein binding; clinical trial phase I and II
Targeting HBsAg	DNA based NAPs (REP-2055 and REP- 2031) or RNA-based NAPs (REP-2139 and REP-2165)	Block HBsAg release and improve the HBV-specific immune response; clinical trial phase II
	NAPs: REP 301, REP 301-LFT and REP 401	Functional cure in the form of undetectable HBV DNA and HBV RNA, decrease HBsAg and HBcrAg, normalize ALT levels, and detect anti-HBsAg; clinical trial phase II
	STOPS	Disrupt HBsAg secretion, ALG-010133; further development of this compound has been discontinued
	mAb against HBsAg, mAb E6F6A, and VIR-3434	Overcome persistent HBV replication; clinical trial phase I and II
	E6F6 immunotherapy	Restore anti-HBV T cell response; clinical trial phase II
	GC1102 mAb and HBIg	Anti-HBs (against HBsAg) and boost humoral immunity; clinical trial phase II
	Apoptosis inducer as APG-1387 and Cyclophilin Inhibitor as CRV 431 (CPI 431-32)	Target host pathways; clinical trial phase II
Immune modulators
-Therapeutic vaccination	GS-4774	Enhance antiviral cytokine production by HBV-specific T cells as CD8+ cells; clinical trial phase III
	DNA vaccines as INO-1800, HB-110, and JNJ-64300535	Encode HBsAg, HBcAg, and polymerase proteins; clinical trial phase I
	NASVAC, Sci-B-Vac derivative BRII-179, and HepTcell	T cell vaccines; clinical trial phase I and II
	TG1050/T101 and TomegaVax HBV	Non-replicative adenovirus serotype 5 encode three HBV proteins; clinical trial phase II
	ChAdOx1 HBV	Adjuvanted ChAd and MVA vector; clinical trial phase I
	AIC 649	iPPVO nonspecific vaccine; clinical trial phase I
	ABX-203	Contain both HBsAg and HBcAg; clinical trial phase I
-Checkpoint inhibitors	Tim-3, CTLA-4 (anti-CTLA-4), Nivolumab, ASC22 (KN035), and Cemiplimab (REGN2810)	Anti-PD-1/anti-PD-L1 antibodies that restore virus-specific CD8+ T cell responses that boost adaptive immunity; clinical trial phase I and II
-Genetically engineered T cells	cTCR with anti-HBs antibody or HBV specific T cell receptor gene	Recognize HBV-infected cells carrying HBV proteins on their surfaces resulting in disappearance of HBV-infected cells and decreasing cccDNA; Pre-clinical trial
	LTCR-H2-1 and CAR-T cells	LTCR-H2-1 targets TCR gene transfer, which boosts adaptive immunity; Preclinical trial
-Pathogen recognition receptors	Vesatolimod (GS-9620), RO7020531 (RG7854), RO6864018 (RG7795), ANA773, and JNJ-4964 (AL-034/TQ-A3334)	TLR-7 agonists activate intrahepatic dendritic cells, NK cells, and mucosal-associated invariant T cells and trigger the production of type I and II IFNs causing inhibition of HBV replication and boost innate immunity; clinical trial phase I and II
	Selgantolimod (GS-9688)	TLR-8 agonists activate intrahepatic dendritic cells, NK cells, and mucosal-associated invariant T cells and enhance the production of antiviral cytokines (IL-12/IL-18) and boost innate immunity; clinical trial phase II
	STING agonist and RIG-I and NOD2 agonist as Inarigivir (SB9200)	Induce production of IFN-stimulated genes and proinflammatory cytokines that can cytopathically or noncytopathically clear virus, inhibit HBV replication, and boost innate immunity; clinical trial phase II
-Other immune approaches	IMC-I109V	Immune mobilizing monoclonal T cell receptors against the virus; clinical trial phase I

ALT: Alanine aminotransferase; ASO: Antisense oligonucleotides; asRNA: Antisense RNA; CAR: Chimeric antigen receptor; cccDNA: Covalently closed circular DNA; CRISPR: Clustered regularly interspaced short palindromic repeats; CRISPR-Cas9: CRISPR-associated protein nine nuclease; cTCR: Chimeric T-cell receptor; CTLA-4: Cytotoxic T-lymphocyte associated protein 4; PDSBs: Double stranded breaks; HAPS: Heteroaryldihydropyrimidines; HBcAg: Hepatitis B core antigen; HBcrAg: Hepatitis B core-related antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HBx: Hepatitis B virus X protein; IFN-α: Interferon-alpha; IL: Interleukin; iPPVO: Inactivated parapoxvirus; mAb: Monoclonal antibody; NAPs: Nucleic acid polymers; NK: Natural killer; NOD2: Nucleotide-binding oligomerization domain-containing protein 2; NTCP: Sodium taurocholate cotransporting polypeptide; PD-1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1; pgRNA: Pre-genomic RNA; PRMT5: Protein arginine methyltransferase 5; RIG-I: Cytosolic retinoic acid inducible gene I; siRNAs: Small interfering RNAs; SMC5/6: structural maintenance of chromosomes protein 5 and 6; STING: Stimulator of interferon genes; STOPS: S-antigen transport-inhibiting oligonucleotide polymers; TALENs: Transcription activator-like effector nucleases; Tim3: T cell immunoglobulin and mucin containing 3; TLR: Toll-like receptor; ZFNs: Zinc finger nucleases.