Copyright ©The Author(s) 2023.
World J Hepatol. May 27, 2023; 15(5): 585-608
Published online May 27, 2023. doi: 10.4254/wjh.v15.i5.585
Table 1 Current therapy regimens for chronic hepatitis B viral infection as recommended by the American Association for the Study of Liver Diseases, 2023[68]
For adult patientsTreatment
Immune-active CHB (HBeAg negative or positive)Antiviral therapy as PEG-IFN, tenofovir, or entecavir to decrease the risk of liver complications
Immune-tolerant CHBAgainst antiviral therapy. Continuous monitoring of ALT levels at least every 6 mo for potential transition to immune-active or inactive CHB
Immune-active CHB HBeAg-negative Indefinite antiviral therapy, unless there is a strong indication for treatment withdrawal
Compensated cirrhosis with low levels of viremia (< 2000 IU/mL)Antiviral therapy to reduce the risk of decompensation, regardless of ALT level
Decompensated cirrhosis with positive HBsAgIndefinite antiviral therapy, irrespective of the level of HBV DNA, ALT, or HBeAg status to decrease risk of worsening the condition
HBeAg-positive CHB without cirrhosis seroconvert to anti-HBe on NA therapyDiscontinue NAs after a period of treatment consolidation
HBeAg-positive CHB with cirrhosis seroconvert to anti-HBe on therapyIndefinite antiviral therapy unless there is a strong indication for treatment withdrawal
For children (2 to < than 18 years)Treatment
HBeAg positive with elevated ALT and HBV DNA levelsAntiviral therapy (IFN-α, PEG-IFN, and NAs) aiming for achieving sustained HBeAg seroconversion. PEG-IFN-α is recommended for use compared to NAs due to absence of viral resistance and finite duration of treatment
HBeAg-positive with persistently normal ALT, regardless of HBV DNA levelAgainst antiviral therapy
Table 2 New hepatitis B virus treatment modalities and clinical trial phases
Drug name
HBV entry inhibitorsHepcludex (Bulevirtid, formerly known as Myrcludex B)Block HBV binding to NTCP receptor; clinical trial phase II
Betulin derivatives and cyclosporin derivatives
IFN-α, γDecreases cccDNA transcription via epigenetic modifications
ZFNsSite-specific cleavage of DNA creates DSBs to target the viral cccDNA; Pre-clinical phase
Agents targeting cccDNATALENs
CRISPR and CRISPR-Cas9 as EBT106 HBV CRISPR Cas9 lipid nanoparticleTarget 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 HBxSMC5/6 complexBlock all HBV mRNA transcription except HBx mRNA transcription
NitazoxanideRestore SMC5/6 protein levels and block HBV transcription by inhibiting the HBx-DDB1 binding; clinical trial phase II
CRV-431Pan-cyclophilin inhibitor that inhibits liver HBV DNA and HBsAg; clinical trial phase I
Agents targeting viral transcriptsASO: IONIS-HBVRx (GSK3228836) IONIS-HBVLRx (GSK33389404) RG6004 RO7062931HBV 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 agentBlock 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-H0731Core 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-001Core protein binding; clinical trial phase I and II
Targeting HBsAgDNA 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 401Functional 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
STOPSDisrupt HBsAg secretion, ALG-010133; further development of this compound has been discontinued
mAb against HBsAg, mAb E6F6A, and VIR-3434Overcome persistent HBV replication; clinical trial phase I and II
E6F6 immunotherapyRestore anti-HBV T cell response; clinical trial phase II
GC1102 mAb and HBIgAnti-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 vaccinationGS-4774Enhance antiviral cytokine production by HBV-specific T cells as CD8+ cells; clinical trial phase III
DNA vaccines as INO-1800, HB-110, and JNJ-64300535Encode HBsAg, HBcAg, and polymerase proteins; clinical trial phase I
NASVAC, Sci-B-Vac derivative BRII-179, and HepTcellT cell vaccines; clinical trial phase I and II
TG1050/T101 and TomegaVax HBVNon-replicative adenovirus serotype 5 encode three HBV proteins; clinical trial phase II
ChAdOx1 HBVAdjuvanted ChAd and MVA vector; clinical trial phase I
AIC 649iPPVO nonspecific vaccine; clinical trial phase I
ABX-203Contain both HBsAg and HBcAg; clinical trial phase I
-Checkpoint inhibitorsTim-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 cellscTCR with anti-HBs antibody or HBV specific T cell receptor geneRecognize 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 cellsLTCR-H2-1 targets TCR gene transfer, which boosts adaptive immunity; Preclinical trial
-Pathogen recognition receptorsVesatolimod (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 approachesIMC-I109VImmune mobilizing monoclonal T cell receptors against the virus; clinical trial phase I