Novel Therapeutic Strategies for Chronic Hepatitis B

Overview

Journal Virulence

Specialty Microbiology

Date 2022 Jun 28

PMID 35763282

Authors

Sandra Phillips

Ravi Jagatia

Shilpa Chokshi

Affiliations

Soon will be listed here.

Abstract

The last few years have seen a resurgence of activity in the hepatitis B drug pipeline, with many compounds in various stages of development. This review aims to provide a comprehensive overview of the latest advances in therapeutics for chronic hepatitis B (CHB). We will discuss the broad spectrum of direct-acting antivirals in clinical development, including capsids inhibitors, siRNA, HBsAg and polymerase inhibitors. In addition, host-targeted therapies (HTT) will be extensively reviewed, focusing on the latest progress in immunotherapeutics such as toll-like receptors and RIG-1 agonists, therapeutic vaccines and immune checkpoints modulators. A growing number of HTT in pre-clinical development directly target the key to HBV persistence, namely the covalently closed circular DNA (cccDNA) and hold great promise for HBV cure. This exciting area of HBV research will be highlighted, and molecules such as cyclophilins inhibitors, APOBEC3 deaminases and epigenetic modifiers will be discussed.

Citing Articles

The association between Clonorchis sinensis seropositivity and hepatocellular carcinoma in an endemic area: a study in Guangxi, China.

Yang Q, Lu X, Fang Z, Gao Y, He Y, Huang Y BMC Infect Dis. 2025; 25(1):270.

PMID: 40000979 PMC: 11852542. DOI: 10.1186/s12879-025-10675-2.

Epigenetic regulation and its therapeutic potential in hepatitis B virus covalently closed circular DNA.

Ren J, Cheng S, Ren F, Gu H, Wu D, Yao X Genes Dis. 2024; 12(1):101215.

PMID: 39534573 PMC: 11555349. DOI: 10.1016/j.gendis.2024.101215.

Histone demethylase enzymes KDM5A and KDM5B modulate immune response by suppressing transcription of endogenous retroviral elements.

Chen H, Sarah L, Pucciarelli D, Mao Y, Diolaiti M, Fujimori D bioRxiv. 2024; .

PMID: 39386707 PMC: 11463504. DOI: 10.1101/2024.09.23.614494.

Viral Factors in Modulation of Host Immune Response: A Route to Novel Antiviral Agents and New Therapeutic Approaches.

Tarasova O, Petrou A, Ivanov S, Geronikaki A, Poroikov V Int J Mol Sci. 2024; 25(17).

PMID: 39273355 PMC: 11395507. DOI: 10.3390/ijms25179408.

Two Concepts of Hepatitis B Core-Related Antigen Assay: A Highly Sensitive and Rapid Assay or an Effective Tool for Widespread Screening.

Inoue T, Yagi S, Tanaka Y Viruses. 2024; 16(6).

PMID: 38932141 PMC: 11209401. DOI: 10.3390/v16060848.

References

Yang Y, Chen Y, Kao J, Ching C, Liu I, Wang C . Permanent Inactivation of HBV Genomes by CRISPR/Cas9-Mediated Non-cleavage Base Editing. Mol Ther Nucleic Acids. 2020; 20:480-490. PMC: 7150432. DOI: 10.1016/j.omtn.2020.03.005. View

Hagiwara S, Nishida N, Watanabe T, Ida H, Sakurai T, Ueshima K . Sustained antiviral effects and clearance of hepatitis surface antigen after combination therapy with entecavir and pegylated interferon in chronic hepatitis B. Antivir Ther. 2018; 23(6):513-521. DOI: 10.3851/IMP3225. View

Sadler A, Williams B . Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008; 8(7):559-68. PMC: 2522268. DOI: 10.1038/nri2314. View

Jeng W, Sheen I, Chen Y, Hsu C, Chien R, Chu C . Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology. 2013; 58(6):1888-96. DOI: 10.1002/hep.26549. View

Li A, Tanner M, Lee C, Hurley A, De Giorgi M, Jarrett K . AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9. Mol Ther. 2020; 28(6):1432-1441. PMC: 7264438. DOI: 10.1016/j.ymthe.2020.04.017. View

Braaten D, FRANKE E, LUBAN J . Cyclophilin A is required for an early step in the life cycle of human immunodeficiency virus type 1 before the initiation of reverse transcription. J Virol. 1996; 70(6):3551-60. PMC: 190230. DOI: 10.1128/JVI.70.6.3551-3560.1996. View

Luk A, Jiang Q, Glavini K, Triyatni M, Zhao N, Racek T . A Single and Multiple Ascending Dose Study of Toll-Like Receptor 7 Agonist (RO7020531) in Chinese Healthy Volunteers. Clin Transl Sci. 2020; 13(5):985-993. PMC: 7485962. DOI: 10.1111/cts.12791. View

Lang J, Neumann-Haefelin C, Thimme R . Immunological cure of HBV infection. Hepatol Int. 2019; 13(2):113-124. DOI: 10.1007/s12072-018-9912-8. View

Selyutina A, Persaud M, Simons L, Bulnes-Ramos A, Buffone C, Martinez-Lopez A . Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the Viral Core. Cell Rep. 2020; 30(11):3766-3777.e6. PMC: 7363000. DOI: 10.1016/j.celrep.2020.02.100. View

10.

Proto S, Taylor J, Chokshi S, Navaratnam N, Naoumov N . APOBEC and iNOS are not the main intracellular effectors of IFN-gamma-mediated inactivation of Hepatitis B virus replication. Antiviral Res. 2008; 78(3):260-7. DOI: 10.1016/j.antiviral.2008.01.006. View

11.

Tamaki N, Kurosaki M, Kusakabe A, Orito E, Joko K, Kojima Y . Hepatitis B surface antigen reduction by switching from long-term nucleoside/nucleotide analogue administration to pegylated interferon. J Viral Hepat. 2017; 24(8):672-678. DOI: 10.1111/jvh.12691. View

12.

Menne S, Tumas D, Liu K, Thampi L, Aldeghaither D, Baldwin B . Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J Hepatol. 2015; 62(6):1237-45. PMC: 4439359. DOI: 10.1016/j.jhep.2014.12.026. View

13.

Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T . First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016; 65(3):483-9. DOI: 10.1016/j.jhep.2016.04.013. View

14.

Du K, Liu J, Broering R, Zhang X, Yang D, Dittmer U . Recent advances in the discovery and development of TLR ligands as novel therapeutics for chronic HBV and HIV infections. Expert Opin Drug Discov. 2018; 13(7):661-670. DOI: 10.1080/17460441.2018.1473372. View

15.

Li J, Lin S, Chen Q, Peng L, Zhai J, Liu Y . Inhibition of hepatitis B virus replication by MyD88 involves accelerated degradation of pregenomic RNA and nuclear retention of pre-S/S RNAs. J Virol. 2010; 84(13):6387-99. PMC: 2903248. DOI: 10.1128/JVI.00236-10. View

16.

Radreau P, Porcherot M, Ramiere C, Mouzannar K, Lotteau V, Andre P . Reciprocal regulation of farnesoid X receptor α activity and hepatitis B virus replication in differentiated HepaRG cells and primary human hepatocytes. FASEB J. 2016; 30(9):3146-54. DOI: 10.1096/fj.201500134. View

17.

LUBAN J . Absconding with the chaperone: essential cyclophilin-Gag interaction in HIV-1 virions. Cell. 1996; 87(7):1157-9. DOI: 10.1016/s0092-8674(00)81811-5. View

18.

Hu C, Liu X, Zeng Y, Liu J, Wu F . DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clin Epigenetics. 2021; 13(1):166. PMC: 8394595. DOI: 10.1186/s13148-021-01154-x. View

19.

Liu Y, Ruan H, Li Y, Sun G, Liu X, He W . Potent and Specific Inhibition of NTCP-Mediated HBV/HDV Infection and Substrate Transporting by a Novel, Oral-Available Cyclosporine A Analogue. J Med Chem. 2020; 64(1):543-565. DOI: 10.1021/acs.jmedchem.0c01484. View

20.

Yuen M, Zhou X, Gane E, Schwabe C, Tanwandee T, Feng S . Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial. Lancet Gastroenterol Hepatol. 2021; 6(9):723-732. DOI: 10.1016/S2468-1253(21)00176-X. View