Advances in Discovery of Novel Investigational Agents for Functional Cure of Chronic Hepatitis B: A Comprehensive Review of Phases II and III Therapeutic Agents

Overview

Journal World J Hepatol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2024 Apr 5

PMID 38577537

Authors

Robert Lam

Joseph K Lim

Affiliations

Soon will be listed here.

Abstract

Chronic hepatitis B virus (HBV) infection affects over 295 million people globally and an estimated 1.6 million people in the United States. It is associated with significant morbidity and mortality due to cirrhosis, liver failure, and liver cancer. Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression, which in turn has been associated with a decreased risk of liver complications. However, current antiviral regimens are limited by concerns with adverse effects, adherence, resistance, long-term treatment, and ongoing risk for liver events. Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen (HBsAg) loss and suppression of HBV DNA. Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B, including core/capsid inhibitors, entry inhibitors, RNA interference (siRNA/ASO), HBsAg inhibitors, Toll-like receptor agonists, checkpoint inhibitors, and therapeutic vaccines.

Citing Articles

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References

Boni C, Janssen H, Rossi M, Yoon S, Vecchi A, Barili V . Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis. Gastroenterology. 2019; 157(1):227-241.e7. DOI: 10.1053/j.gastro.2019.03.044. View

Carman W . The clinical significance of surface antigen variants of hepatitis B virus. J Viral Hepat. 1997; 4 Suppl 1:11-20. DOI: 10.1111/j.1365-2893.1997.tb00155.x. View

Fanning G, Zoulim F, Hou J, Bertoletti A . Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat Rev Drug Discov. 2019; 18(11):827-844. DOI: 10.1038/s41573-019-0037-0. View

Yuen M, Heo J, Jang J, Yoon J, Kweon Y, Park S . Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial. Nat Med. 2021; 27(10):1725-1734. PMC: 8516644. DOI: 10.1038/s41591-021-01513-4. View

Mak L, Seto W, Yuen M . Novel Antivirals in Clinical Development for Chronic Hepatitis B Infection. Viruses. 2021; 13(6). PMC: 8235765. DOI: 10.3390/v13061169. View

Liu J, Yang H, Lee M, Lu S, Jen C, Batrla-Utermann R . Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma. Gut. 2013; 63(10):1648-57. DOI: 10.1136/gutjnl-2013-305785. View

Sulkowski M, Agarwal K, Ma X, Nguyen T, Schiff E, Hann H . Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection. J Hepatol. 2022; 77(5):1265-1275. DOI: 10.1016/j.jhep.2022.05.027. View

Hui R, Mak L, Seto W, Yuen M . RNA interference as a novel treatment strategy for chronic hepatitis B infection. Clin Mol Hepatol. 2022; 28(3):408-424. PMC: 9293617. DOI: 10.3350/cmh.2022.0012. View

Wedemeyer H, Schoneweis K, Bogomolov P, Blank A, Voronkova N, Stepanova T . Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis. 2022; 23(1):117-129. DOI: 10.1016/S1473-3099(22)00318-8. View

10.

Lam Y, Yuen M, Seto W, Lai C . Current Antiviral Therapy of Chronic Hepatitis B: Efficacy and Safety. Curr Hepat Rep. 2011; 10(4):235-243. PMC: 3210946. DOI: 10.1007/s11901-011-0109-z. View

11.

Gupta S, Fanget M, MacLauchlin C, Clausen V, Li J, Cloutier D . Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection. Drugs R D. 2021; 21(4):455-465. PMC: 8602582. DOI: 10.1007/s40268-021-00369-w. View

12.

Ryu S, Chung Y . [Resistance to adefovir in patients with chronic hepatitis B]. Korean J Hepatol. 2007; 12(4):484-92. View

13.

Yuen M, Wong D, Fung J, Ip P, But D, Hung I . HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008; 135(4):1192-9. DOI: 10.1053/j.gastro.2008.07.008. View

14.

Feray C, Lopez-Labrador F . Is PD-1 blockade a potential therapy for HBV?. JHEP Rep. 2020; 1(3):142-144. PMC: 7001582. DOI: 10.1016/j.jhepr.2019.07.007. View

15.

Riddler S, Para M, Benson C, Mills A, Ramgopal M, DeJesus E . Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1. Clin Infect Dis. 2020; 72(11):e815-e824. DOI: 10.1093/cid/ciaa1534. View

16.

Vaillant A . Editorial: mechanistic evaluation of nucleic acid polymers: A cautionary tale. Mol Ther Nucleic Acids. 2022; 28:168-174. PMC: 8956958. DOI: 10.1016/j.omtn.2022.03.002. View

17.

Tseng T, Liu C, Su T, Wang C, Chen C, Chen P . Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis B e antigen seroconverters. Gastroenterology. 2011; 141(2):517-25, 525.e1-2. DOI: 10.1053/j.gastro.2011.04.046. View

18.

Isogawa M, Robek M, Furuichi Y, Chisari F . Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005; 79(11):7269-72. PMC: 1112123. DOI: 10.1128/JVI.79.11.7269-7272.2005. View

19.

Hadziyannis S, Tassopoulos N, Heathcote E, Chang T, Kitis G, Rizzetto M . Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006; 131(6):1743-51. DOI: 10.1053/j.gastro.2006.09.020. View

20.

Flink H, van Zonneveld M, Hansen B, de Man R, Schalm S, Janssen H . Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol. 2006; 101(2):297-303. DOI: 10.1111/j.1572-0241.2006.00418.x. View