Therapeutic Options against Chronic HBV: History
Please note this is an old version of this entry, which may differ significantly from the current revision.

Currently, Chronic Hepatitis B (CHB) is controlled but not cured by approved antivirals. For instance, transcriptionally active HBV DNA in the nucleus is not directly targeted. Except for interferon-α (IFN-α) and pegylated IFN-α, all other licensed drugs are nucleoside (Lamivudine, Clevudine, Entecavir, Telbivudine) and nucleotide analogues (Adefovir dipivoxil, Tenofovir disoproxil fumarate, Tenofovir alafenamide). All these drugs are potent at reducing viral loads and normalizing alanine transaminase levels in CHB patients. However, long-term treatment with many of these drugs leads to the development of multiple drug resistance mutations. In addition, while a limited reduction in cccDNA is achieved, long-term nucleos(t)ide analogue treatment does not reduce hepatitis B surface antigen (HBsAg) levels.

  • Chronic Hepatitis B
  • Therapeutics
  • Drug Development

1. Introduction

In the past decade, global deaths from viral hepatitis have increased to become the seventh leading cause of mortality, annually causing more deaths than AIDS, diabetes, and tuberculosis (1.4 million/year) [1]. Viral hepatitis results in liver inflammation and is caused by hepatotropic viruses, with both acute or chronic disease courses described. These liver-tropic pathogens represent a range of DNA and RNA viruses from diverse viral families with distinct modes of transmission: Hepatitis A virus (HAV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Hepatitis delta virus (HDV), and Hepatitis E virus (HEV). Both HCV and HBV can cause chronic infections in immune-competent individuals [2], potentially leading to progressive liver injury. According to the World Health Organization, HBV and HCV chronically infect 240 million and 71 million people, respectively. Chronic infections may ultimately result in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Indeed, an estimated 75% of all HCC cases are attributed to chronic infection with HBV (CHB) or HCV [3,4].

2. Approved Drugs and Potential Therapeutic Options against Chronic Hepatitis B

Both virus and host druggable targets exist at multiple stages of the HBV life cycle, including viral entry, replication, assembly, and the secretion of subviral particles [1].
Myristoylated preS1-derived lipopeptide (Myrcludex B) specifically bound to the human sodium taurocholate co-transporting polypeptide (hNTCP), the bona fide HBV and HDV receptor, prevents HBV entry in urokinase-type plasminogen activator and severe immunodeficient (uPA-SCID) mice repopulated with primary human hepatocytes [2]. Myrcludex B also potently blocked HBV spreading from initially infected hepatocytes to uninfected cells [3]. Although HBsAg levels remained, HBV viral load was significantly decreased at week 24 in the pegylated IFN-α-Myrcludex B cohort (n = 7) compared with Myrcludex B monotherapy (n = 8) in a phase 1b/IIa trial [4].
For HBV replication, the RNase H domain within viral polymerase has also been effectively targeted by specific inhibitors in previous preclinical trials [5][6][7].
The availability of high-resolution structures for HBV nucleocapsids has facilitated the development of multiple capsid allosteric modulators [8][9][10]. Recently, one leading compound, NVR 3-778, showed reduced HBV DNA and RNA levels in patient serum (n = 43) when administered as monotherapy, with a larger reduction observed in combination with pegylated IFN-α (n = 10) [11]. Morphothiadin (GLS4), a derivative of heteroaryldihydropyrimidine targeting capsid maturation, showed a potent in vitro antiviral activity and tolerability in healthy participants (n = 8) when co-administered with Ritonavir, which boosted plasma concentrations of morphothiadin [12]. More recently, JNJ-56136379 (JNJ-6379) showed good tolerability in treatment-naïve chronic HBV patients in a phase I study. Remarkably, 32% of patients (13/41) had undetectable HBV DNA levels at 4 weeks treatment, despite no alteration in HBsAg levels [13]. In another trial, ABI-H0731 showed safety at 300 mg/day but non-specific side effects at higher doses in some participants. The treatment resulted in dose-dependent declines in both HBV DNA and RNA levels [14].
Two nucleic acid polymers were shown to inhibit the secretion of subviral particles. Both REP 2139 and REP 2165 were well tolerated and showed a substantial activity in treatment-naive patients. The combination of Tenovofir, pegylated IFN-α, and REP promoted HBsAg seroconversion (<0.05 IU/mL) in 60% of patients (24/40). During 48 weeks of follow-up, no viral rebound was observed in 35% of patients (14/40) [15].
All lines of evidence detailed above demonstrate that HBV replication can be controlled, but a permanent cure has not been achieved. Notably, none of the above drugs (except IFN-α) target transcriptionally active templates and decompose viral transcripts. Thus, transcriptionally active templates should be recognized as novel drug targets, and any new-class antivirals targeting this virus life-cycle stage could represent a potential therapeutic option against CHB.
Indeed, taking advantage of authentic infection models that allow cccDNA-mediated replication, a number of candidates were identified that either inhibit transcription or impact on the stability of existing viral transcripts [16].

This entry is adapted from the peer-reviewed paper 10.3390/v13071327


  1. David Durantel; Fabien Zoulim; New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus. Journal of Hepatology 2016, 64, S117-S131, 10.1016/j.jhep.2016.02.016.
  2. Joerg Petersen; Maura Dandri; Walter Mier; Marc Lütgehetmann; Tassilo Volz; Fritz Von Weizsäcker; Uwe Haberkorn; Lutz Fischer; Joerg-Matthias Pollok; Berit Erbes; et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nature Biotechnology 2008, 26, 335-341, 10.1038/nbt1389.
  3. Tassilo Volz; Lena Allweiss; Mounira Ben Ḿbarek; Michael Warlich; Ansgar W. Lohse; Jörg M. Pollok; Alexander Alexandrov; Stephan Urban; Jörg Petersen; Marc Lütgehetmann; et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. Journal of Hepatology 2013, 58, 861-867, 10.1016/j.jhep.2012.12.008.
  4. Pavel Bogomolov; Alexander Alexandrov; Natalia Voronkova; Maria Macievich; Ksenia Kokina; Maria Petrachenkova; Thorsten Lehr; Florian A. Lempp; Heiner Wedemeyer; Mathias Haag; et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study. Journal of Hepatology 2016, 65, 490-498, 10.1016/j.jhep.2016.04.016.
  5. John E. Tavis; Xiaohong Cheng; Yuan Hu; Michael Totten; Feng Cao; Eleftherios Michailidis; Rajeev Aurora; Marvin Meyers; E. Jon Jacobsen; Michael A. Parniak; et al. The Hepatitis B Virus Ribonuclease H Is Sensitive to Inhibitors of the Human Immunodeficiency Virus Ribonuclease H and Integrase Enzymes. PLOS Pathogens 2013, 9, e1003125, 10.1371/journal.ppat.1003125.
  6. John E. Tavis; Elena Lomonosova; The hepatitis B virus ribonuclease H as a drug target. Antiviral Research 2015, 118, 132-138, 10.1016/j.antiviral.2015.04.002.
  7. Elena Lomonosova; Jil Daw; Aswin K. Garimallaprabhakaran; Nana B. Agyemang; Yashkumar Ashani; Ryan P. Murelli; John E. Tavis; Efficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of hepatitis B virus ribonuclease H. Antiviral Research 2017, 144, 164-172, 10.1016/j.antiviral.2017.06.014.
  8. R A Crowther; Three-dimensional structure of hepatitis B virus core particles determined by electron cryomicroscopy. Cell 1994, 77, 943-950, 10.1016/0092-8674(94)90142-2.
  9. S.A Wynne; R.A Crowther; A.G.W Leslie; The Crystal Structure of the Human Hepatitis B Virus Capsid. Molecular Cell 1999, 3, 771-780, 10.1016/s1097-2765(01)80009-5.
  10. Adam Zlotnick; Balasubramanian Venkatakrishnan; Zhenning Tan; Eric Lewellyn; William Turner; Samson Francis; Core protein: A pleiotropic keystone in the HBV lifecycle. Antiviral Research 2015, 121, 82-93, 10.1016/j.antiviral.2015.06.020.
  11. Man Fung Yuen; Edward J. Gane; Dong Joon Kim; Frank Weilert; Henry Lik Yuen Chan; Jacob Lalezari; Seong Gyu Hwang; Tuan Nguyen; Osvaldo Flores; George Hartman; et al. Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection. Gastroenterology 2019, 156, 1392-1403.e7, 10.1053/j.gastro.2018.12.023.
  12. Nan Zhao; Bo Jia; Hong Zhao; Junyu Xu; Xiaoyan Sheng; Lin Luo; Zhangma Huang; Xingan Wang; Qingyun Ren; Yingjun Zhang; et al. A First-in-Human Trial of GLS4, a Novel Inhibitor of Hepatitis B Virus Capsid Assembly, following Single- and Multiple-Ascending-Oral-Dose Studies with or without Ritonavir in Healthy Adult Volunteers. Antimicrobial Agents and Chemotherapy 2019, 64, e01686-19, 10.1128/aac.01686-19.
  13. Fabien Zoulim; Oliver Lenz; Joris J. Vandenbossche; Willem Talloen; Thierry Verbinnen; Iurie Moscalu; Adrian Streinu-Cercel; Stefan Bourgeois; Maria Buti; Javier Crespo; et al. JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection. Gastroenterology 2020, 159, 521-533.e9, 10.1053/j.gastro.2020.04.036.
  14. Man-Fung Yuen; Kosh Agarwal; Edward J Gane; Christian Schwabe; Sang Hoon Ahn; Dong Joon Kim; Young-Suk Lim; Wendy Cheng; William Sievert; Kumar Visvanathan; et al. Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial. The Lancet Gastroenterology & Hepatology 2020, 5, 152-166, 10.1016/s2468-1253(19)30346-2.
  15. Michel Bazinet; Victor Pântea; Gheorghe Placinta; Iurie Moscalu; Valentin Cebotarescu; Lilia Cojuhari; Pavlina Jimbei; Liviu Iarovoi; Valentina Smesnoi; Tatiana Musteata; et al. Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy. Gastroenterology 2020, 158, 2180-2194, 10.1053/j.gastro.2020.02.058.
  16. Bingqian Qu; Richard Brown; Strategies to Inhibit Hepatitis B Virus at the Transcript Level. Viruses 2021, 13, 1327, 10.3390/v13071327.
This entry is offline, you can click here to edit this entry!
Video Production Service