Therapeutic Options against Chronic HBV: History
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Subjects: Gastroenterology & Hepatology | Virology
Contributor:
Bingqian Qu

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
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

References

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  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.
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  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.
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