Hepatitis B Virus Cure: Targets and Future Therapies
Abstract
:1. Introduction
2. What is the Definition of an HBV Cure?
3. Targets for an HBV Cure
3.1. Direct-Acting Antivirals
3.1.1. Entry Inhibitors
3.1.2. Core Protein Allosteric Modulators
3.1.3. RNA Interference
3.1.4. Inhibition of HBsAg Release
3.1.5. Neutralization
3.1.6. Inhibitors of cccDNA
3.2. Immune Modulatory Therapies or Indirect Antivirals
3.2.1. Toll-Like Receptor Agonists
3.2.2. Engineered T Cells
3.2.3. Immune Checkpoint Inhibitors
3.2.4. Therapeutic Vaccine
4. Future Perspectives
5. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Nassal, M. HBV cccDNA: Viral persistence reservoir and key obstacle for a cure of chronic hepatitis, B. Gut 2015, 64, 1972–1984. [Google Scholar] [CrossRef] [Green Version]
- Liang, T.J.; Block, T.M.; McMahon, B.J.; Ghany, M.G.; Urban, S.; Guo, J.T.; Locarnini, S.; Zoulim, F.; Chang, K.M.; Lok, A.S. Present and future therapies of hepatitis B: From discovery to cure. Hepatology 2015, 62, 1893–1908. [Google Scholar] [CrossRef] [Green Version]
- Seeger, C.; Mason, W.S. Molecular biology of hepatitis B virus infection. Virology 2015, 479, 672–686. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, H.; Zhong, G.; Xu, G.; He, W.; Jing, Z.; Gao, Z.; Huang, Y.; Qi, Y.; Peng, B.; Wang, H.; et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. elife 2012, 1, e00049. [Google Scholar] [CrossRef]
- Blanchet, M.; Sureau, C. Infectivity determinants of the hepatitis B virus pre-S domain are confined to the N-terminal 75 amino acid residues. J. Virol. 2007, 81, 5841–5849. [Google Scholar] [CrossRef] [Green Version]
- Summers, J.; O’Connell, A.; Millman, I. Genome of hepatitis B virus: Restriction enzyme cleavage and structure of DNA extracted from Dane particles. Proc. Natl. Acad. Sci. USA 1975, 72, 4597–4601. [Google Scholar] [CrossRef] [Green Version]
- Kann, M.; Schmitz, A.; Rabe, B. Intracellular transport of hepatitis B virus. World J.Gastroenterol. WJG 2007, 13, 39. [Google Scholar] [CrossRef]
- Jiang, B.; Hildt, E. Intracellular Trafficking of HBV Particles. Cells 2020, 9, 2023. [Google Scholar] [CrossRef]
- Naggie, S.; Lok, A.S. New Therapeutics for Hepatitis B: The Road to Cure. Ann. Rev. Med. 2020, 72. [Google Scholar] [CrossRef]
- Cornberg, M.; Lok, A.S.F.; Terrault, N.A.; Zoulim, F.; Berg, T.; Brunetto, M.R.; Buchholz, S.; Buti, M.; Chan, H.L.; The 2019 EASL-AASLD HBV Treatment Endpoints Conference Faculty; et al. Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL-AASLD HBV Treatment Endpoints Conference. Hepatology 2020, 71, 1070–1092. [Google Scholar] [CrossRef]
- Tout, I.; Loureiro, D.; Mansouri, A.; Soumelis, V.; Boyer, N.; Asselah, T. Hepatitis B surface antigen seroclearance: Immune mechanisms, clinical impact, importance for drug development. J. Hepatol. 2020, 73, 409–422. [Google Scholar] [CrossRef] [PubMed]
- Song, C.; Zhu, J.; Ge, Z.; Yu, C.; Tian, T.; Wang, H.; Han, J.; Shen, H.; Dai, J.; Lu, J.; et al. Spontaneous Seroclearance of Hepatitis B Surface Antigen and Risk of Hepatocellular Carcinoma. Clin. Gastroenterol. Hepatol. 2019, 17, 1204–1206. [Google Scholar] [CrossRef] [PubMed]
- Yip, T.C.; Wong, V.W.; Tse, Y.K.; Liang, L.Y.; Hui, V.W.; Zhang, X.; Li, G.L.; Lui, G.C.Y.; Chan, H.L.Y.; Wong, G.L.H. Similarly low risk of hepatocellular carcinoma after either spontaneous or nucleos(t)ide analogue-induced hepatitis B surface antigen loss. Aliment. Pharmacol. Ther. 2020, 53, 321–331. [Google Scholar]
- Asselah, T.; Loureiro, D.; Boyer, N.; Mansouri, A. Targets and future direct-acting antiviral approaches to achieve hepatitis B virus cure. Lancet Gastroenterol. Hepatol. 2019, 4, 883–892. [Google Scholar] [CrossRef]
- Pfefferkorn, M.; Böhm, S.; Schott, T.; Deichsel, D.; Bremer, C.M.; Schröder, K.; Gerlich, W.H.; Glebe, D.; Berg, T.; van Bömmel, T. Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers. Gut 2018, 67, 2045–2053. [Google Scholar] [CrossRef]
- Urban, S.; Bartenschlager, R.; Kubitz, R.; Zoulim, F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 2014, 147, 48–64. [Google Scholar] [CrossRef]
- Asselah, T.; Loureiro, D.; Tout, I.; Castelnau, C.; Boyer, N.; Marcellin, P.; Mansouri, A. Future treatments for hepatitis delta virus infection. Liver Int. 2020, 40 (Suppl. 1), 54–60. [Google Scholar] [CrossRef] [Green Version]
- Kang, C.; Syed, Y.Y. Bulevirtide: First Approval. Drugs 2020, 80, 1601–1605. [Google Scholar] [CrossRef]
- Bogomolov, P.; Alexandrov, A.; Voronkova, N.; Macievich, M.; Kokina, K.; Petrachenkova, M.; Lehr, T.; Lempp, F.A.; Wedemeyer, H.; Haag, M.; et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study. J. Hepatol. 2016, 65, 490–498. [Google Scholar] [CrossRef]
- Wedemeyer, H.; Schoneweis, K.; Bogomolov, P.O.; Voronkova, N.; Chulanov, V.; Stepanova, T.; Bremer, B.; Allweiss, L.; Dandri, M.; Burhenne, J.; et al. Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in cwith PEG-interferon Alpha 2a in patients with chronic HBV/HDV co-infection. J. Hepatol. 2019, 70, 81. [Google Scholar] [CrossRef]
- Spyrou, E.; Smith, C.I.; Ghany, M.G. Hepatitis B: Current Status of Therapy and Future Therapies. Gastroenterol. Clin. N. Am. 2020, 49, 215–238. [Google Scholar] [CrossRef]
- Yuen, M.F.; Gane, E.J.; Kim, D.J.; Weilert, F.; Yuen Chan, H.L.; Lalezari, J.; Hwang, S.G.; Nguyen, T.; Flores, O.; Hartman, G.; 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. [Google Scholar] [CrossRef] [Green Version]
- Zoulim, F.; Lenz, O.; Vandenbossche, J.J.; Talloen, W.; Verbinnen, T.; Moscalu, I.; Streinu-Cercel, A.; Bourgeois, S.; Buti, M.; Crespo, J.; 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. [Google Scholar] [CrossRef]
- Yuen, M.-F.; Schwabe, C.; Tanwandee, T.; Jin, Y.; Gao, L.; Zhou, X.; Das, S.; Wang, Y.; Lemenuel-Diot, A.; Cosson, V.; et al. RO7049389, a core protein allosteric modulator, demonstrates robust decline in HBV DNA and HBV RNA in chronic HBV infected patients. Sci. HBV Cure 2019. [Google Scholar] [CrossRef]
- Ma, X.; Lalezari, J.; Nguyen, T.; Bae, H.; Schiff, E.R.; Fung, S.; Yuen, R.M.F.; Hassanein, T.; Hann, H.W.; Elkhashab, M.; et al. LBO-06-Interim safety and efficacy results of the ABI-H0731 phase 2a program exploring the combination of ABI-H0731 with Nuc therapy in treatment-naive and treatment-suppressed chronic hepatitis B patients. J. Hepatol. 2019, 70 (Suppl. 1), e130. [Google Scholar] [CrossRef]
- Nayagam, J.S.; Cargill, Z.C.; Agarwal, K. The Role of RNA Interference in Functional Cure Strategies for Chronic Hepatitis, B. Curr. Hepatol. Rep. 2020, 19, 362–369. [Google Scholar] [CrossRef]
- Yuen, M.F.; Schiefke, I.; Yoon, J.H.; Ahn, S.H.; Heo, J.; Kim, J.H.; Lik Yuen Chan, H.; Yoon, K.T.; Klinker, H.; Manns, M.; et al. RNA Interference Therapy With ARC-520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients With Chronic Hepatitis B Infection. Hepatology 2020, 72, 19–31. [Google Scholar] [CrossRef] [Green Version]
- Gane, E.J.; Locarnini, S.; Lim, T.H.; Strasser, S.; Sievert, W.; Cheng, W.; Thompson, A.; Given, B.; Schluep, T.; Hamilton, J.; et al. First results with rna interference (rnai) in chronic hepatitis b (chb) using ARO-HBV. Hepatology 2018, 68, 1463A. [Google Scholar]
- Han, K.; Cremer, J.; Elston, R.; Oliver, S.; Baptiste-Brown, S.; Chen, S.; Gardiner, D.; Davies, M.; Saunders, J.; Hamatake, R.; et al. A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects. Clin. Pharmacol. Drug Dev. 2019, 8, 790–801. [Google Scholar] [CrossRef] [Green Version]
- Real, C.I.; Werner, M.; Paul, A.; Gerken, G.; Schlaak, J.F.; Vaillant, A.; Broering, R. Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells. Sci. Rep. 2017, 7, 43838. [Google Scholar] [CrossRef]
- Franke, C.; Matschl, U.; Bruns, M. Enzymatic treatment of duck hepatitis B virus: Topology of the surface proteins for virions and noninfectious subviral particles. Virology 2007, 359, 126–136. [Google Scholar] [CrossRef] [Green Version]
- Chai, N.; Chang, H.E.; Nicolas, E.; Han, Z.; Jarnik, M.; Taylor, J. Properties of subviral particles of hepatitis B virus. J. Virol. 2008, 82, 7812–7817. [Google Scholar] [CrossRef] [Green Version]
- Hu, J.; Liu, K. Complete and Incomplete Hepatitis B Virus Particles: Formation, Function, and Application. Viruses 2017, 9, 56. [Google Scholar] [CrossRef] [Green Version]
- Bazinet, M.; Pântea, V.; Cebotarescu, V.; Cojuhari, L.; Jimbei, P.; Albrecht, J.; Schmid, P.; Le Gal, F.; Gordien, E.; Krawczyk, A.; et al. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): A non-randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 2017, 2, 877–889. [Google Scholar]
- Bazinet, M.; Pântea, V.; Placinta, G.; Moscalu, I.; Cebotarescu, V.; Cojuhari, L.; Jimbei, P.; Iarovoi, L.; Smesnoi, V.; Musteata, T.; 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. [Google Scholar] [CrossRef]
- Lee, H.W.; Park, J.Y.; Hong, T.; Park, M.S.; Ahn, S.H. Efficacy of Lenvervimab, a Recombinant Human Immunoglobulin, in Treatment of Chronic Hepatitis B Virus Infection. Clin. Gastroenterol. Hepatol. 2020, 18, 3043–3045.e1. [Google Scholar] [CrossRef]
- Ruiz de Galarreta, M.; Lujambio, A. Therapeutic editing of hepatocyte genome in vivo. J. Hepatol. 2017, 67, 818–828. [Google Scholar] [CrossRef] [Green Version]
- Liu, X.; Hao, R.; Chen, S.; Guo, D.; Chen, Y. Inhibition of hepatitis B virus by the CRISPR/Cas9 system via targeting the conserved regions of the viral genome. J. Gen. Virol. 2015, 96, 2252–2261. [Google Scholar] [CrossRef]
- Chen, J.; Zhang, W.; Lin, J.; Wang, F.; Wu, M.; Chen, C.; Zheng, Y.; Peng, X.; Li, J.; Yuan, Z.; et al. An efficient antiviral strategy for targeting hepatitis B virus genome using transcription activator-like effector nucleases. Mol. Ther. 2014, 22, 303–311. [Google Scholar] [CrossRef] [Green Version]
- Hong, X.; Kim, E.S.; Guo, H. Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis, B. Hepatology 2017, 66, 2066–2077. [Google Scholar] [CrossRef]
- Ye, B.; Liu, X.; Li, X.; Kong, H.; Tian, L.; Chen, Y. T-cell exhaustion in chronic hepatitis B infection: Current knowledge and clinical significance. Cell Death Dis. 2015, 6, e1694. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, Z.; Cao, Q.; Xiong, Y.; Zhang, E.; Lu, M. Interaction between Hepatitis B Virus and Toll-Like Receptors: Current Status and Potential Therapeutic Use for Chronic Hepatitis, B. Vaccines 2018, 6, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Janssen, H.L.; Brunetto, M.R.; Kim, Y.J.; Ferrari, C.; Massetto, B.; Nguyen, A.H.; Joshi, A.; Woo, J.; Lau, A.H.; Gaggar, A.; et al. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis, B. J. Hepatol. 2018, 68, 431–440. [Google Scholar] [CrossRef] [PubMed]
- Bertoletti, A.; Le Bert, N. Immunotherapy for Chronic Hepatitis B Virus Infection. Gut Liver 2018, 12, 497–507. [Google Scholar] [CrossRef] [Green Version]
- Gehring, A.J.; Xue, S.A.; Ho, Z.Z.; Teoh, D.; Ruedl, C.; Chia, A.; Koh, S.; Lim, S.G.; Maini, M.K.; Stauss, H.; et al. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J. Hepatol. 2011, 55, 103–110. [Google Scholar] [CrossRef]
- Krebs, K.; Böttinger, N.; Huang, L.R.; Chmielewski, M.; Arzberger, S.; Gasteiger, G.; Jäger, C.; Schmitt, E.; Bohne, F.; Aichler, M.; et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 2013, 145, 456–465. [Google Scholar] [CrossRef] [Green Version]
- Fisicaro, P.; Valdatta, C.; Massari, M.; Loggi, E.; Biasini, E.; Sacchelli, L.; Cavallo, M.C.; Silini, E.M.; Andreone, P.; Missale, G.; et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis, B. Gastroenterology 2010, 138, 682–693. [Google Scholar] [CrossRef]
- Liu, J.; Zhang, E.; Ma, Z.; Wu, W.; Kosinska, A.; Zhang, X.; Möller, I.; Seiz, P.; Glebe, D.; Wang, B.; et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog. 2014, 10, e1003856. [Google Scholar] [CrossRef] [Green Version]
- Gane, E.; Verdon, D.J.; Brooks, A.E.; Gaggar, A.; Nguyen, A.H.; Subramanian, G.M.; Schwabe, C.; Dunbar, P.R. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study. J. Hepatol. 2019, 71, 900–907. [Google Scholar] [CrossRef]
- Lim, S.G.; Agcaoili, J.; De Souza, N.N.A.; Chan, E. Therapeutic vaccination for chronic hepatitis B: A systematic review and meta-analysis. J Viral. Hepat. 2019, 26, 803–817. [Google Scholar] [CrossRef]
- Gehring, A.J.; Protzer, U. Targeting Innate and Adaptive Immune Responses to Cure Chronic HBV Infection. Gastroenterology 2019, 156, 325–337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yuen, M.-F.; Locarnini, S.; Given, B.; Schluep, T.; Hamilton, J.; Biermer, M.; Kalmeijer, R.; Beumont, M.; Lenz, O.; Cloherty, G.; et al. First clinical experience with RNA interference-based triple combination therapy in chronic hepatitis B: JNJ-3989, JNJ-6379 and a Nucleos (t) ide analogue. Hepatology 2019, 70, 1489A. [Google Scholar]
Target | Phase | Drug Name | Mode of Action | Company | Administration | NCT Number |
---|---|---|---|---|---|---|
Entry inhibitors | II | Bulevirtide | HBV entry inhibition | Hepateral Ltd | SC | NCT03852433 |
Core protein allosteric modulators | I | NVR 3–778 | Assembly modulator | Novira Therapeutics, Inc. | Oral | NCT02401737 |
II | GLS4 | Core protein binding | Sunshine Lake Pharma Co., Ltd. | Oral | NCT04147208 | |
I | RO7049389 | Core protein binding | Hoffmann-La Roche | Oral | NCT02952924 | |
II | JNJ-56136379 (JNJ-6379) | Assembly modulator | Janssen, Scotland | Oral | NCT03982186 | |
II | ABI-H0731 (Vebicorvir) | Core protein binding | Assembly Biosciences | Oral | NCT03780543 | |
II | ABI-H2158 | Core protein binding | Assembly Biosciences | Oral | NCT04398134 | |
1 | JNJ-64530440 (JNJ-0440) | Assembly modulator | Alios Biopharma Inc. | Oral | NCT03439488 | |
II | QL-007 | Assembly modulator | Qilu Pharmaceutical Co., Ltd. | Oral | NCT04157699 | |
RNA interference | II | ARC-520 | RNA interference | Arrowhead Pharmaceuticals | IV | NCT02577029 |
II | INOIS-HBVRx (GSK3228836) | Antisense oligonucleotides | GlaxoSmithKline | SC | NCT02981602 | |
Preclinical | INOIS-HBVLRx (GSK33389404) | Antisense oligonucleotides | GlaxoSmithKline | - | - | |
II | VIR-2218 | RNA interference | Vir Biotechnology, Inc. | SC | NCT04412863 | |
II | ARO-HBV (JNJ-3989) | RNA interference | Arrowhead Pharmaceuticals | SC | NCT03365947 | |
I | DCR-HBVS | RNA interference | Dicerna Pharmaceuticals, Inc. | SC | NCT03772249 | |
Inhibition of HBsAg release | II | REP 2139-Ca | Inhibition of HBsAg release | Replicor Inc. | IV | NCT02726789 |
II | REP 2139-Mg | Inhibition of HBsAg release | Replicor Inc. | IV | NCT02565719 | |
HBsAg neutralization | II | GC 1102 (Lenvervimab) | Neutralization and inhibiting reentry | Green Cross Corporation | IV | NCT03801798 |
Inhibitors of cccDNA | Preclinical | TALENs | cccDNA disruption | - | - | - |
Preclinical | CRISPR-Cas9 | cccDNA disruption | - | - | - | |
Toll-like receptor agonists | II | GS-9620 (vesatolimod) | TLR7 agonist | Gilead Sciences | Oral | NCT02166047 |
II | GS-9688 (selgantolimod) | TLR8 agonist | Gilead, USA | Oral | NCT03615066 | |
I | RO7020531 | TLR7 agonist | Hoffmann-La Roche | Oral | NCT02956850 | |
Immune checkpoint inhibitors | I | Nivolumab | Anti-PD-1 | PharmaEssentia | IV | NCT04638439 |
I/II | REGN2810 (cemiplimab) | Anti-PD-1 | Regeneron Pharmaceuticals | IV | NCT04046107 | |
Therapeutic vaccines | I | INO-1800 | DNA plasmids | Inovio Pharmaceuticals | E-IM | NCT02431312 |
I | TG1050 | HBV proteins | Transgene | SC | NCT02428400 | |
I | ChAdOx1 HBV | Adjuvanted ChAd and MVA vectored | Vaccitech Limited | IM | NCT04297917 | |
I | JNJ-64300535 | DNA vaccines | Janssen Sciences Ireland UC | E-IM | NCT03463369 | |
II | GS-4774 | DNA vaccines | Gilead Sciences | SC | NCT02174276 |
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Lee, H.W.; Lee, J.S.; Ahn, S.H. Hepatitis B Virus Cure: Targets and Future Therapies. Int. J. Mol. Sci. 2021, 22, 213. https://doi.org/10.3390/ijms22010213
Lee HW, Lee JS, Ahn SH. Hepatitis B Virus Cure: Targets and Future Therapies. International Journal of Molecular Sciences. 2021; 22(1):213. https://doi.org/10.3390/ijms22010213
Chicago/Turabian StyleLee, Hye Won, Jae Seung Lee, and Sang Hoon Ahn. 2021. "Hepatitis B Virus Cure: Targets and Future Therapies" International Journal of Molecular Sciences 22, no. 1: 213. https://doi.org/10.3390/ijms22010213