{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:48:21Z","timestamp":1792792101599,"version":"4.5.0"},"reference-count":119,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T00:00:00Z","timestamp":1601510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.<\/jats:p>","DOI":"10.3390\/jcm9103187","type":"journal-article","created":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T09:04:12Z","timestamp":1601543052000},"page":"3187","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["New Approaches to the Treatment of Chronic Hepatitis B"],"prefix":"10.3390","volume":"9","author":[{"given":"Alexandra","family":"Alexopoulou","sequence":"first","affiliation":[{"name":"Department of Medicine, Medical School, National &amp; Kapodistrian University of Athens, Hippokration General Hospital, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa","family":"Vasilieva","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical School, National &amp; Kapodistrian University of Athens, Hippokration General Hospital, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5195-7863","authenticated-orcid":false,"given":"Peter","family":"Karayiannis","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Sciences, Medical School, University of Nicosia, Engomi, CY-1700 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,1]]},"reference":[{"key":"#cr-split#-ref_1.1","unstructured":"European Association for the Study of the Liver (2017). Electronic address: Easloffice@easloffice.eu"},{"key":"#cr-split#-ref_1.2","unstructured":"European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol., 67, 370-398."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s11938-019-00236-3","article-title":"Updates on Chronic HBV: Current Challenges and Future Goals","volume":"17","author":"Lee","year":"2019","journal-title":"Curr. Treat. Options Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S117","DOI":"10.1016\/j.jhep.2016.02.016","article-title":"New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus","volume":"64","author":"Durantel","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/S2468-1253(19)30015-9","article-title":"Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: A prespecified follow-up analysis of two randomised trials","volume":"4","author":"Buti","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1007\/s12072-017-9829-7","article-title":"Hepatitis B virus: Virology, molecular biology, life cycle and intrahepatic spread","volume":"11","author":"Karayiannis","year":"2017","journal-title":"Hepatol. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/S0140-6736(70)90926-8","article-title":"Virus-like particles in serum of patients with Australia-antigen-associated hepatitis","volume":"1","author":"Dane","year":"1970","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1056\/NEJMra031087","article-title":"Hepatitis B virus infection\u2013natural history and clinical consequences","volume":"350","author":"Ganem","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3748\/wjg.v13.i1.8","article-title":"Recent advances in hepatitis B virus research: A German point of view","volume":"13","author":"Glebe","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/0092-8674(94)90142-2","article-title":"Three-dimensional structure of hepatitis B virus core particles determined by electron cryomicroscopy","volume":"77","author":"Borisova","year":"1994","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1128\/MMBR.64.1.51-68.2000","article-title":"Hepatitis B virus biology","volume":"4","author":"Seeger","year":"2000","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5841","DOI":"10.1128\/JVI.00096-07","article-title":"Infectivity determinants of the hepatitis B virus pre-S domain are confined to the N-terminal 75 amino acid residues","volume":"81","author":"Blanchet","year":"2007","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3748\/wjg.v13.i1.39","article-title":"Intracellular transport of hepatitis B virus","volume":"13","author":"Kann","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/0092-8674(86)90602-1","article-title":"Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells","volume":"47","author":"Tuttleman","year":"1986","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1006\/jmbi.2000.4481","article-title":"Structural organization of the hepatitis B virus minichromosome","volume":"307","author":"Bock","year":"2001","journal-title":"J. Mol. Boil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1172\/JCI58847","article-title":"IFN-\u03b1 inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome","volume":"122","author":"Belloni","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.jhep.2009.05.022","article-title":"Control of cccDNA function in hepatitis B virus infection","volume":"51","author":"Levrero","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1053\/j.gastro.2006.01.001","article-title":"Hepatitis B Virus Replication Is Regulated by the Acetylation Status of Hepatitis B Virus cccDNA-Bound H3 and H4 Histones","volume":"130","author":"Pollicino","year":"2006","journal-title":"Gastroenterol."},{"key":"ref_18","first-page":"3591","article-title":"Multiple topogenic sequences determine the transmembrane orientation of the hepatitis B surface antigen","volume":"7","author":"Eble","year":"1987","journal-title":"Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10205","DOI":"10.1073\/pnas.0704000104","article-title":"Involvement of host cellular multivesicular body functions in hepatitis B virus budding","volume":"104","author":"Watanabe","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1016\/j.cgh.2018.11.001","article-title":"Efficacy and Safety of Besifovir Dipivoxil Maleate Compared With Tenofovir Disoproxil Fumarate in Treatment of Chronic Hepatitis B Virus Infection","volume":"17","author":"Ahn","year":"2019","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S522","DOI":"10.1016\/S0168-8278(18)31292-3","article-title":"Pharmacokinetic-pharmacodynamic modeling of Tenofovir Exalidex in HBV subjects","volume":"68","author":"Foster","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1053\/j.gastro.2018.07.057","article-title":"Development of Direct-acting Antiviral and Host-targeting Agents for Treatment of Hepatitis B Virus Infection","volume":"156","author":"Xia","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1007\/s11684-015-0376-0","article-title":"Reproductive toxicity study with a novel deoxyguanosine analogue (Metacavir) in pregnant SD rats","volume":"9","author":"Luo","year":"2014","journal-title":"Front. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1053\/j.gastro.2013.12.024","article-title":"Hepatitis B and D Viruses Exploit Sodium Taurocholate Co-transporting Polypeptide for Species-Specific Entry into Hepatocytes","volume":"146","author":"Ni","year":"2014","journal-title":"Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e81","DOI":"10.1016\/S0618-8278(19)30141-0","article-title":"Final results of a multicenter open lebel phase 2 clinical trial (MYR203) to assess safety and efficacy of Myrcludex B with Peg interferon a-2a in Patients with Chronic Hepatitis HBV\/HDV Co-Infection","volume":"70","author":"Weldemeyer","year":"2019","journal-title":"J Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/j.jhep.2017.05.012","article-title":"Therapeutic editing of hepatocyte genome in vivo","volume":"67","author":"Lujambio","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.virusres.2017.01.003","article-title":"Advances with using CRISPR\/Cas-mediated gene editing to treat infections with hepatitis B virus and hepatitis C virus","volume":"244","author":"Moyo","year":"2018","journal-title":"Virus Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/mt.2010.20","article-title":"Zinc-finger nucleases as a novel therapeutic strategy for targeting hepatitis B virus DNAs","volume":"18","author":"Cradick","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1126\/science.1178811","article-title":"Breaking the Code of DNA Binding Specificity of TAL-Type III Effectors","volume":"326","author":"Boch","year":"2009","journal-title":"Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/mt.2013.212","article-title":"An Efficient Antiviral Strategy for Targeting Hepatitis B Virus Genome Using Transcription Activator-Like Effector Nucleases","volume":"22","author":"Chen","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.virol.2014.12.001","article-title":"Suppression of hepatitis B virus DNA accumulation in chronically infected cells using a bacterial CRISP\/Cas RNA-guided DNA endonuclease","volume":"476","author":"Kennedy","year":"2015","journal-title":"Virology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1099\/vir.0.000159","article-title":"Inhibition of hepatitis B virus by the CRISPR\/Cas9 system via targeting the conserved regions of the viral genome","volume":"96","author":"Liu","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Bloom, K., Maepa, M.B., Ely, A., and Arbuthnot, P. (2018). Gene Therapy for Chronic HBV-Can We Eliminate cccDNA?. Genes, 9.","DOI":"10.3390\/genes9040207"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-38526-6","article-title":"Suppressing the NHEJ pathway by DNA-PKcs inhibitor NU7026 prevents degradation of HBV cccDNA cleaved by CRISPR\/Cas9","volume":"9","author":"Kostyushev","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.omtn.2018.05.006","article-title":"One-Vector System for Multiplexed CRISPR\/Cas9 against Hepatitis B Virus cccDNA Utilizing High-Capacity Adenoviral Vectors","volume":"12","author":"Schiwon","year":"2018","journal-title":"Mol. Ther. - Nucleic Acids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1002\/hep.29479","article-title":"Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B","volume":"66","author":"Hong","year":"2017","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19975","DOI":"10.1073\/pnas.0908365106","article-title":"Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function","volume":"106","author":"Belloni","year":"2009","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/1348-0421.12345","article-title":"Interaction of the hepatitis B virus X protein with the lysine methyltransferase SET and MYND domain-containing 3 induces activator protein 1 activation","volume":"60","author":"Hayashi","year":"2016","journal-title":"Microbiol. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/hep.29133","article-title":"PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation","volume":"66","author":"Zhang","year":"2017","journal-title":"Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.3892\/or.2017.5518","article-title":"HBx represses RIZ1 expression by DNA methyltransferase 1 involvement in decreased miR-152 in hepatocellular carcinoma","volume":"37","author":"Zhao","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/nature17170","article-title":"Hepatitis B virus X protein identifies the Smc5\/6 complex as a host restriction factor","volume":"531","author":"Mueller","year":"2016","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e48","DOI":"10.1016\/S0618-8278(19)30086-6","article-title":"A first-in-class orally available HBV cccDNA destabilizer ccc_R08 achieved sustainable HBsAg and cccDNA reduction in the HBV circle mouse model through elimination of cccDNA-like molecules in the mouse liver","volume":"70","author":"Wang","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1080\/14712598.2018.1472231","article-title":"siRNA drug development against hepatitis B virus infection","volume":"18","author":"Flisiak","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.cell.2009.01.035","article-title":"Origins and mechanisms of miRNAs and siRNAs","volume":"136","author":"Carthew","year":"2009","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nature07754","article-title":"On the road to reading the RNA-interference code","volume":"457","author":"Siomi","year":"2009","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"s18","DOI":"10.1016\/S0168-8278(18)30254-X","article-title":"Durable inhibition of hepatitis B virus replication and antigenemia using subcutaneously administered siRNA agent AB-729 in preclinical models","volume":"68","author":"Lee","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"S688","DOI":"10.1016\/S0168-8278(17)31850-0","article-title":"A phase 2a study evaluating the multi-dose activity of ARB-1467 in HBeAg positive and negative virally suppressed subjects with hepatitis B","volume":"66","author":"Gane","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1016\/S0618-8278(19)30092-1","article-title":"Short term RNA interference (RNAi) therapy in chronic hepatitis B (CHB) using JNJ-3989 brings majority of patients to HBsAg <100 IU\/mL (PS 080)","volume":"70","author":"Yuen","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S20","DOI":"10.1016\/S0168-8278(20)30597-3","article-title":"Short-term treatment with RNA interference therapy, JNJ-3989, results in sustained hepatitis B surface antigen supression in patients with chronic hepatitis B receiving nucleos(t)ide analogue treatment","volume":"73","author":"Gane","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.jhep.2015.11.032","article-title":"In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides","volume":"64","author":"Billioud","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_51","first-page":"433A","article-title":"Results after 12 weeks treatment of multiple doses of GSK3389404 in chronic hepatitis B subjects on stable nucleos(t)ide therapy in a phase 2a double-blind, placebo-controlled study","volume":"70","author":"Yuen","year":"2019","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.antiviral.2014.05.007","article-title":"Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity","volume":"108","author":"Cai","year":"2014","journal-title":"Antivir. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.antiviral.2017.04.012","article-title":"Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles","volume":"143","author":"Edwards","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.coph.2016.08.004","article-title":"Modulators of HBV capsid assembly as an approach to treating hepatitis B virus infection","volume":"30","author":"Cole","year":"2016","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/ncpgasthep0056","article-title":"Drug insight: Nucleoside and nucleotide analog inhibitors for hepatitis B","volume":"1","author":"Fung","year":"2004","journal-title":"Nat. Clin. Pract. Gastroenterol. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1126\/science.1077215","article-title":"Inhibition of Hepatitis B Virus Replication by Drug-Induced Depletion of Nucleocapsids","volume":"299","author":"Deres","year":"2003","journal-title":"Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"S878","DOI":"10.1016\/S0168-8278(20)32197-8","article-title":"Efficay and safety of GLS4\/ritonavir combined with entecavir in HBeAg-positive patients with chronic hepatitis B: Interim results from phase 2b, multi-center study","volume":"73","author":"Zhang","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1128\/AAC.46.9.3057-3060.2002","article-title":"Phenylpropenamide Derivatives AT-61 and AT-130 Inhibit Replication of Wild-Type and Lamivudine-Resistant Strains of Hepatitis B Virus In Vitro","volume":"46","author":"Iv","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5344","DOI":"10.1128\/AAC.01091-13","article-title":"Preclinical Characterization of GLS4, an Inhibitor of Hepatitis B Virus Core Particle Assembly","volume":"57","author":"Wu","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e491","DOI":"10.1016\/S0618-8278(19)30964-8","article-title":"FRI-219-RO7049389, a core protein allosteric modulator, demonstrates robust decline in HBV DNA and HBV RNA in chronic HBV infected patients","volume":"70","author":"Gane","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/hep.30514","article-title":"Direct Inhibition of Hepatitis B e Antigen by Core Protein Allosteric Modulator","volume":"70","author":"Yan","year":"2019","journal-title":"Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e474","DOI":"10.1016\/S0618-8278(19)30936-3","article-title":"FRI-191-EDP-514, a novel HBV core inhibitor with potent antiviral activity both in vitro and in vivo","volume":"70","author":"Vaine","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S2468-1253(19)30346-2","article-title":"Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: A randomised, placebo-controlled phase 1 trial","volume":"5","author":"Yuen","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_64","first-page":"1489A","article-title":"First clinical experience with rna interference [RNAi]-based triple combination therapy in chronic hepatitis B (CHB): JNJ-73763989 (JNJ-3989), JNJ-56136379 (JNJ-6379) and a nucleos(t)ide analogue (NA)","volume":"70","author":"Yuen","year":"2019","journal-title":"Hepatology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.antiviral.2017.10.022","article-title":"Activity of nucleic acid polymers in rodent models of HBV infection","volume":"149","author":"Motter","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omtn.2017.04.019","article-title":"Nucleic Acid Polymers with Accelerated Plasma and Tissue Clearance for Chronic Hepatitis B Therapy","volume":"8","author":"Roehl","year":"2017","journal-title":"Mol. Ther. - Nucleic Acids"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Guillot, C., Martel, N., Berby, F., Bordes, I., Hantz, O., Blanchet, M., Sureau, C., Vaillant, A., and Chemin, I. (2017). Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179697"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"43838","DOI":"10.1038\/srep43838","article-title":"Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don\u2019t harbor immunostimulatory properties in primary isolated liver cells","volume":"7","author":"Real","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1021\/acsinfecdis.8b00156","article-title":"REP 2139: Antiviral Mechanisms and Applications in Achieving Functional Control of HBV and HDV Infection","volume":"5","author":"Vaillant","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.antiviral.2016.07.004","article-title":"Nucleic acid polymers: Broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection","volume":"133","author":"Vaillant","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Noordeen, F., Scougall, C.A., Grosse, A., Qiao, Q., Ajilian, B.B., Reaiche-Miller, G., Finnie, J., Werner, M., Broering, R., and Schlaak, J.F. (2015). Therapeutic Antiviral Effect of the Nucleic Acid Polymer REP 2055 against Persistent Duck Hepatitis B Virus Infection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140909"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/S2468-1253(17)30288-1","article-title":"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","volume":"2","author":"Bazinet","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1111\/jvh.13180","article-title":"Kinetics of hepatitis B surface antigen quasispecies during REP 2139-Ca therapy in HBeAg-positive chronic HBV infection","volume":"26","author":"Usman","year":"2019","journal-title":"J. Viral Hepat."},{"key":"ref_74","first-page":"e486","article-title":"FRI-210-Establishment of high rates of functional cure of HBeAg negative chronic HBV infection with REP 2139-Mg based combination therapy: Ongoing follow-up results from the REP 401 study","volume":"70","author":"Bazinet","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"S256","DOI":"10.1016\/S0168-8278(17)30821-8","article-title":"Update on safety and efficacy in the REP 401 protocol: REP 2139-Mg or REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated Interferon alpha-2a in treatment na\u00efve caucasian patients with chronic HBeAg negative HBV infection","volume":"66","author":"Bazinet","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1016\/j.jhep.2016.01.028","article-title":"The role of innate immunity in the immunopathology and treatment of HBV infection","volume":"64","author":"Maini","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1016\/j.jhep.2016.01.026","article-title":"Adaptive immunity in HBV infection","volume":"64","author":"Bertoletti","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1053\/j.gastro.2014.10.038","article-title":"American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy","volume":"148","author":"Perrillo","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.jhep.2018.01.025","article-title":"For whom the interferons toll\u2014TLR7 mediated boosting of innate and adaptive immunity against chronic HBV infection","volume":"68","author":"Bengsch","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/j.jhep.2014.12.026","article-title":"Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B","volume":"62","author":"Menne","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1053\/j.gastro.2013.02.003","article-title":"GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees","volume":"144","author":"Lanford","year":"2013","journal-title":"Gastroenterol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1053\/j.gastro.2018.01.030","article-title":"TLR7 Agonist Increases Responses of Hepatitis B Virus\u2013Specific T Cells and Natural Killer Cells in Patients With Chronic Hepatitis B Treated With Nucleos(T)Ide Analogues","volume":"154","author":"Boni","year":"2018","journal-title":"Gastroenterol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.jhep.2017.10.027","article-title":"Safety, efficacy and pharmaco- dynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B","volume":"68","author":"Janssen","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1016\/S0168-8278(18)30253-8","article-title":"Combination treatment of a TLR7 agonist RO7020531 and a capsid assembly modulator RO7049389 achieved sustainable viral load suppression and HBsAg loss in an AAV-HBV mouse mode","volume":"68","author":"Gao","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Luk, A., Jiang, Q., Glavini, K., Triyatni, M., Zhao, N., Racek, T., Zhu, Y., and Grippo, J.F. (2020). A Single and Multiple Ascending Dose Study of Toll-Like Receptor 7 Agonist (RO7020531) in Chinese Healthy Volunteers. Clin. Transl. Sci.","DOI":"10.1111\/cts.12791"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.immuni.2014.12.016","article-title":"The RNA Sensor RIG-I Dually Functions as an Innate Sensor and Direct Antiviral Factor for Hepatitis B Virus","volume":"42","author":"Sato","year":"2015","journal-title":"Immun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1016\/S0618-8278(19)30084-2","article-title":"GS-12-Ascending dose cohort study of inarigivir - A novel RIG I agonist in chronic HBV patients: Final results of the ACHIEVE trial","volume":"70","author":"Yuen","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1128\/AAC.04321-14","article-title":"STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus","volume":"59","author":"Guo","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3368","DOI":"10.1099\/jgv.0.000647","article-title":"Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway","volume":"97","author":"He","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.molimm.2007.07.038","article-title":"PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients","volume":"45","author":"Peng","year":"2008","journal-title":"Mol. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1053\/j.gastro.2009.09.052","article-title":"Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B","volume":"138","author":"Fisicaro","year":"2010","journal-title":"Gastroenterol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.jhep.2019.06.028","article-title":"Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study","volume":"71","author":"Gane","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1002\/hep.23936","article-title":"The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function","volume":"52","author":"Raziorrouh","year":"2010","journal-title":"Hepatol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1002\/hep.24249","article-title":"Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection","volume":"53","author":"Schurich","year":"2011","journal-title":"Hepatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40425-014-0033-1","article-title":"Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: A multicenter, retrospective case series","volume":"2","author":"Ravi","year":"2014","journal-title":"J. Immunother. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1053\/j.gastro.2018.03.021","article-title":"Dysregulated Response of Follicular Helper T Cells to Hepatitis B Surface Antigen Promotes HBV Persistence in Mice and Associates With Outcomes of Patients","volume":"154","author":"Wang","year":"2018","journal-title":"Gastroenterol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"8585","DOI":"10.1016\/j.vaccine.2007.09.072","article-title":"Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: A randomized, controlled study of co-administration of HBsAg\/AS02 candidate vaccine and lamivudine","volume":"25","author":"Lau","year":"2007","journal-title":"Vaccine"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S0168-8278(01)00028-9","article-title":"Efficacy and limitations of a specific immunotherapy in chronic hepatitis B","volume":"34","author":"Pol","year":"2001","journal-title":"J. Hepatol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.jhep.2013.05.003","article-title":"Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: Experiences and findings","volume":"59","author":"Xu","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/mt.2013.274","article-title":"Immunological and Antiviral Responses After Therapeutic DNA Immunization in Chronic Hepatitis B Patients Efficiently Treated by Analogues","volume":"22","author":"Godon","year":"2014","journal-title":"Mol. Ther."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1136\/gutjnl-2013-305707","article-title":"Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: A randomised trial--ANRS HB02 VAC-ADN","volume":"64","author":"Fontaine","year":"2015","journal-title":"Gut"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1053\/jhep.2001.21594","article-title":"DNA prime\/canarypox boost\u2014based immunotherapy of chronic hepatitis B virus infection in a chimpanzee","volume":"33","author":"Pancholi","year":"2001","journal-title":"Hepatol."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Cavenaugh, J.S., Awi, D., Mendy, M., Hill, A.V., Whittle, H., and McConkey, S.J. (2011). Partially randomized, non-blinded trial of DNA and MVA therapeutic vaccines based on hepatitis B virus surface protein for chronic HBV infection. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0014626"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Al Mahtab, M., Akbar, S.M.F., Aguilar, J.C., Guillen, G., Penton, E., Tuero, A., Yoshida, O., Hiasa, Y., and Onji, M. (2018). Treatment of chronic hepatitis B na\u00efve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial). PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201236"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"133","DOI":"10.5005\/jp-journals-10018-1279","article-title":"Five-year Follow-up of Chronic Hepatitis B Patients Immunized by Nasal Route with the Therapeutic Vaccine HeberNasvac","volume":"8","author":"Aguilar","year":"2018","journal-title":"Euroasian J. Hepato-Gastroenterology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1038\/cgt.2013.65","article-title":"DNA vaccine cocktail expressing genotype A and C HBV surface and consensus core antigens generates robust cytotoxic and antibody responses in mice and Rhesus macaques","volume":"20","author":"Yan","year":"2013","journal-title":"Cancer Gene Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1111\/liv.12530","article-title":"Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice","volume":"35","author":"Yoon","year":"2014","journal-title":"Liver Int."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.jhep.2016.05.016","article-title":"Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B","volume":"65","author":"Lok","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1053\/j.gastro.2019.03.044","article-title":"Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis","volume":"157","author":"Boni","year":"2019","journal-title":"Gastroenterol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1080\/21645515.2019.1651141","article-title":"Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: A phase 1b placebo-controlled trial","volume":"16","author":"Zoulim","year":"2019","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1002\/hep.510250631","article-title":"Clearance of hepatitis B surface antigen after bone marrow transplantation: Role of adoptive immunity transfer","volume":"25","author":"Lau","year":"1997","journal-title":"Hepatol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.jhep.2008.08.026","article-title":"Anti-HBs re-seroconversion after liver transplantation in a patient with past HBV infection receiving a HBsAg positive graft","volume":"50","author":"Loggi","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.jhep.2014.10.001","article-title":"Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient","volume":"62","author":"Qasim","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1053\/j.gastro.2013.04.047","article-title":"T Cells Expressing a Chimeric Antigen Receptor That Binds Hepatitis B Virus Envelope Proteins Control Virus Replication in Mice","volume":"145","author":"Krebs","year":"2013","journal-title":"Gastroenterol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3177","DOI":"10.1172\/JCI93024","article-title":"Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection","volume":"127","author":"Kah","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1053\/j.gastro.2018.03.027","article-title":"Nonlytic Lymphocytes Engineered to Express Virus-Specific T-Cell Receptors Limit HBV Infection by Activating APOBEC3","volume":"155","author":"Koh","year":"2018","journal-title":"Gastroenterol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1053\/j.gastro.2007.11.002","article-title":"T Cells Redirected Against Hepatitis B Virus Surface Proteins Eliminate Infected Hepatocytes","volume":"134","author":"Bohne","year":"2008","journal-title":"Gastroenterol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.jcyt.2018.02.002","article-title":"HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice","volume":"20","author":"Kruse","year":"2018","journal-title":"Cytotherapy"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/10\/3187\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:15:36Z","timestamp":1760177736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/10\/3187"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,1]]},"references-count":119,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["jcm9103187"],"URL":"https:\/\/doi.org\/10.3390\/jcm9103187","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,1]]}}}