Korean J Gastroenterol KJG The Korean Journal of Gastroenterology 1598-9992 2233-6869 The Korean Society of Gastroenterology 10.4166/kjg.2019.74.5.267 Special Review Diagnosis and Treatment of Chronic Hepatitis B: How Far Have We Come? New Potential Therapies for Chronic Hepatitis B Yoo Sun Hong https://orcid.org/0000-0002-5484-5864 Kwon Jung Hyun Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea. Correspondence to: Jung Hyun Kwon, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 56 Dongsu-ro, Bupyeong-gu, Incheon 21431, Korea. Tel: +82-32-280-5886, Fax: +82-32-280-5023, doctorkwon@catholic.ac.kr 11 2019 27 11 2019 74 5 267 273 12 10 2019 23 10 2019 25 10 2019 Copyright © 2019. Korean Society of Gastroenterology 2019 Korean Society of Gastroenterology This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

A HBV infection is a dynamic disease and long-term liver inflammation contributes to the development of liver cirrhosis and hepatocellular carcinoma. Currently available nucleos(t)ide analogues and pegylated interferon are effective in inhibiting HBV replication but rarely achieve HBsAg clearance. The present article introduces a new definition of HBV cure and several emerging therapies for HBV cure, including direct acting antivirals and immune modulatory antivirals.

 Hepatitis B virus Therapeutics

None.

None.

 Korean Association for the Study of the Liver (KASL) KASL clinical practice guidelines for management of chronic hepatitis B Clin Mol Hepatol 2019 25 93 159 Global hepatitis report, 2017. [Internet] Geneva World Health Organization 2017 Apr cited 2019 April 4 Available from: https://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/ Revill PA Chisari FV Block JM A global scientific strategy to cure hepatitis B Lancet Gastroenterol Hepatol 2019 4 545 558 Lok AS Zoulim F Dusheiko G Ghany MG Hepatitis B cure: from discovery to regulatory approval Hepatology 2017 66 1296 1313 Likhitsup A Lok AS Understanding the natural history of hepatitis B virus infection and the new definitions of cure and the endpoints of clinical trials Clin Liver Dis 2019 23 401 416 Blank A Markert C Hohmann N First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B J Hepatol 2016 65 483 489 Bogomolov P Alexandrov A Voronkova N 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 Liang TJ Block TM McMahon BJ Present and future therapies of hepatitis B: from discovery to cure Hepatology 2015 62 1893 1908 Lee HM Banini BA Updates on chronic HBV: current challenges and future goals Curr Treat Options Gastroenterol 2019 17 271 291 Wang XJ Hu W Zhang TY Mao YY Liu NN Wang SQ Irbesartan, an FDA approved drug for hypertension and diabetic nephropathy, is a potent inhibitor for hepatitis B virus entry by disturbing Na(+)-dependent taurocholate cotransporting polypeptide activity Antiviral Res 2015 120 140 146 Belloni L Allweiss L Guerrieri F IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome J Clin Invest 2012 122 529 537 Cai D Mills C Yu W Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation Antimicrob Agents Chemother 2012 56 4277 4288 Moyo B Bloom K Scott T Ely A Arbuthnot P Advances with using CRISPR/Cas-mediated gene editing to treat infections with hepatitis B virus and hepatitis C virus Virus Res 2018 244 311 320 Hynes RO Coller BS Porteus M Toward responsible human genome editing JAMA 2017 317 1829 1830 Lucifora J Xia Y Reisinger F Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA Science 2014 343 1221 1228 Seeger C Sohn JA Complete spectrum of CRISPR/Cas9-induced mutations on HBV cccDNA Mol Ther 2016 24 1258 1266 Flisiak R Jaroszewicz J Łucejko M siRNA drug development against hepatitis B virus infection Expert Opin Biol Ther 2018 18 609 617 Streinu-Cercel A Gane E Cheng W A phase 2a study evaluating the multi-dose activity of ARB-1467 in HBeAg positive and negative virally suppressed subjects with hepatitis B J Hepatol 2017 66 S688 S689 Javanbakht H Mueller H Walther J Liver-targeted anti-HBV single-stranded oligonucleotides with locked nucleic acid potently reduce HBV gene expression in vivo Mol Ther Nucleic Acids 2018 11 441 454 Brezillon N Brunelle MN Massinet H Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice PLoS One 2011 6 e25096 Ren Q Liu X Luo Z Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4) Bioorg Med Chem 2017 25 1042 1056 Al-Mahtab M Bazinet M Vaillant A Safety and efficacy of nucleic acid polymers in monotherapy and combined with immunotherapy in treatment-naive Bangladeshi patients with HBeAg+ chronic hepatitis B infection PLoS One 2016 11 e0156667 Bazinet M Pantea V Placinta G Update on safety and efficacy in the REP 401 protocol: REP 2139-Mgor REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated interferon lpha-2a in treatment naïve caucasian patients with chronic HBeAg negative HBV infection J Hepatol 2017 66 S688 S699 Lanford RE Guerra B Chavez D GS-9620, an oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees Gastroenterology 2013 144 1508 1517 Gane EJ Lim YS Gordon SC The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection J Hepatol 2015 63 320 328 Boni C Vecchi A Rossi M TLR7 agonist increases responses of hepatitis B virus-specific T cells and natural killer cells in patients with chronic hepatitis B treated with nucleos(t)ide analogues Gastroenterology 2018 154 1764 1777 Janssen HLA Brunetto MR Kim YJ Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B J Hepatol 2018 68 431 440 Koh S Kah J Tham CYL Nonlytic lymphocytes engineered to express virus-specific T-cell receptors limit HBV infection by activating APOBEC3 Gastroenterology 2018 155 180 193 Rao M Valentini D Dodoo E Zumla A Maeurer M Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm Int J Infect Dis 2017 56 221 228 Pei Y Wang C Yan SF Liu G Past, current, and future developments of therapeutic agents for treatment of chronic hepatitis B virus infection J Med Chem 2017 60 6461 6479 Lok AS Pan CQ Han SH Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B J Hepatol 2016 65 509 516 Boni C Janssen HLA Rossi M Combined GS-4774 and tenofovir therapy can improve HBV-specific T-cell responses in patients with chronic hepatitis Gastroenterology 2019 157 227 241.e7 Höner Zu Siederdissen C Hui AJ Sukeepaisarnjaroen W Contrasting timing of virological relapse after discontinuation of tenofovir or entecavir in hepatitis B e antigen-negative patients J Infect Dis 2018 218 1480 1484 Wedemeyer H Hui AJ Sukeepaisarnjaroen W Therapeutic vaccination of chronic hepatitis B patients with ABX203 (NASVAC) to prevent relapse after stopping NUCs: contrasting timing rebound between tenofovir and entecavir J Hepatol 2017 66 S101 HBV replication cycle and targets for new treatment. HBV, hepatitis B virus; cccDNA, covalently closed circular DNA; RNA, ribonucleic acid; siRNAs, small interfering RNAs. Definitions of HBV Cure

HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; Anti-HBs, antibody to hepatitis B s antigen; HBeAg, hepatitis B e antigen; cccDNA, covalently closed circular DNA.

 Direct Acting Antiviral Agents for HBV in the Developmental Pipeline (Modified from Lee and Banini<xref ref-type="bibr" rid="B9">9</xref>, with permission from Curr Treat Options Gastroenterol)

HBV, hepatitis B virus; FDA, Food and Drug Administration; mRNA, messenger ribonucleic acid; TALEN, transcription activator-like endonucleases; IND, investigational new drug; HBsAg, hepatitis B surface antigen.

 Indirect Acting Antiviral Agents for HBV in the Developmental Pipeline (Modified from Lee and Banini<xref ref-type="bibr" rid="B9">9</xref>, with permission from Curr Treat Options Gastroenterol)

HBV, hepatitis B virus; PD-1, programmed death-1.