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Semin Liver Dis 2017; 37(03): 231-242
DOI: 10.1055/s-0037-1606212
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Challenges to a Cure for HBV Infection

Barbara Testoni
1   INSERM, U1052, Lyon, France
2   Cancer Research Center of Lyon (CRCL), Lyon, France
3   University of Lyon, UMR_S1052, UCBL, Lyon, France
,
Massimo Levrero
1   INSERM, U1052, Lyon, France
2   Cancer Research Center of Lyon (CRCL), Lyon, France
4   Hospices Civils de Lyon (HCL), Lyon, France
5   Department of Internal Medicine - DMISM, Sapienza University, Rome, Italy
6   CLNS@SAPIENZA, Istituto Italiano di Tecnologia (IIT), Rome, Italy
,
Fabien Zoulim
1   INSERM, U1052, Lyon, France
2   Cancer Research Center of Lyon (CRCL), Lyon, France
3   University of Lyon, UMR_S1052, UCBL, Lyon, France
4   Hospices Civils de Lyon (HCL), Lyon, France
› Author Affiliations
Further Information

Publication History

Publication Date:
28 August 2017 (online)

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Abstract

Current first-choice treatments for chronic hepatitis B are able to efficiently induce viral suppression in the majority of patients, but life-long therapy is needed to maintain infection under control due to their inability to eliminate the virus from infected hepatocytes. The residual viral replication and antigen production in most patients under treatment substantially contributes to the residual risk of hepatocarcinogenesis. New therapeutic approaches are needed to overcome hepatitis B virus persistence in the infected cells, or at least to control its transcriptional and replicative activity. In this review, the authors discuss the key points of the viral life cycle and host immune responses that need to be addressed to achieve a “functional cure,” or even a “complete cure,” allowing a finite duration of treatment and preventing virus reactivation and liver disease progression in a significantly higher number of patients than what is currently attained.

Keywords

chronic hepatitis B (CHB) - covalently-closed-circular DNA - hepatitis B virus (HBV) integration - HBV cure - clinical endpoints - surrogate markers
 

  • References

  • 1 El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142 (06) 1264-1273.e1
    CrossrefPubMedGoogle Scholar
  • 2 Papatheodoridis GV, Chan HL-Y, Hansen BE, Janssen HLA, Lampertico P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol 2015; 62 (04) 956-967
    CrossrefPubMedGoogle Scholar
  • 3 Wu C-Y, Lin J-T, Ho HJ. , et al. Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study. Gastroenterology 2014; 147 (01) 143-151.e5
    CrossrefPubMedGoogle Scholar
  • 4 Lampertico P, Maini M, Papatheodoridis G. Optimal management of hepatitis B virus infection - EASL Special Conference. J Hepatol 2015; 63 (05) 1238-1253
    CrossrefPubMedGoogle Scholar
  • 5 Kim WR, Loomba R, Berg T. , et al. Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B. Cancer 2015; 121 (20) 3631-3638
    CrossrefPubMedGoogle Scholar
  • 6 European Association for the Study of the Liver. EASL 2017 Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017; 67: 370-398
    CrossrefPubMedGoogle Scholar
  • 7 Zoulim F, Lebossé F, Levrero M. Current treatments for chronic hepatitis B virus infections. Curr Opin Virol 2016; 18: 109-116
    CrossrefPubMedGoogle Scholar
  • 8 Gish RG, Given BD, Lai C-L. , et al. Chronic hepatitis B: virology, natural history, current management and a glimpse at future opportunities. Antiviral Res 2015; 121: 47-58
    CrossrefPubMedGoogle Scholar
  • 9 Lok A, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. Hepatology 2017; DOI: 10.1002/hep.29323. . [Epub ahead of print]
    CrossrefPubMedGoogle Scholar
  • 10 Kim G-A, Lee HC, Kim M-J. , et al. Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance. J Hepatol 2015; 62 (05) 1092-1099
    CrossrefPubMedGoogle Scholar
  • 11 Gounder PP, Bulkow LR, Snowball M. , et al. Nested case-control study: hepatocellular carcinoma risk after hepatitis B surface antigen seroclearance. Aliment Pharmacol Ther 2016; 43 (11) 1197-1207
    CrossrefPubMedGoogle Scholar
  • 12 Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology 2015; 479-480: 672-686
    PubMedGoogle Scholar
  • 13 Yan H, Zhong G, Xu G. , et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 2012; 1: e00049
    CrossrefPubMedGoogle Scholar
  • 14 Ni Y, Lempp FA, Mehrle S. , et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 2014; 146 (04) 1070-1083
    CrossrefPubMedGoogle Scholar
  • 15 Schmitz A, Schwarz A, Foss M. , et al. Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket. PLoS Pathog 2010; 6 (01) e1000741
    CrossrefPubMedGoogle Scholar
  • 16 Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 2015; 64 (12) 1972-1984
    CrossrefPubMedGoogle Scholar
  • 17 Bock CT, Schwinn S, Locarnini S. , et al. Structural organization of the hepatitis B virus minichromosome. J Mol Biol 2001; 307 (01) 183-196
    CrossrefPubMedGoogle Scholar
  • 18 Werle-Lapostolle B, Bowden S, Locarnini S. , et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 2004; 126 (07) 1750-1758
    CrossrefPubMedGoogle Scholar
  • 19 Boyd A, Lacombe K, Lavocat F. , et al. Decay of ccc-DNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients. J Hepatol 2016; 65 (04) 683-691
    CrossrefPubMedGoogle Scholar
  • 20 Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky J-M. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol 2013; 58 (04) 676-683
    CrossrefPubMedGoogle Scholar
  • 21 Wong DK-H, Seto W-K, Fung J. , et al. Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos(t)ide analogues of different potency. Clin Gastroenterol Hepatol 2013; 11 (08) 1004-10.e1
    CrossrefPubMedGoogle Scholar
  • 22 Zhang X, Lu W, Zheng Y. , et al. In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection. J Clin Invest 2016; 126 (03) 1079-1092
    CrossrefPubMedGoogle Scholar
  • 23 Watanabe T, Sorensen EM, Naito A, Schott M, Kim S, Ahlquist P. Involvement of host cellular multivesicular body functions in hepatitis B virus budding. Proc Natl Acad Sci U S A 2007; 104 (24) 10205-10210
    CrossrefPubMedGoogle Scholar
  • 24 Lentz TB, Loeb DD. Roles of the envelope proteins in the amplification of covalently closed circular DNA and completion of synthesis of the plus-strand DNA in hepatitis B virus. J Virol 2011; 85 (22) 11916-11927
    CrossrefPubMedGoogle Scholar
  • 25 Belloni L, Pollicino T, De Nicola F. , et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc Natl Acad Sci U S A 2009; 106 (47) 19975-19979
    CrossrefPubMedGoogle Scholar
  • 26 Lucifora J, Arzberger S, Durantel D. , et al. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. J Hepatol 2011; 55 (05) 996-1003
    CrossrefPubMedGoogle Scholar
  • 27 Rivière L, Gerossier L, Ducroux A. , et al. HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase. J Hepatol 2015; 63 (05) 1093-1102
    CrossrefPubMedGoogle Scholar
  • 28 Benhenda S, Ducroux A, Rivière L. , et al. Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription. J Virol 2013; 87 (08) 4360-4371
    CrossrefPubMedGoogle Scholar
  • 29 Addison WR, Walters K-A, Wong WWS. , et al. Half-life of the duck hepatitis B virus covalently closed circular DNA pool in vivo following inhibition of viral replication. J Virol 2002; 76 (12) 6356-6363
    CrossrefPubMedGoogle Scholar
  • 30 Lutgehetmann M, Volz T, Köpke A. , et al. In vivo proliferation of hepadnavirus-infected hepatocytes induces loss of covalently closed circular DNA in mice. Hepatology 2010; 52 (01) 16-24
    PubMedGoogle Scholar
  • 31 Reaiche-Miller GY, Thorpe M, Low HC. , et al. Duck hepatitis B virus covalently closed circular DNA appears to survive hepatocyte mitosis in the growing liver. Virology 2013; 446 (1-2): 357-364
    CrossrefPubMedGoogle Scholar
  • 32 Dandri M, Petersen J. Hepatitis B virus cccDNA clearance: killing for curing?. Hepatology 2005; 42 (06) 1453-1455
    CrossrefPubMedGoogle Scholar
  • 33 Lucifora J, Xia Y, Reisinger F. , et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 2014; 343 (6176): 1221-1228
    CrossrefPubMedGoogle Scholar
  • 34 Xia Y, Stadler D, Lucifora J. , et al. Interferon-γ and tumor necrosis factor-α produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis. Gastroenterology 2016; 150 (01) 194-205
    CrossrefPubMedGoogle Scholar
  • 35 Newbold JE, Xin H, Tencza M. , et al. The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes. J Virol 1995; 69 (06) 3350-3357
    PubMedGoogle Scholar
  • 36 Bloom K, Ely A, Mussolino C, Cathomen T, Arbuthnot P. Inactivation of hepatitis B virus replication in cultured cells and in vivo with engineered transcription activator-like effector nucleases. Mol Ther 2013; 21 (10) 1889-1897
    CrossrefPubMedGoogle Scholar
  • 37 Kennedy EM, Kornepati AVR, Cullen BR. Targeting hepatitis B virus cccDNA using CRISPR/Cas9. Antiviral Res 2015; 123: 188-192
    CrossrefPubMedGoogle Scholar
  • 38 Seeger C, Sohn JA. Targeting hepatitis B virus with CRISPR/Cas9. Mol Ther Nucleic Acids 2014; 3: e216
    CrossrefPubMedGoogle Scholar
  • 39 Kennedy EM, Bassit LC, Mueller H. , et al. Suppression of hepatitis B virus DNA accumulation in chronically infected cells using a bacterial CRISPR/Cas RNA-guided DNA endonuclease. Virology 2015; 476: 196-205
    CrossrefPubMedGoogle Scholar
  • 40 Ramanan V, Shlomai A, Cox DBT. , et al. CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus. Sci Rep 2015; 5: 10833
    CrossrefPubMedGoogle Scholar
  • 41 Lin S-R, Yang H-C, Kuo Y-T. , et al. The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo. Mol Ther Nucleic Acids 2014; 3: e186
    CrossrefPubMedGoogle Scholar
  • 42 Seeger C, Sohn JA. Complete spectrum of CRISPR/Cas9-induced mutations on HBV cccDNA. Mol Ther 2016; 24 (07) 1258-1266
    CrossrefPubMedGoogle Scholar
  • 43 Pollicino T, Belloni L, Raffa G. , et al. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology 2006; 130 (03) 823-837
    CrossrefPubMedGoogle Scholar
  • 44 Tropberger P, Mercier A, Robinson M, Zhong W, Ganem DE, Holdorf M. Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. Proc Natl Acad Sci U S A 2015; 112 (42) E5715-E5724
    CrossrefPubMedGoogle Scholar
  • 45 Belloni L, Allweiss L, Guerrieri F. , et al. 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 (02) 529-537
    CrossrefPubMedGoogle Scholar
  • 46 Zhang W, Chen J, Wu M. , et al. PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation. Hepatology 2017; 66 (02) 398-415
    PubMedGoogle Scholar
  • 47 Palumbo GA, Belloni L, Valente S. , et al. Silencing HBV transcription by targeting cccDNA-bound chromatin modifiers. Hepatology 2014; 60: 309A-309A
    PubMedGoogle Scholar
  • 48 Gilmore SA, Snyder CA, Dick R. , et al. THU-171 - In vivo pharmacodynamics of GS-5801, a liver targeted prodrug of a lysine demethylase 5 inhibitor with antiviral activity against hepatitis B virus. J Hepatol 2017; 66: S263
    PubMedGoogle Scholar
  • 49 Decorsière A, Mueller H, van Breugel PC. , et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature 2016; 531 (7594): 386-389
    CrossrefPubMedGoogle Scholar
  • 50 Niu C, Livingston CM, Li L. , et al. The Smc5/6 complex restricts HBV when localized to ND10 without inducing an innate immune response and is counteracted by the HBV X protein shortly after infection. PLoS One 2017; 12 (01) e0169648
    CrossrefPubMedGoogle Scholar
  • 51 Li T, Robert EI, van Breugel PC, Strubin M, Zheng N. A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery. Nat Struct Mol Biol 2010; 17 (01) 105-111
    CrossrefPubMedGoogle Scholar
  • 52 Gish RG, Yuen M-F, Chan HLY. , et al. Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent. Antiviral Res 2015; 121: 97-108
    CrossrefPubMedGoogle Scholar
  • 53 Gane E, Schwabe C, Given B. , et al. THU-176 - A phase 1 study to evaluate safety and tolerability of escalating single doses of the hepatitis B virus RNA interference drug ARC-521 in a healthy volunteer population. J Hepatol 2017; 66: S265
    PubMedGoogle Scholar
  • 54 Guo Y-H, Li Y-N, Zhao J-R, Zhang J, Yan Z. HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state. Epigenetics 2011; 6 (06) 720-726
    CrossrefPubMedGoogle Scholar
  • 55 Chong CK, Cheng CYS, Tsoi SYJ. , et al. Role of hepatitis B core protein in HBV transcription and recruitment of histone acetyltransferases to cccDNA minichromosome. Antiviral Res 2017; 144: 1-7
    CrossrefPubMedGoogle Scholar
  • 56 Zlotnick A, Venkatakrishnan B, Tan Z, Lewellyn E, Turner W, Francis S. Core protein: a pleiotropic keystone in the HBV lifecycle. Antiviral Res 2015; 121: 82-93
    CrossrefPubMedGoogle Scholar
  • 57 Belloni L, Li L, Palumbo GA. , et al. HAPs hepatitis B virus (HBV) capsid inhibitors block core protein interaction with the viral minichromosome and host cell genes and affect cccDNA transcription and stability. Hepatology 2013; 58: 277-277
    PubMedGoogle Scholar
  • 58 Liu F, Campagna M, Qi Y. , et al. Alpha-interferon suppresses hepadnavirus transcription by altering epigenetic modification of cccDNA minichromosomes. PLoS Pathog 2013; 9 (09) e1003613
    CrossrefPubMedGoogle Scholar
  • 59 Isorce N, Testoni B, Locatelli M. , et al. Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus. Antiviral Res 2016; 130: 36-45
    CrossrefPubMedGoogle Scholar
  • 60 Isorce N, Lucifora J, Zoulim F, Durantel D. Immune-modulators to combat hepatitis B virus infection: from IFN-α to novel investigational immunotherapeutic strategies. Antiviral Res 2015; 122: 69-81
    CrossrefPubMedGoogle Scholar
  • 61 Palumbo GA, Scisciani C, Pediconi N. , et al. IL6 Inhibits HBV transcription by targeting the epigenetic control of the nuclear cccDNA minichromosome. PLoS One 2015; 10 (11) e0142599
    CrossrefPubMedGoogle Scholar
  • 62 Hong M-H, Chou Y-C, Wu Y-C. , et al. Transforming growth factor-β1 suppresses hepatitis B virus replication by the reduction of hepatocyte nuclear factor-4α expression. PLoS One 2012; 7 (01) e30360
    CrossrefPubMedGoogle Scholar
  • 63 Hösel M, Quasdorff M, Wiegmann K. , et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology 2009; 50 (06) 1773-1782
    CrossrefPubMedGoogle Scholar
  • 64 Lin S-J, Shu P-Y, Chang C, Ng A-K, Hu CP. IL-4 suppresses the expression and the replication of hepatitis B virus in the hepatocellular carcinoma cell line Hep3B. J Immunol 2003; 171 (09) 4708-4716
    CrossrefPubMedGoogle Scholar
  • 65 Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol 2016; 64 (1, Suppl): S71-S83
    CrossrefPubMedGoogle Scholar
  • 66 Maini MK, Gehring AJ. The role of innate immunity in the immunopathology and treatment of HBV infection. J Hepatol 2016; 64 (1, Suppl): S60-S70
    CrossrefPubMedGoogle Scholar
  • 67 Ferrari C. HBV and the immune response. Liver Int 2015; 35 (Suppl. 01) 121-128
    CrossrefPubMedGoogle Scholar
  • 68 Rehermann B, Lau D, Hoofnagle JH, Chisari FV. Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection. J Clin Invest 1996; 97 (07) 1655-1665
    CrossrefPubMedGoogle Scholar
  • 69 Boni C, Laccabue D, Lampertico P. , et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012; 143 (04) 963-73.e9
    CrossrefPubMedGoogle Scholar
  • 70 Boni C, Rossi M, Vecchi A. , et al. PS-050 - Combined GS-4774 and tenofovir therapy can improve HBV-specific T cell responses in patients with chronic active hepatitis B. J Hepatol 2017; 66: S29
    PubMedGoogle Scholar
  • 71 Michler T, Kosinska A, Bunse T. , et al. LBP-538 - Preclinical study of a combinatorial RNAi/vaccination therapy as a potential cure for chronic hepatitis B. J Hepatol 2017; 66: S112
    PubMedGoogle Scholar
  • 72 Lanford RE, Guerra B, Chavez D. , et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 2013; 144 (07) 1508-1517 , 1517.e1–1517.e10
    CrossrefPubMedGoogle Scholar
  • 73 Menne S, Tumas DB, Liu KH. , et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J Hepatol 2015; 62 (06) 1237-1245
    PubMedGoogle Scholar
  • 74 Gane EJ, Lim Y-S, Gordon SC. , et al. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. J Hepatol 2015; 63 (02) 320-328
    CrossrefPubMedGoogle Scholar
  • 75 Qasim W, Brunetto M, Gehring AJ. , et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol 2015; 62 (02) 486-491
    CrossrefPubMedGoogle Scholar
  • 76 Krebs K, Böttinger N, Huang L-R. , et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 2013; 145 (02) 456-465
    CrossrefPubMedGoogle Scholar
  • 77 Wisskirchen K, Kah J, Metzger K. , et al. PS-051 - Hepatitis B virus-specific T cell receptors with high functional avidity redirect T cells to eliminate HBV. J Hepatol 2017; 66: S29-S30
    PubMedGoogle Scholar
  • 78 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
    CrossrefPubMedGoogle Scholar
  • 79 Rehermann B, Bertoletti A. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections. Hepatology 2015; 61 (02) 712-721
    CrossrefPubMedGoogle Scholar
  • 80 Nebbia G, Peppa D, Schurich A. , et al. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS One 2012; 7 (10) e47648
    CrossrefPubMedGoogle Scholar
  • 81 Tzeng H-T, Tsai H-F, Liao H-J. , et al. PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model. PLoS One 2012; 7 (06) e39179
    CrossrefPubMedGoogle Scholar
  • 82 Liu J, Zhang E, Ma Z. , et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog 2014; 10 (01) e1003856
    CrossrefPubMedGoogle Scholar
  • 83 Fisicaro P, Valdatta C, Massari M. , et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 2010; 138 (02) 682-693 , 693.e1–693.e4
    CrossrefPubMedGoogle Scholar
  • 84 Boni C, Fisicaro P, Valdatta C. , et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007; 81 (08) 4215-4225
    CrossrefPubMedGoogle Scholar
  • 85 Schurich A, Khanna P, Lopes AR. , et al. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection. Hepatology 2011; 53 (05) 1494-1503
    CrossrefPubMedGoogle Scholar
  • 86 Fisicaro P, Valdatta C, Massari M. , et al. Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology 2012; 143 (06) 1576-1585.e4
    CrossrefPubMedGoogle Scholar
  • 87 Schurich A, Pallett LJ, Lubowiecki M. , et al. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLoS Pathog 2013; 9 (03) e1003208
    CrossrefPubMedGoogle Scholar
  • 88 Isogawa M, Chung J, Murata Y, Kakimi K, Chisari FV. CD40 activation rescues antiviral CD8+ T cells from PD-1-mediated exhaustion. PLoS Pathog 2013; 9 (07) e1003490
    CrossrefPubMedGoogle Scholar
  • 89 Pauken KE, Sammons MA, Odorizzi PM. , et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016; 354 (6316): 1160-1165
    CrossrefPubMedGoogle Scholar
  • 90 Schurich A, Pallett LJ, Jajbhay D. , et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Reports 2016; 16 (05) 1243-1252
    CrossrefPubMedGoogle Scholar
  • 91 Fisicaro P, Barili V, Montanini B. , et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat Med 2017; 23 (03) 327-336
    CrossrefPubMedGoogle Scholar
  • 92 Vanwolleghem T, Hou J, van Oord G. , et al. Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells. Hepatology 2015; 62 (01) 87-100
    CrossrefPubMedGoogle Scholar
  • 93 Michel M-L, Bourgine M, Fontaine H, Pol S. Therapeutic vaccines in treating chronic hepatitis B: the end of the beginning or the beginning of the end?. Med Microbiol Immunol (Berl) 2015; 204 (01) 121-129
    CrossrefPubMedGoogle Scholar
  • 94 Lok AS, Pan CQ, Han S-HB. , et al. Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B. J Hepatol 2016; 65 (03) 509-516
    CrossrefPubMedGoogle Scholar
  • 95 Martin P, Dubois C, Jacquier E. , et al. TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice. Gut 2015; 64 (12) 1961-1971
    CrossrefPubMedGoogle Scholar
  • 96 Summers J, Jilbert AR, Yang W. , et al. Hepatocyte turnover during resolution of a transient hepadnaviral infection. Proc Natl Acad Sci U S A 2003; 100 (20) 11652-11659
    CrossrefPubMedGoogle Scholar
  • 97 Yang W, Summers J. Integration of hepadnavirus DNA in infected liver: evidence for a linear precursor. J Virol 1999; 73 (12) 9710-9717
    CrossrefPubMedGoogle Scholar
  • 98 Shamay M, Agami R, Shaul Y. HBV integrants of hepatocellular carcinoma cell lines contain an active enhancer. Oncogene 2001; 20 (47) 6811-6819
    CrossrefPubMedGoogle Scholar
  • 99 Takada S, Gotoh Y, Hayashi S, Yoshida M, Koike K. Structural rearrangement of integrated hepatitis B virus DNA as well as cellular flanking DNA is present in chronically infected hepatic tissues. J Virol 1990; 64 (02) 822-828
    PubMedGoogle Scholar
  • 100 Schlüter V, Meyer M, Hofschneider PH, Koshy R, Caselmann WH. Integrated hepatitis B virus X and 3′ truncated preS/S sequences derived from human hepatomas encode functionally active transactivators. Oncogene 1994; 9 (11) 3335-3344
    PubMedGoogle Scholar
  • 101 Tu T, Mason WS, Clouston AD. , et al. Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection. J Viral Hepat 2015; 22 (09) 737-753
    CrossrefPubMedGoogle Scholar
  • 102 Mason WS, Gill US, Litwin S. , et al. HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant. Gastroenterology 2016; 151 (05) 986-998.e4
    CrossrefPubMedGoogle Scholar
  • 103 Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol 2016; 64 (1, Suppl) S84-S101
    CrossrefPubMedGoogle Scholar
  • 104 Sung W-K, Zheng H, Li S. , et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012; 44 (07) 765-769
    CrossrefPubMedGoogle Scholar
  • 105 Zhao L-H, Liu X, Yan H-X. , et al. Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma. Nat Commun 2016; 7: 12992
    CrossrefPubMedGoogle Scholar
  • 106 Jiang Z, Jhunjhunwala S, Liu J. , et al. The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients. Genome Res 2012; 22 (04) 593-601
    CrossrefPubMedGoogle Scholar
  • 107 Coppola N, Onorato L, Iodice V. , et al. Occult HBV infection in HCC and cirrhotic tissue of HBsAg-negative patients: a virological and clinical study. Oncotarget 2016; 7 (38) 62706-62714
    CrossrefPubMedGoogle Scholar
  • 108 Pollicino T, Squadrito G, Cerenzia G. , et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004; 126 (01) 102-110
    CrossrefPubMedGoogle Scholar
  • 109 Xu Z, Chavez D, Guerra B. , et al. Treatment of chronically HBV-infected chimpanzees with RNA interference therapeutic ARC-520 led to potent reduction of viral MRNA, DNA and proteins without observed drug resistance. J Hepatol 2016; 64: S398-S398
    PubMedGoogle Scholar
  • 110 Yuen M-F, Chan HL-Y, Liu SHK. , et al. ARC-520 produces deep and durable knockdown of viral antigens and DNA in a phase II study in patients with chronic hepatitis B. Hepatology 2015; 62: 1385-1385
    PubMedGoogle Scholar
  • 111 Walsh R, Hammond R, Yuen L. , et al. Predicting HBsAG clearance responses during ARC-520 RNA interference (RNAi) therapy based on HBsAG epitope profile analysis. J Hepatol 2016; 64: S602-S602
    PubMedGoogle Scholar
  • 112 Yuen M-F, Liu K, Chan HL. , et al. Prolonged RNA interference therapy with ARC-520 injection in treatment naive, HBeAg positive and negative patients with chronic HBV results in significant reductions of HBs antigen. J Hepatol 2017; 66: S27-S27
    PubMedGoogle Scholar
  • 113 Lebossé F, Testoni B, Fresquet J. , et al. Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B. J Hepatol 2017; 66 (05) 897-909
    CrossrefPubMedGoogle Scholar
  • 114 Wooddell CI, Chavez D, Goetzmann JE. , et al. Reductions in cccDNA under NUC and ARC-520 therapy in chimpanzees with chronic hepatitis B virus infection implicate integrated DNA in maintaining circulating HBsAg. Hepatology 2015; 62: 222A-223A
    CrossrefPubMedGoogle Scholar
  • 115 Thompson AJV, Nguyen T, Iser D. , et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010; 51 (06) 1933-1944
    CrossrefPubMedGoogle Scholar
  • 116 Li M-R, Xi H-L, Wang Q-H. , et al. Kinetics and prediction of HBsAg loss during long-term therapy with nucleos(t)ide analogues of different potency in patients with chronic hepatitis B. PLoS One 2014; 9 (06) e98476
    CrossrefPubMedGoogle Scholar
  • 117 Manesis EK, Papatheodoridis GV, Tiniakos DG. , et al. Hepatitis B surface antigen: relation to hepatitis B replication parameters in HBeAg-negative chronic hepatitis B. J Hepatol 2011; 55 (01) 61-68
    CrossrefPubMedGoogle Scholar
  • 118 van Bömmel F, Bartens A, Mysickova A. , et al. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology 2015; 61 (01) 66-76
    CrossrefPubMedGoogle Scholar
  • 119 Wang J, Shen T, Huang X. , et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol 2016; 65 (04) 700-710
    CrossrefPubMedGoogle Scholar
  • 120 Kimura T, Ohno N, Terada N. , et al. Hepatitis B virus DNA-negative dane particles lack core protein but contain a 22-kDa precore protein without C-terminal arginine-rich domain. J Biol Chem 2005; 280 (23) 21713-21719
    CrossrefPubMedGoogle Scholar
  • 121 Suzuki F, Miyakoshi H, Kobayashi M, Kumada H. Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol 2009; 81 (01) 27-33
    CrossrefPubMedGoogle Scholar
  • 122 Hosaka T, Suzuki F, Kobayashi M. , et al. HBcrAg is a predictor of post-treatment recurrence of hepatocellular carcinoma during antiviral therapy. Liver Int 2010; 30 (10) 1461-1470
    CrossrefPubMedGoogle Scholar
  • 123 Seto W-K, Wong DK-H, Fung J. , et al. Linearized hepatitis B surface antigen and hepatitis B core-related antigen in the natural history of chronic hepatitis B. Clin Microbiol Infect 2014; 20 (11) 1173-1180
    CrossrefPubMedGoogle Scholar
  • 124 Maasoumy B, Wiegand SB, Jaroszewicz J. , et al. Hepatitis B core-related antigen (HBcrAg) levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D. Clin Microbiol Infect 2015; 21 (06) 606.e1-606.e10
    CrossrefPubMedGoogle Scholar
  • 125 Honda M, Shirasaki T, Terashima T. , et al. Hepatitis B virus (HBV) core-related antigen during nucleos(t)ide analog therapy is related to intra-hepatic HBV replication and development of hepatocellular carcinoma. J Infect Dis 2016; 213 (07) 1096-1106
    CrossrefPubMedGoogle Scholar
  • 126 Chuaypen N, Posuwan N, Payungporn S. , et al. Serum hepatitis B core-related antigen as a treatment predictor of pegylated interferon in patients with HBeAg-positive chronic hepatitis B. Liver Int 2016; 36 (06) 827-836
    CrossrefPubMedGoogle Scholar
  • 127 Jung KS, Park JY, Chon YE. , et al. Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients. J Gastroenterol 2016; 51 (08) 830-839
    CrossrefPubMedGoogle Scholar
  • 128 Testoni B, Berby F, Miaglia C. , et al. Hepatitis B core-related antigen correlates with intrahepatic covalently closed circular DNA (cccDNA) levels and activity in untreated chronic hepatitis B (CHB) patients. Hepatology 2016; 64: 58A-59A
    CrossrefPubMedGoogle Scholar