Gastroenterology
Volume 137, Issue 5 , Pages 1593-1608.e2 , November 2009

Hepatitis B Virus Resistance to Nucleos(t)ide Analogues

  • Fabien Zoulim

      Affiliations

    • INSERM, U871, Lyon, France
    • Université Lyon 1, Lyon, France
    • Hospices Civils de Lyon, Service d'hépatologie et de gastroentérologie, Lyon, France
    • Corresponding Author InformationReprint requests Address requests for reprints to: Fabien Zoulim, MD, INSERM UNIT 871, 151 Cours Albert Thomas, 69003 Lyon, France. fax: +33 472 681971
  • ,
  • Stephen Locarnini

      Affiliations

    • Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia

Received 19 June 2009 ,Accepted 28 August 2009.

References 

  1. Summers J, Mason WS. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell. 1982;29:403–415
  2. Dienstag JL. Hepatitis B virus infection. N Engl J Med. 2008;359:1486–1500
  3. Nafa S, Ahmed S, Tavan D, et al. Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B. Hepatology. 2000;32:1078–1088
  4. Yuen MF, Sablon E, Hui CK, et al. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology. 2001;34:785–791
  5. Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687–696
  6. Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125:1714–1722
  7. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124:105–117
  8. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531
  9. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743–1751
  10. Fung SK, Andreone P, Han SH, et al. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol. 2005;43:937–943
  11. Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007;357:2576–2588
  12. Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009;136:486–495
  13. Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008;48:750–758
  14. Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43:1385–1391
  15. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442–2455
  16. Snow-Lampart A, Chappell BJ, Curtis M, et al. Week 96 resistance surveillance for HBeAg-positive and negative subjects with chronic HBV infection randomized to receive Tenofovir DF 300 mg QD. In: 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA. October 31–November 04, 2008;Hepatology. 2008;
  17. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–1514
  18. Tenney DJ, Pokornowski KA, Rose RE, et al. Entecavir maintains a high genetic barrier to HBV resistance through 6 years in naive patients. J Hepatol. 2009;50:S10;Abstract 20
  19. Zoulim F. New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA. J Hepatol. 2005;42:302–308
  20. Zoulim F. Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection. Antiviral Res. 2004;64:1–15
  21. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2000;64:51–68
  22. Kock J, Baumert TF, Delaney WEt, et al. Inhibitory effect of adefovir and lamivudine on the initiation of hepatitis B virus infection in primary tupaia hepatocytes. Hepatology. 2003;38:1410–1418
  23. Delmas J, Schorr O, Jamard C, et al. Inhibitory effect of adefovir on viral DNA synthesis and covalently closed circular DNA formation in duck hepatitis B virus-infected hepatocytes in vivo and in vitro. Antimicrob Agents Chemother. 2002;46:425–433
  24. Zhou T, Saputelli J, Aldrich CE, et al. Emergence of drug-resistant populations of woodchuck hepatitis virus in woodchucks treated with the antiviral nucleoside lamivudine. Antimicrob Agents Chemother. 1999;43:1947–1954
  25. 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;126:1750–1758
  26. Sung JJ, Wong ML, Bowden S, et al. Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy. Gastroenterology. 2005;128:1890–1897
  27. Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon α-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology. 2006;44:675–684
  28. Lutgehetmann M, Volzt T, Quaas A, et al. Sequential combination therapy leads to biochemical and histological improvement despite low ongoing intrahepatic hepatitis B virus replication. Antivir Ther. 2008;13:57–66
  29. Moraleda G, Saputelli J, Aldrich CE, et al. Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus. J Virol. 1997;71:9392–9399
  30. Mason WS, Cullen J, Moraleda G, et al. Lamivudine therapy of WHV-infected woodchucks. Virology. 1998;245:18–32
  31. Le Guerhier F, Pichoud C, Jamard C, et al. Antiviral activity of β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine in woodchucks chronically infected with woodchuck hepatitis virus. Antimicrob Agents Chemother. 2001;45:1065–1077
  32. Le Guerhier F, Pichoud C, Guerret S, et al. Characterization of the antiviral effect of 2′,3′-dideoxy-2′,3′- didehydro-β-L-5-fluorocytidine in the duck hepatitis B virus infection model. Antimicrob Agents Chemother. 2000;44:111–122
  33. Nowak MA, Bonhoeffer S, Hill AM, et al. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci U S A. 1996;93:4398–4402
  34. Lewin SR, Ribeiro RM, Walters T, et al. Analysis of hepatitis B viral load decline under potent therapy: complex decay profiles observed. Hepatology. 2001;34:1012–1020
  35. Pawlotsky JM. The concept of hepatitis B virus mutant escape. J Clin Virol. 2005;34(Suppl 1):S125–S129
  36. Gunther S, Fischer L, Pult I, et al. Naturally occurring variants of hepatitis B virus. Adv Virus Res. 1999;52:25–137
  37. Villet S, Pichoud C, Villeneuve JP, et al. Selection of a multiple drug-resistant hepatitis B virus strain in a liver-transplanted patient. Gastroenterology. 2006;131:1253–1261
  38. Seigneres B, Pichoud C, Ahmed SS, et al. Evolution of hepatitis B virus polymerase gene sequence during famciclovir therapy for chronic hepatitis B. J Infect Dis. 2000;181:1221–1233
  39. Pallier C, Castera L, Soulier A, et al. Dynamics of hepatitis B virus resistance to lamivudine. J Virol. 2006;80:643–653
  40. Pallier C, Rodriguez C, Brillet R, et al. Complex dynamics of hepatitis B virus resistance to adefovir. Hepatology. 2009;49:50–59
  41. Litwin S, Toll E, Jilbert AR, et al. The competing roles of virus replication and hepatocyte death rates in the emergence of drug-resistant mutants: theoretical considerations. J Clin Virol. 2005;34(Suppl 1):S96–S107
  42. Villet S, Billioud G, Pichoud C, et al. In vitro characterization of viral fitness of therapy-resistant hepatitis B variants. Gastroenterology. 2009;136:168–176
  43. Warner N, Locarnini S. The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology. 2008;48:88–98
  44. Kamili S, Sozzi V, Thompson G, et al. Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model. Hepatology. 2009;49:1483–1491
  45. Richman DD. The impact of drug resistance on the effectiveness of chemotherapy for chronic hepatitis B. Hepatology. 2000;32:866–867
  46. Nowak M, Bonhoeffer S, Hill A, et al. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci U S A. 1996;93:4398–4402
  47. Okamoto H, Imai M, Kametani M, et al. Genomic heterogeneity of hepatitis B virus in a 54-year-old woman who contracted the infection through materno-fetal transmission. Jpn J Exp Med. 1987;57:231–236
  48. Girones R, Miller RH. Mutation rate of the hepadnavirus genome. Virology. 1989;170:595–597
  49. Domingo E. Quasispecies and the development of new antiviral strategies. Prog Drug Res. 2003;60:133–158
  50. Richman DD. The implications of drug resistance for strategies of combination antiviral chemotherapy. Antiviral Res. 1996;29:31–33
  51. Durantel D, Carrouee-Durantel S, Werle-Lapostolle B, et al. A new strategy for studying in vitro the drug susceptibility of clinical isolates of human hepatitis B virus. Hepatology. 2004;40:855–864
  52. Zhang YY, Summers J. Low dynamic state of viral competition in a chronic avian hepadnavirus infection. J Virol. 2000;74:5257–5265
  53. Lok AS, Zoulim F, Locarnini S, et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology. 2007;46:254–265
  54. Zoulim F, Poynard T, Degos F, et al. A prospective study of the evolution of lamivudine resistance mutations in patients with chronic hepatitis B treated with lamivudine. J Viral Hepat. 2006;13:278–288
  55. Ghany M, Liang TJ. Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B. Gastroenterology. 2007;132:1574–1585
  56. Stuyver LJ, Locarnini SA, Lok A, et al. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region. Hepatology. 2001;33:751–757
  57. Yeh CT, Chien RN, Chu CM, et al. Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy. Hepatology. 2000;31:1318–1326
  58. Ogata N, Fujii K, Takigawa S, et al. Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudine therapy in japanese patients with chronic hepatitis B. J Med Virol. 1999;59:270–276
  59. Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother. 2004;48:3498–3507
  60. Delaney WEt, Yang H, Westland CE, et al. The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro. J Virol. 2003;77:11833–11841
  61. Shaw T, Bartholomeusz A, Locarnini S. HBV drug resistance: mechanisms, detection and interpretation. J Hepatol. 2006;44:593–606
  62. Villet S, Pichoud C, Billioud G, et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol. 2008;48:747–755
  63. Villet S, Ollivet A, Pichoud C, et al. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol. 2007;46:531–538
  64. Delaney WEt, Locarnini S, Shaw T. Resistance of hepatitis B virus to antiviral drugs: current aspects and directions for future investigation. Antivir Chem Chemother. 2001;12:1–35
  65. Zollner B, Petersen J, Puchhammer-Stockl E, et al. Viral features of lamivudine resistant hepatitis B genotypes A and D. Hepatology. 2004;39:42–50
  66. Angus P, Vaughan R, Xiong S, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology. 2003;125:292–297
  67. Villeneuve JP, Durantel D, Durantel S, et al. Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J Hepatol. 2003;39:1085–1089
  68. Brunelle MN, Jacquard AC, Pichoud C, et al. Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology. 2005;41:1391–1398
  69. Schildgen O, Sirma H, Funk A, et al. Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med. 2006;354:1807–1812
  70. Carrouee-Durantel S, Durantel D, Werle-Lapostolle B, et al. Suboptimal response to adefovir dipivoxil therapy for chronic hepatitis B in nucleoside-naive patients is not due to pre-existing drug-resistant mutants. Antivir Ther. 2008;13:381–388
  71. Curtis M, Zhu Y, Borroto-Esoda K. Hepatitis B virus containing the I233V mutation in the polymerase reverse-transcriptase domain remains sensitive to inhibition by Adefovir. J Infect Dis. 2007;196:1483–1486
  72. Yuen LK, Ayres A, Littlejohn M, et al. SeqHepB: a sequence analysis program and relational database system for chronic hepatitis B. Antiviral Res. 2007;75:64–74
  73. Sheldon J, Camino N, Rodes B, et al. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Antivir Ther. 2005;10:727–734
  74. Delaney WEt, Ray AS, Yang H, et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother. 2006;50:2471–2477
  75. Van Bommel F, deMann RA, Wedemeyer H, et al. Efficacy of Tenofovir DF for the treatment of adefovir resistance. Hepatology. 2009;In press
  76. Angus P, Locarnini S. Lamivudine-resistant hepatitis B virus and ongoing lamivudine therapy: stop the merry-go-round, it's time to get off!. Antivir Ther. 2004;9:145–148
  77. Ono-Nita SK, Kato N, Shiratori Y, et al. Novel nucleoside analogue MCC-478 (LY582563) is effective against wild-type or lamivudine-resistant hepatitis B virus. Antimicrob Agents Chemother. 2002;46:2602–2605
  78. Levine S, Hernandez D, Yamanaka G, et al. Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro. Antimicrob Agents Chemother. 2002;46:2525–2532
  79. Chin R, Shaw T, Torresi J, et al. In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (−)-β-D-2,6-diaminopurine dioxolane and 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil. Antimicrob Agents Chemother. 2001;45:2495–2501
  80. Yuen L, Bartholomeusz A, Ayres A, et al. Multidrug resistance and cross-resistance pathways in HBV as a consequence of treatment failure. In 58th Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA, November 02–06 Hepatology. 2007;
  81. Yim HJ, Hussain M, Liu Y, et al. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology. 2006;44:703–712
  82. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med. 2004;350:1023–1035
  83. Lok AS, Zoulim F, Locarnini S, et al. Monitoring drug resistance in chronic hepatitis B virus (HBV)-infected patients during lamivudine therapy: evaluation of performance of INNO-LiPA HBV DR assay. J Clin Microbiol. 2002;40:3729–3734
  84. Margeridon-Thermet S, Shulman NS, Ahmed A, et al. Ultra-deep pyrosequencing of hepatitis B virus quasispecies from nucleoside and nucleotide reverse-transcriptase inhibitor (NRTI)-treated patients and NRTI-naive patients. J Infect Dis. 2009;199:1275–1285
  85. Solmone M, Vincenti D, Prosperi MC, et al. Use of massively parallel ultradeep pyrosequencing to characterize the genetic diversity of hepatitis B virus in drug-resistant and drug-naive patients and to detect minor variants in reverse transcriptase and hepatitis B S antigen. J Virol. 2009;83:1718–1726
  86. Kim HS, Han KH, Ahn SH, et al. Evaluation of methods for monitoring drug resistance in chronic hepatitis B patients during lamivudine therapy based on mass spectrometry and reverse hybridization. Antivir Ther. 2005;10:441–449
  87. Stuyver L, Van Geyt C, De Gendt S, et al. Line probe assay for monitoring drug resistance in hepatitis B virus-infected patients during antiviral therapy. J Clin Microbiol. 2000;38:702–707
  88. Hussain M, Fung S, Libbrecht E, et al. Sensitive line probe assay that simultaneously detects mutations conveying resistance to lamivudine and adefovir. J Clin Microbiol. 2006;44:1094–1097
  89. Tran N, Berne R, Chann R, et al. European multicenter evaluation of high-density DNA probe arrays for detection of hepatitis B virus resistance mutations and identification of genotypes. J Clin Microbiol. 2006;44:2792–2800
  90. Jang H, Cho M, Heo J, et al. Oligonucleotide chip for detection of Lamivudine-resistant hepatitis B virus. J Clin Microbiol. 2004;42:4181–4188
  91. Zoulim F. In vitro models for studying hepatitis B virus drug resistance. Semin Liver Dis. 2006;26:171–180
  92. Fournier C, Zoulim F. Antiviral therapy of chronic hepatitis B: prevention of drug resistance. Clin Liver Dis. 2007;11:869–892
  93. Locarnini S, Hatzakis A, Heathcote J, et al. Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther. 2004;9:679–693
  94. Pawlotsky JM, Dusheiko G, Hatzakis A, et al. Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach. Gastroenterology. 2008;134:405–415
  95. Zoulim F, Perrillo R. Hepatitis B: reflections on the current approach to antiviral therapy. J Hepatol. 2008;48(Suppl 1):S2–S19
  96. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227–242
  97. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010
  98. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–1020
  99. Keeffe EB, Zeuzem S, Koff RS, et al. Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol. 2007;5:890–897
  100. Chan HL, Heathcote EJ, Marcellin P, et al. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann Intern Med. 2007;147:745–754
  101. Lampertico P, Vigano M, Manenti E, et al. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 Lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445–1451
  102. Sung JJ, Lai JY, Zeuzem S, et al. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol. 2008;48:728–735
  103. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206–1217
  104. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682–2695
  105. Thibault V, Aubron-Olivier C, Agut H, et al. Primary infection with a lamivudine-resistant hepatitis B virus. Aids. 2002;16:131–133
  106. Torresi J, Earnest-Silveira L, Deliyannis G, et al. Reduced antigenicity of the hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by lamivudine therapy. Virology. 2002;293:305–313
  107. Sloan RD, Ijaz S, Moore PL, et al. Antiviral resistance mutations potentiate hepatitis B virus immune evasion through disruption of its surface antigen a determinant. Antivir Ther. 2008;13:439–447
  108. Bartholomew MM, Jansen RW, Jeffers LJ, et al. Hepatitis B virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet. 1997;349:20–22
  109. Gripon P, Rumin S, Urban S, et al. Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci U S A. 2002;99:15655–15660
  110. Clements J, Coghlan B, Creati M, et al. Global control of hepatitis B infection: does the potential for antigenic change of the virus in the face of antiviral treatment affect the global hepatitis B immunization programme?. Bull WHO. 2009;In press
  111. Gripon P, Cannie I, Urban S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol. 2005;79:1613–1622
  112. Petersen J, Dandri M, Mier W, et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol. 2008;26:335–341
  113. 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;130:823–837
  114. King RW, Ladner SK, Miller TJ, et al. Inhibition of human hepatitis B virus replication by AT-61, a phenylpropenamide derivative, alone and in combination with (−)b-L-2′,3′-dideoxy-3′-thiacytidine. Antimicrob Agents Chemother. 1998;42:3179–3186
  115. Delaney WEt, Edwards R, Colledge D, et al. Phenylpropenamide derivatives AT-61 and AT-130 inhibit replication of wild-type and lamivudine-resistant strains of hepatitis B virus in vitro. Antimicrob Agents Chemother. 2002;46:3057–3060
  116. Weber O, Schlemmer KH, Hartmann E, et al. Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Antiviral Res. 2002;54:69–78
  117. Deres K, Schroder CH, Paessens A, et al. Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids. Science. 2003;299:893–896
  118. Lazar C, Durantel D, Macovei A, et al. Treatment of hepatitis B virus-infected cells with α-glucosidase inhibitors results in production of virions with altered molecular composition and infectivity. Antiviral Res. 2007;76:30–37
  119. Block TM, Lu X, Mehta AS, et al. Treatment of chronic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking. Nat Med. 1998;4:610–614
  120. Thompson AJ, Colledge D, Rodgers S, et al. Stimulation of the interleukin-1 receptor and Toll-like receptor 2 inhibits hepatitis B virus replication in hepatoma cell lines in vitro. Antiviral Therapy. 2009;14:In press
  121. Lucifora J, Durantel D, Testoni B, et al. Control of hepatitis B virus replication by innate response of HepaRG cells. Hepatology. 2009;In press
  122. Vincent IE, Lucifora J, Durantel D, et al. Inhibitory effect of the combination of CpG-induced cytokines with lamivudine against hepatitis B virus replication in vitro. Antivir Ther. 2009;14:131–135
  123. Das A, Hoare M, Davies N, et al. Functional skewing of the global CD8 T-cell population in chronic hepatitis B virus infection. J Exp Med. 2008;205:2111–2124
  124. Lopes AR, Kellam P, Das A, et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J Clin Invest. 2008;118:1835–1845
  125. Dunn C, Brunetto M, Reynolds G, et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med. 2007;204:667–680

 Conflicts of interest The authors disclose the following: F.Z. has received consulting and speaker honoraria from Gilead Sc, Bristol Myers Squibb, Novartis, and Roche and has received research support from Gilead Sc and Roche. S.L. has received consulting and speaking honoraria from Gilead Sciences, Bristol-Myers Squibb, Roche Pharmaceuticals, Abbott Diagnostic, and Evivar Medical Pty Ltd.

 Funding Supported by the European Community (ViRgil network of excellence; ViRgil LSHM-CT-2004-503359; to F.Z.) and grants from the National Agency for Research against AIDS and Hepatitis (ANRS; to F.Z.) and funding from the US National Institutes of Health (RO1 AIO60449 and RO1 AI071820; to S.L.).

PII: S0016-5085(09)01556-X

doi: 10.1053/j.gastro.2009.08.063

Gastroenterology
Volume 137, Issue 5 , Pages 1593-1608.e2 , November 2009