1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Virology
  4. Volume 8, 2021
  5. Article

Annual Review of Virology

Volume 8, 2021

Prospects for the Global Elimination of Hepatitis B

Abstract

Chronic hepatitis B virus (HBV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, estimated to be globally responsible for ∼800,000 deaths annually. Although effective vaccines are available to prevent new HBV infection, treatment of existing chronic hepatitis B (CHB) is limited, as the current standard-of-care antiviral drugs can only suppress viral replication without achieving cure. In 2016, the World Health Organization called for the elimination of viral hepatitis as a global public health threat by 2030. The United States and other nations are working to meet this ambitious goal by developing strategies to cure CHB, as well as prevent HBV transmission. This review considers recent research progress in understanding HBV pathobiology and development of therapeutics for the cure of CHB, which is necessary for elimination of hepatitis B by 2030.

Keyword(s): chronic hepatitis B, direct-acting antivirals, functional cure, hepatitis B virus, immunotherapy
Loading

Article metrics loading...

/content/journals/10.1146/annurev-virology-091919-062728
2021-09-29
2024-05-14
Loading full text...

Full text loading...

/deliver/fulltext/virology/8/1/annurev-virology-091919-062728.html?itemId=/content/journals/10.1146/annurev-virology-091919-062728&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    WHO (World Health Organ.) 2017. Global Hepatitis Report, 2017 Geneva: WHO
  2. 2. 
    Liang TJ, Block TM, McMahon BJ, Ghany MG, Urban S et al. 2015. Present and future therapies of hepatitis B: from discovery to cure. Hepatology 62:1893–908
     [Google Scholar]
  3. 3. 
    Thiele M, Gluud LL, Dahl EK, Krag A. 2013. Antiviral therapy for prevention of hepatocellular carcinoma and mortality in chronic hepatitis B: systematic review and meta-analysis. BMJ Open 3:e003265
     [Google Scholar]
  4. 4. 
    Gordon SC, Lamerato LE, Rupp LB, Li J, Holmberg SD et al. 2014. Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population. Clin. Gastroenterol. Hepatol. 12:885–93
     [Google Scholar]
  5. 5. 
    Papatheodoridis GV, Idilman R, Dalekos GN, Buti M, Chi H et al. 2017. The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. Hepatology 66:1444–53
     [Google Scholar]
  6. 6. 
    Liem KS, Fung S, Wong DK, Yim C, Noureldin S et al. 2019. Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study). Gut 68:2206–13
     [Google Scholar]
  7. 7. 
    Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. 2018. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology 68:425–34
     [Google Scholar]
  8. 8. 
    Block TM, Gish R, Guo H, Mehta A, Cuconati A et al. 2013. Chronic hepatitis B: What should be the goal for new therapies?. Antivir. Res. 98:27–34
     [Google Scholar]
  9. 9. 
    Cox AL, El-Sayed MH, Kao JH, Lazarus JV, Lemoine M et al. 2020. Progress towards elimination goals for viral hepatitis. Nat. Rev. Gastroenterol. Hepatol. 17:533–42
     [Google Scholar]
  10. 10. 
    Thomas DL. 2019. Global elimination of chronic hepatitis. N. Engl. J. Med. 380:2041–50
     [Google Scholar]
  11. 11. 
    Seeger C, Mason WS. 2015. Molecular biology of hepatitis B virus infection. Virology 479–480 672–86
     [Google Scholar]
  12. 12. 
    Yan H, Zhong G, Xu G, He W, Jing Z et al. 2012. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1:e00049
     [Google Scholar]
  13. 13. 
    Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C et al. 2014. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146:1070–83
     [Google Scholar]
  14. 14. 
    Iwamoto M, Saso W, Sugiyama R, Ishii K, Ohki M et al. 2019. Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization. PNAS 116:8487–92
     [Google Scholar]
  15. 15. 
    Guo JT, Guo H. 2015. Metabolism and function of hepatitis B virus cccDNA: implications for the development of cccDNA-targeting antiviral therapeutics. Antivir. Res. 122:91–100
     [Google Scholar]
  16. 16. 
    Decorsiere A, Mueller H, van Breugel PC, Abdul F, Gerossier L et al. 2016. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature 531:386–89
     [Google Scholar]
  17. 17. 
    Summers J, Mason WS. 1982. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 29:403–15
     [Google Scholar]
  18. 18. 
    Wang GH, Seeger C. 1993. Novel mechanism for reverse transcription in hepatitis B viruses. J. Virol. 67:6507–12
     [Google Scholar]
  19. 19. 
    Ning X, Nguyen D, Mentzer L, Adams C, Lee H et al. 2011. Secretion of genome-free hepatitis B virus–single strand blocking model for virion morphogenesis of para-retrovirus. PLOS Pathog 7:e1002255
     [Google Scholar]
  20. 20. 
    Zhao Q, Hu Z, Cheng J, Wu S, Luo Y et al. 2018. Hepatitis B virus core protein dephosphorylation occurs during pregenomic RNA encapsidation. J. Virol. 92:e02139-17
     [Google Scholar]
  21. 21. 
    Hu Z, Ban H, Zheng H, Liu M, Chang J, Guo JT 2020. Protein phosphatase 1 catalyzes HBV core protein dephosphorylation and is co-packaged with viral pregenomic RNA into nucleocapsids. PLOS Pathog 16:e1008669
     [Google Scholar]
  22. 22. 
    Mason WS, Aldrich C, Summers J, Taylor JM 1982. Asymmetric replication of duck hepatitis B virus DNA in liver cells: free minus-strand DNA. PNAS 79:3997–4001
     [Google Scholar]
  23. 23. 
    Tuttleman JS, Pourcel C, Summers J. 1986. Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 47:451–60
     [Google Scholar]
  24. 24. 
    Liu Y, Liu H, Hu Z, Ding Y, Pan XB et al. 2020. Hepatitis B virus virions produced under nucleos(t)ide analogue treatment are mainly not infectious because of irreversible DNA chain termination. Hepatology 71:463–76
     [Google Scholar]
  25. 25. 
    Wei L, Ploss A. 2020. Core components of DNA lagging strand synthesis machinery are essential for hepatitis B virus cccDNA formation. Nat. Microbiol. 5:5715–26
     [Google Scholar]
  26. 26. 
    Kitamura K, Que L, Shimadu M, Koura M, Ishihara Y et al. 2018. Flap endonuclease 1 is involved in cccDNA formation in the hepatitis B virus. PLOS Pathog 14:e1007124
     [Google Scholar]
  27. 27. 
    Qi Y, Gao Z, Xu G, Peng B, Liu C et al. 2016. DNA polymerase κ is a key cellular factor for the formation of covalently closed circular DNA of hepatitis B virus. PLOS Pathog. 12:e1005893
     [Google Scholar]
  28. 28. 
    Sheraz M, Cheng J, Tang L, Chang J, Guo JT 2019. Cellular DNA topoisomerases are required for the synthesis of hepatitis B virus covalently closed circular DNA. J. Virol. 93:e02230-18
     [Google Scholar]
  29. 29. 
    Tang L, Sheraz M, McGrane M, Chang J, Guo JT 2019. DNA polymerase alpha is essential for intracellular amplification of hepatitis B virus covalently closed circular DNA. PLOS Pathog 15:e1007742
     [Google Scholar]
  30. 30. 
    Long Q, Yan R, Hu J, Cai D, Mitra B et al. 2017. The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation. PLOS Pathog 13:e1006784
     [Google Scholar]
  31. 31. 
    Koniger C, Wingert I, Marsmann M, Rosler C, Beck J, Nassal M 2014. Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses. PNAS 111:E4244–53
     [Google Scholar]
  32. 32. 
    Luo J, Luckenbaugh L, Hu H, Yan Z, Gao L, Hu J. 2020. Involvement of host ATR-CHK1 pathway in hepatitis B virus covalently closed circular DNA formation. mBio 11:e03423-19
     [Google Scholar]
  33. 33. 
    Staprans S, Loeb DD, Ganem D. 1991. Mutations affecting hepadnavirus plus-strand DNA synthesis dissociate primer cleavage from translocation and reveal the origin of linear viral DNA. J. Virol. 65:1255–62
     [Google Scholar]
  34. 34. 
    Guo H, Xu C, Zhou T, Block TM, Guo JT. 2012. Characterization of the host factors required for hepadnavirus covalently closed circular (ccc) DNA formation. PLOS ONE 7:e43270
     [Google Scholar]
  35. 35. 
    Yang W, Summers J. 1999. Integration of hepadnavirus DNA in infected liver: evidence for a linear precursor. J. Virol. 73:9710–17
     [Google Scholar]
  36. 36. 
    Wang J, Zindy F, Chenivesse X, Lamas E, Henglein B, Brechot C. 1992. Modification of cyclin A expression by hepatitis B virus DNA integration in a hepatocellular carcinoma. Oncogene 7:1653–56
     [Google Scholar]
  37. 37. 
    Wooddell CI, Yuen MF, Chan HL, Gish RG, Locarnini SA et al. 2017. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci. Transl. Med. 9:eaan0241
     [Google Scholar]
  38. 38. 
    Gish RG, Given BD, Lai CL, Locarnini SA, Lau JY et al. 2015. Chronic hepatitis B: virology, natural history, current management and a glimpse at future opportunities. Antivir. Res. 121:47–58
     [Google Scholar]
  39. 39. 
    Chang J, Guo JT, Du Y, Block T. 2013. Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents. Emerg. Microbes Infect. 2:e77
     [Google Scholar]
  40. 40. 
    Chang J, Guo JT. 2015. Treatment of chronic hepatitis B with pattern recognition receptor agonists: current status and potential for a cure. Antivir. Res. 121:152–59
     [Google Scholar]
  41. 41. 
    Cheng X, Xia Y, Serti E, Block PD, Chung M et al. 2017. Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages. Hepatology 66:1779–93
     [Google Scholar]
  42. 42. 
    Mutz P, Metz P, Lempp FA, Bender S, Qu B et al. 2018. HBV bypasses the innate immune response and does not protect HCV from antiviral activity of interferon. Gastroenterology 154:1791–1804.e22
     [Google Scholar]
  43. 43. 
    Lauterbach-Riviere L, Bergez M, Monch S, Qu B, Riess M et al. 2020. Hepatitis B virus DNA is a substrate for the cGAS/STING pathway but is not sensed in infected hepatocytes. Viruses 12:592
     [Google Scholar]
  44. 44. 
    Sato S, Li K, Kameyama T, Hayashi T, Ishida Y et al. 2015. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 42:123–32
     [Google Scholar]
  45. 45. 
    Shlomai A, Schwartz RE, Ramanan V, Bhatta A, de Jong YP et al. 2014. Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems. PNAS 111:12193–98
     [Google Scholar]
  46. 46. 
    Fisicaro P, Valdatta C, Boni C, Massari M, Mori C et al. 2009. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut 58:974–82
     [Google Scholar]
  47. 47. 
    Chang KM. 2010. Hepatitis B immunology for clinicians. Clin. Liver Dis. 14:409–24
     [Google Scholar]
  48. 48. 
    Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. 2007. Management of hepatitis B: summary of a clinical research workshop. Hepatology 45:1056–75
     [Google Scholar]
  49. 49. 
    Rehermann B, Nascimbeni M. 2005. Immunology of hepatitis B virus and hepatitis C virus infection. Nat. Rev. Immunol. 5:215–29
     [Google Scholar]
  50. 50. 
    Milich DR, McLachlan A, Thornton GB, Hughes JL. 1987. Antibody production to the nucleocapsid and envelope of the hepatitis B virus primed by a single synthetic T cell site. Nature 329:547–49
     [Google Scholar]
  51. 51. 
    Hwang JP, Barbo AG, Perrillo RP. 2015. Hepatitis B reactivation during cancer chemotherapy: an international survey of the membership of the American Association for the Study of Liver Diseases. J. Viral Hepat. 22:346–52
     [Google Scholar]
  52. 52. 
    Tsutsumi Y, Yamamoto Y, Ito S, Ohigashi H, Shiratori S et al. 2015. Hepatitis B virus reactivation with a rituximab-containing regimen. World J. Hepatol. 7:2344–51
     [Google Scholar]
  53. 53. 
    Farci P, Diaz G, Chen Z, Govindarajan S, Tice A et al. 2010. B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus-associated acute liver failure. PNAS 107:8766–71
     [Google Scholar]
  54. 54. 
    Das A, Ellis G, Pallant C, Lopes AR, Khanna P et al. 2012. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J. Immunol. 189:3925–35
     [Google Scholar]
  55. 55. 
    Salimzadeh L, Le Bert N, Dutertre CA, Gill US, Newell EW et al. 2018. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J. Clin. Invest. 128:4573–87
     [Google Scholar]
  56. 56. 
    Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE et al. 2018. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J. Clin. Invest. 128:4588–603
     [Google Scholar]
  57. 57. 
    Rehermann B. 2013. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat. Med. 19:859–68
     [Google Scholar]
  58. 58. 
    Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. 1996. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T–lymphocyte response. Nat. Med. 2:1104–8
     [Google Scholar]
  59. 59. 
    Moriyama T, Guilhot S, Klopchin K, Moss B, Pinkert CA et al. 1990. Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. Science 248:361–64
     [Google Scholar]
  60. 60. 
    Ando K, Moriyama T, Guidotti LG, Wirth S, Schreiber RD et al. 1993. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J. Exp. Med. 178:1541–54
     [Google Scholar]
  61. 61. 
    Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV 1999. Viral clearance without destruction of infected cells during acute HBV infection. Science 284:825–29
     [Google Scholar]
  62. 62. 
    Guidotti LG, Chisari FV. 2006. Immunobiology and pathogenesis of viral hepatitis. Annu. Rev. Pathol. Mech. Dis. 1:23–61
     [Google Scholar]
  63. 63. 
    Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE et al. 2009. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J. Virol. 83:9652–62
     [Google Scholar]
  64. 64. 
    Park JJ, Wong DK, Wahed AS, Lee WM, Feld JJ et al. 2016. Hepatitis B virus-specific and global T-cell dysfunction in chronic hepatitis B. Gastroenterology 150:684–95.e5
     [Google Scholar]
  65. 65. 
    Milich D, Liang TJ. 2003. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 38:1075–86
     [Google Scholar]
  66. 66. 
    Boni C, Laccabue D, Lampertico P, Giuberti T, Vigano M et al. 2012. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 143:963–73.e9
     [Google Scholar]
  67. 67. 
    Lopes AR, Kellam P, Das A, Dunn C, Kwan A et al. 2008. Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection. J. Clin. Invest. 118:1835–45
     [Google Scholar]
  68. 68. 
    Stoop JN, van der Molen RG, Kuipers EJ, Kusters JG, Janssen HL. 2007. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B. Virology 361:141–48
     [Google Scholar]
  69. 69. 
    Franzese O, Kennedy PT, Gehring AJ, Gotto J, Williams R et al. 2005. Modulation of the CD8+-T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection. J. Virol. 79:3322–28
     [Google Scholar]
  70. 70. 
    Das A, Hoare M, Davies N, Lopes AR, Dunn C et al. 2008. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205:2111–24
     [Google Scholar]
  71. 71. 
    Sandalova E, Laccabue D, Boni C, Watanabe T, Tan A et al. 2012. Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells. Gastroenterology 143:78–87.e3
     [Google Scholar]
  72. 72. 
    Boni C, Bertoletti A, Penna A, Cavalli A, Pilli M et al. 1998. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J. Clin. Invest. 102:968–75
     [Google Scholar]
  73. 73. 
    Chang KM, Traum D, Park JJ, Ho S, Ojiro K et al. 2019. Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT-cells in acute and chronic hepatitis B. PLOS Pathog 15:e1007715
     [Google Scholar]
  74. 74. 
    Champion CR. 2021. Heplisav-B: a hepatitis B vaccine with a novel adjuvant. Ann. Pharmacother. 55:783–91
     [Google Scholar]
  75. 75. 
    Hu J, Cheng J, Tang L, Hu Z, Luo Y et al. 2018. Virological basis for the cure of chronic hepatitis B. ACS Infect. Dis. 5:659–74
     [Google Scholar]
  76. 76. 
    Shi Y, Zheng M. 2020. Hepatitis B virus persistence and reactivation. BMJ 370:m2200
     [Google Scholar]
  77. 77. 
    Cornberg M, Tacke F, Karlsen TH. 2019. Clinical Practice Guidelines of the European Association for the Study of the Liver—advancing methodology but preserving practicability. J. Hepatol. 70:5–7
     [Google Scholar]
  78. 78. 
    Seeger C, Sohn JA. 2016. Complete spectrum of CRISPR/Cas9-induced mutations on HBV cccDNA. Mol. Ther. 24:1258–66
     [Google Scholar]
  79. 79. 
    Yin W, Rogge M. 2019. Targeting RNA: a transformative therapeutic strategy. Clin. Transl. Sci. 12:98–112
     [Google Scholar]
  80. 80. 
    van den Berg F, Limani SW, Mnyandu N, Maepa MB, Ely A, Arbuthnot P. 2020. Advances with RNAi-based therapy for hepatitis B virus infection. Viruses 12:851
     [Google Scholar]
  81. 81. 
    Billioud G, Kruse RL, Carrillo M, Whitten-Bauer C, Gao D et al. 2016. In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides. J. Hepatol. 64:781–89
     [Google Scholar]
  82. 82. 
    Han K, Cremer J, Elston R, Oliver S, Baptiste-Brown S et al. 2019. A randomized, double-blind, placebo-controlled, first-time-in-human study to assess the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of GSK3389404 in healthy subjects. Clin. Pharmacol. Drug Dev. 8:790–801
     [Google Scholar]
  83. 83. 
    Han X, Zhou C, Jiang M, Wang Y, Wang J et al. 2018. Discovery of RG7834: the first-in-class selective and orally available small molecule hepatitis B virus expression inhibitor with novel mechanism of action. J. Med. Chem. 61:10619–34
     [Google Scholar]
  84. 84. 
    Zhou T, Block T, Liu F, Kondratowicz AS, Sun L et al. 2018. HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends on the HBV posttranscriptional regulatory element. Antivir. Res. 149:191–201
     [Google Scholar]
  85. 85. 
    Mueller H, Lopez A, Tropberger P, Wildum S, Schmaler J et al. 2019. PAPD5/7 are host factors that are required for hepatitis B virus RNA stabilization. Hepatology 69:1398–411
     [Google Scholar]
  86. 86. 
    Kim D, Lee YS, Jung SJ, Yeo J, Seo JJ et al. 2020. Viral hijacking of the TENT4-ZCCHC14 complex protects viral RNAs via mixed tailing. Nat. Struct. Mol. Biol. 27:581–88
     [Google Scholar]
  87. 87. 
    Hyrina A, Jones C, Chen D, Clarkson S, Cochran N et al. 2019. A genome-wide CRISPR screen identifies ZCCHC14 as a host factor required for hepatitis B surface antigen production. Cell Rep 29:2970–8.e6
     [Google Scholar]
  88. 88. 
    Sun L, Zhang F, Guo F, Liu F, Kulsuptrakul J et al. 2020. The dihydroquinolizinone compound RG7834 inhibits the polyadenylase function of PAPD5 and PAPD7 and accelerates the degradation of matured hepatitis B virus surface protein mRNA. Antimicrob. Agents Chemother. 65:e00640-20
     [Google Scholar]
  89. 89. 
    Menne S, Wildum S, Steiner G, Suresh M, Korolowicz K et al. 2020. Efficacy of an inhibitor of hepatitis B virus expression in combination with entecavir and interferon-α in woodchucks chronically infected with woodchuck hepatitis virus. Hepatol. Commun. 4:916–31
     [Google Scholar]
  90. 90. 
    Long KR, Lomonosova E, Li Q, Ponzar NL, Villa JA et al. 2018. Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice. Antivir. Res. 149:41–47
     [Google Scholar]
  91. 91. 
    Tavis JE, Lomonosova E. 2015. The hepatitis B virus ribonuclease H as a drug target. Antivir. Res. 118:132–38
     [Google Scholar]
  92. 92. 
    Viswanathan U, Mani N, Hu Z, Ban H, Du Y et al. 2020. Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B. Antivir. Res. 182:104917
     [Google Scholar]
  93. 93. 
    Guo F, Zhao Q, Sheraz M, Cheng J, Qi Y et al. 2017. HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways. PLOS Pathog 13:e1006658
     [Google Scholar]
  94. 94. 
    Ko C, Bester R, Zhou X, Xu Z, Blossey C et al. 2019. A new role for capsid assembly modulators to target mature hepatitis B virus capsids and prevent virus infection. Antimicrob. Agents Chemother. 64:e01440-19
     [Google Scholar]
  95. 95. 
    Berke JM, Dehertogh P, Vergauwen K, Mostmans W, Vandyck K et al. 2020. Antiviral properties and mechanism of action studies of the hepatitis B virus capsid assembly modulator JNJ-56136379. Antimicrob. Agents Chemother. 64:e02439-19
     [Google Scholar]
  96. 96. 
    Sulkowski MS, Agarwal K, Fung S, Yuen MF, Ma X et al. 2019. Continued therapy with ABI-H0731 + NrtI results in sequential reduction/loss of HBV DNA, HBV RNA, HBeAg, HBcrAg and HBsAg in HBeAg-positive patients. Hepatology 70:61487A
     [Google Scholar]
  97. 97. 
    Petersen J, Dandri M, Mier W, Lutgehetmann M, Volz T et al. 2008. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat. Biotechnol. 26:335–41
     [Google Scholar]
  98. 98. 
    Urban S, Bartenschlager R, Kubitz R, Zoulim F. 2014. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 147:48–64
     [Google Scholar]
  99. 99. 
    Liu Y, Ruan H, Li Y, Sun G, Liu X et al. 2020. Potent and specific inhibition of NTCP-mediated HBV/HDV infection and substrate transporting by a novel, oral-available cyclosporine A analogue. J. Med. Chem. 64:543–65
     [Google Scholar]
  100. 100. 
    Blank A, Markert C, Hohmann N, Carls A, Mikus G et al. 2016. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J. Hepatol. 65:483–89
     [Google Scholar]
  101. 101. 
    Isogawa M, Furuichi Y, Chisari FV. 2005. Oscillating CD8+ T cell effector functions after antigen recognition in the liver. Immunity 23:53–63
     [Google Scholar]
  102. 102. 
    Bazinet M, Pantea V, Placinta G, Moscalu I, Cebotarescu V et al. 2020. Safety and efficacy of 48 weeks REP 2139 or REP 2165, tenofovir disoproxil, and pegylated interferon alfa-2a in patients with chronic HBV infection naive to nucleos(t)ide therapy. Gastroenterology 158:2180–94
     [Google Scholar]
  103. 103. 
    Vaillant A. 2016. Nucleic acid polymers: broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection. Antivir. Res. 133:32–40
     [Google Scholar]
  104. 104. 
    Boulon R, Blanchet M, Lemasson M, Vaillant A, Labonte P. 2020. Characterization of the antiviral effects of REP 2139 on the HBV lifecycle in vitro. Antivir. Res. 183:104853
     [Google Scholar]
  105. 105. 
    Blanchet M, Sinnathamby V, Vaillant A, Labonte P. 2019. Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells. Antivir. Res. 164:97–105
     [Google Scholar]
  106. 106. 
    Hamid O, Robert C, Daud A, Hodi FS, Hwu W-J et al. 2013. Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N. Engl. J. Med. 369:134–44
     [Google Scholar]
  107. 107. 
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC et al. 2012. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N. Engl. J. Med. 366:2443–54
     [Google Scholar]
  108. 108. 
    Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE et al. 2015. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–77
     [Google Scholar]
  109. 109. 
    Maini MK, Pallett LJ. 2018. Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand. Lancet Gastroenterol. Hepatol. 3:192–202
     [Google Scholar]
  110. 110. 
    Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M et al. 2001. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology 33:963–71
     [Google Scholar]
  111. 111. 
    Boni C, Penna A, Bertoletti A, Lamonaca V, Rapti I et al. 2003. Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. J. Hepatol. 39:595–605
     [Google Scholar]
  112. 112. 
    Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E et al. 2010. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 138:682–93
     [Google Scholar]
  113. 113. 
    Liu J, Zhang E, Ma Z, Wu W, Kosinska A et al. 2014. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLOS Pathog 10:e1003856
     [Google Scholar]
  114. 114. 
    Yau T, Hsu C, Kim TY, Choo SP, Kang YK et al. 2019. Nivolumab in advanced hepatocellular carcinoma: sorafenib-experienced Asian cohort analysis. J. Hepatol. 71:543–52
     [Google Scholar]
  115. 115. 
    El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M et al. 2017. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389:2492–502
     [Google Scholar]
  116. 116. 
    Gane E, Verdon DJ, Brooks AE, Gaggar A, Nguyen AH et al. 2019. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J. Hepatol. 71:900–7
     [Google Scholar]
  117. 117. 
    Knolle PA, Thimme R. 2014. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 146:1193–207
     [Google Scholar]
  118. 118. 
    Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T. 2003. PD-1 inhibits antiviral immunity at the effector phase in the liver. J. Exp. Med. 198:39–50
     [Google Scholar]
  119. 119. 
    Kido M, Watanabe N, Okazaki T, Akamatsu T, Tanaka J et al. 2008. Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology 135:1333–43
     [Google Scholar]
  120. 120. 
    Scholler J, Brady TL, Binder-Scholl G, Hwang W-T, Plesa G et al. 2012. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4:132ra53
     [Google Scholar]
  121. 121. 
    Kalos M, Levine BL, Porter DL, Katz S, Grupp SA et al. 2011. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3:95ra73
     [Google Scholar]
  122. 122. 
    June CH, Levine BL. 2015. T cell engineering as therapy for cancer and HIV: our synthetic future. Philos. Trans. R. Soc. B 370:20140374
     [Google Scholar]
  123. 123. 
    Bohne F, Chmielewski M, Ebert G, Wiegmann K, Kurschner T et al. 2008. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes. Gastroenterology 134:239–47
     [Google Scholar]
  124. 124. 
    Wisskirchen K, Kah J, Malo A, Asen T, Volz T et al. 2019. T cell receptor grafting allows virological control of hepatitis B virus infection. J. Clin. Invest. 129:2932–45
     [Google Scholar]
  125. 125. 
    Krebs K, Böttinger N, Huang LR, Chmielewski M, Arzberger S et al. 2013. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 145:456–65
     [Google Scholar]
  126. 126. 
    Qasim W, Brunetto M, Gehring AJ, Maini MK, Bonino F et al. 2015. Reply to: “To target or not to target viral antigens in HBV related HCC?. ” J. Hepatol. 62:1450–52
     [Google Scholar]
  127. 127. 
    Lim SG, Agcaoili J, De Souza NNA, Chan E 2019. Therapeutic vaccination for chronic hepatitis B: a systematic review and meta-analysis. J. Viral Hepat. 26:803–17
     [Google Scholar]
  128. 128. 
    Lok AS, Pan CQ, Han SB, Trinh HN, Fessel WJ et al. 2016. Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B. J. Hepatol. 65:509–16
     [Google Scholar]
  129. 129. 
    Gehring AJ, Haniffa M, Kennedy PT, Ho ZZ, Boni C et al. 2013. Mobilizing monocytes to cross-present circulating viral antigen in chronic infection. J. Clin. Invest. 123:3766–76
     [Google Scholar]
  130. 130. 
    Isogawa M, Robek MD, Furuichi Y, Chisari FV. 2005. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J. Virol. 79:7269–72
     [Google Scholar]
  131. 131. 
    Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL et al. 2013. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection. Nat. Immunol. 14:574–83
     [Google Scholar]
  132. 132. 
    Crozat K, Beutler B 2004. TLR7: a new sensor of viral infection. PNAS 101:6835–36
     [Google Scholar]
  133. 133. 
    Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC et al. 2004. Recognition of single-stranded RNA viruses by Toll-like receptor 7. PNAS 101:5598–603
     [Google Scholar]
  134. 134. 
    Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H et al. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3:196–200
     [Google Scholar]
  135. 135. 
    Menne S, Tumas DB, Liu KH, Thampi L, AlDeghaither D et al. 2015. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J. Hepatol. 62:1237–45
     [Google Scholar]
  136. 136. 
    Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL et al. 2013. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 144:1508–17
     [Google Scholar]
  137. 137. 
    Gane EJ, Lim YS, Gordon SC, Visvanathan K, Sicard E et al. 2015. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. J. Hepatol. 63:320–28
     [Google Scholar]
  138. 138. 
    Boni C, Vecchi A, Rossi M, Laccabue D, Giuberti T et al. 2018. 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 154:1764–77.e7
     [Google Scholar]
  139. 139. 
    Janssen HLA, Brunetto MR, Kim YJ, Ferrari C, Massetto B et al. 2018. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. J. Hepatol. 68:431–40
     [Google Scholar]
  140. 140. 
    Schurich A, Pallett LJ, Lubowiecki M, Singh HD, Gill US et al. 2013. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLOS Pathog 9:e1003208
     [Google Scholar]
  141. 141. 
    Li L, Liu X, Sanders KL, Edwards JL, Ye J et al. 2019. TLR8-mediated metabolic control of human Treg function: a mechanistic target for cancer immunotherapy. Cell Metab 29:103–23.e5
     [Google Scholar]
  142. 142. 
    Jo J, Tan AT, Ussher JE, Sandalova E, Tang XZ et al. 2014. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver. PLOS Pathog 10:e1004210
     [Google Scholar]
  143. 143. 
    Korolowicz K, Czerwinski S, Iyer R, Skell J, Yang J et al. 2015. Antiviral efficacy and induction of host immune responses with SB 9200, an oral prodrug of the dinucleotide SB 9000, in the woodchuck model of chronic hepatitis B virus (HBV) infection. J. Hepatol. 62:S557
     [Google Scholar]
  144. 144. 
    Guo F, Tang L, Shu S, Sehgal M, Sheraz M et al. 2017. Activation of stimulator of interferon genes in hepatocytes suppresses the replication of hepatitis B virus. Antimicrob. Agents Chemother. 61:e00771-17
     [Google Scholar]
  145. 145. 
    Guo F, Han Y, Zhao X, Wang J, Liu F et al. 2015. STING agonists induce an innate antiviral immune response against hepatitis B virus. Antimicrob. Agents Chemother. 59:1273–81
     [Google Scholar]
  146. 146. 
    Zhang X, Liu B, Tang L, Su Q, Hwang N et al. 2019. Discovery and mechanistic study of a novel human-stimulator-of-interferon-genes agonist. ACS Infect. Dis. 5:1139–49
     [Google Scholar]
  147. 147. 
    Zhang H, You QD, Xu XL. 2020. Targeting stimulator of interferon genes (STING): a medicinal chemistry perspective. J. Med. Chem. 63:3785–816
     [Google Scholar]
  148. 148. 
    Pley CM, McNaughton AL, Matthews PC, Lourenco J. 2021. The global impact of the COVID-19 pandemic on the prevention, diagnosis and treatment of hepatitis B virus (HBV) infection. BMJ Glob. Health 6:e004275
     [Google Scholar]
  149. 149. 
    Chen CJ, Yang HI. 2011. Natural history of chronic hepatitis B REVEALed. J. Gastroenterol. Hepatol. 26:628–38
     [Google Scholar]
  150. 150. 
    Fattovich G, Bortolotti F, Donato F 2008. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J. Hepatol 48:2335–52
     [Google Scholar]
  151. 151. 
    McMahon BJ 2010. Natural history of chronic hepatitis B. Clin. Liver Dis 14:3381–96
     [Google Scholar]
  152. 152. 
    Poh Z, Goh BBG, Chang PEJ, Tan CK 2015. Rates of cirrhosis and hepatocellular carcinoma in chronic hepatitis B and the role of surveillance: a 10-year follow-up of 673 patients. Eur. J. Gastroenterol. Hepatol 27:6638–43
     [Google Scholar]
/content/journals/10.1146/annurev-virology-091919-062728
Loading
Prospects for the Global Elimination of Hepatitis B
Annual Review of Virology 8, 437 (2021); https://doi.org/10.1146/annurev-virology-091919-062728
/content/journals/10.1146/annurev-virology-091919-062728
/content/journals/10.1146/annurev-virology-091919-062728
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error