Pathogenic immunity and protective immunity in chronic hepatitis B
Main Article Content
Abstract
Abstract
Hepatitis B virus (HBV) infects human being and at present about 2 billion people of the world has been infected by HBV at some point of their life and about 240-370 million are chronically infected with HBV. The natural course of HBV infection exhibits considerable variability. In one hand, the majority of HBV-infected persons control HBV replication and liver damages after initial infection. On the other hand, considerable numbers of HBV-infected patients develop chronic hepatitis B (CHB) and complications like cirrhosis of liver (LC) and hepatocellular carcinoma (HCC). The mechanisms underlying these dichotomies have not been properly explored and accordingly evidence-based therapeutic approaches for chronic HBV infection could not be developed. HBV is a non-cytopathic virus with no direct role on liver damage in HBV-infected patients. In one hand, host immunity of HBV-infected patients has important roles in control of HBV and containment of liver damages. On the other hand, recent evidences have unmasked that host immunity is also responsible for ongoing viral replication and progressive liver damages. Thus, host immunity in HBV infection may be categorized in two broad headings; (1) pathogenic immunity and (2) protective immunity. In this review, a comprehensive discussion will be made about the nature of ‘pathogenic immunity’ and ‘protective immunity’ during chronic HBV infection and their implications for developing new and innovative therapy.
Article Details
How to Cite
AKBAR, Sheikh Mohammad Fazle et al.
Pathogenic immunity and protective immunity in chronic hepatitis B.
Medical Research Archives, [S.l.], v. 4, n. 6, oct. 2016.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/673>. Date accessed: 21 dec. 2024.
Keywords
Antigen-specific immunocytes; chronic hepatitis B; HBV replication; immune therapy; non-antigen-specific immunocytes; pathogenic immunity; protective immunity, therapeutic immunity
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
References
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2. Hadziyannis SJ, Vassilopoulos D, Hadziyannis E. The natural course of chronic hepatitis B virus infection and its management. Adv Pharmacol 2013; 67: 247-91
3. Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatology 2014;60(6):2099-2108
4. 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(1):61-8
5. Al-Mahtab M, Akbar SM, Rahman S, Kamal M, Khan MSI. Biochemical, virological, immunological and histopathological features of 702 incidentally detected chronic hepatitis B virus carriers in Bangladesh. Digestion 2012;86(1):1-5
6. Farag MM, Tedjokusumo R, Flechtenmacher C, et al. Immune tolerance against HBV can be overcome in HBV transgenic mice by immunization with dendritic cells pulsed by HBVsvp. Vaccine 2012; 30(42): 6034-9
7. Buchmann P, Dembek C, Kuklick L ,et al. A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic mice. Vaccine. 2013;31(8):1197-203.
8. Akbar SM, Chen S, Al-Mahtab M, Abe M, Hiasa Y, Onji M.. Strong and multi-antigen specific immunity by hepatitis B core antigen (HBcAg)-based vaccines in a murine model of chronic hepatitis B: HBcAg is a candidate for a therapeutic vaccine against hepatitis B virus. Antiviral Res. 2012;96(1):59-64.
9. Chu CM, Chen YC, Tai DI, Liaw YF. Level of hepatitis B virus DNA in inactive carriers with persistently normal levels of alanine aminotransferase. Clin Gastroenterol Hepatol. 2010;8(6):535-40.
10. Kumar M, Sarin SK, Hissar S, et al. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology 2008;134(5): 1376-84
11. Tseng TC, Liu CJ, Yang HC, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology 2013;57(2):441-50
12. Ando K, Moriyama T, Guidotti LG, et al. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J Exp Med 1993; 178:1541–54
13. Maini MK, Boni C, Lee CK, et al. The role of virus- specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000; 191: 1269–80
14. Zheng Q, Zhu YY, Chen J, et al. Activated natural killer cells accelerate liver damage in patients with chronic hepatitis B virus infection. Clin Exp Immunol 2015;180(3):499-508
15. 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; 20: 667–680
16. Zhang Z, Zhang S, Zou Z, et al. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients. Hepatology 2011; 53: 73–85.
17. Zheng SJ, Wang P, Tsabary G, Chen YH. Critical roles of TRAIL inhepatic cell death and hepatic inflammation. J Clin Invest 2004; 113: 58–64
18. Zou Y, Chen T, Han M, et al. Increased killing of liver NK cells by Fas/Fas ligand and NKG2D/NKG2D ligand contributes to hepatocyte necrosis in virus-induced liver failure. J Immunol 2010; 184:466–75
19. Wu HL, Kao JH, Chen TC, et al. Serum cytokine/chemokine profiles in acute exacerbation of chronic hepatitis B: clinical and mechanistic implications. J Gastroenterol Hepatol. 2014;29(8):1629-36
20. Bayard F, Godon O, Nalpas B, et al. T-cell responses to hepatitis B splice-generated protein of hepatitis B virus and inflammatory cytokines/chemokines in chronic hepatitis B patients. ANRS study: HB EP 02 HBSP-FIBRO. J Viral Hepat. 2012 ;19(12):872-80.
21. Zhou Y, Wang S, Ma JW, et al. Hepatitis B virus protein X-induced expression of the CXC chemokine IP-10 is mediated through activation of NF-kappaB and increases migration of leukocytes. J Biol Chem 2010;285(16):12159-68.
22. Ishiyama, K., H. Ohdan, M. Ohira, H. Mitsuta, K. Arihiro, and T. Asahara. Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. Hepatology 2006; 43:362–72.
23. Peppa D, Gill US, Reynolds G, et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 2013; 210(1):99-114
24. Ramadori G, Saile B. Inflammation, damage repair, immune cells, and liver fibrosis: specific or nonspecific, this is the question. Gastroenterology 2004; 127: 997-1000.
25. Larrubia JR, Benito-Martínez S, Miquel-Plaza J, et al. Cytokines - their pathogenic and therapeutic role in chronic viral hepatitis. Rev Esp Enferm Dig 2009;101(5):343-51
26. Cobleigh MA, Robek MD. Protective and pathological properties of IL-22 in liver disease: Implication for viral hepatitis. Am J Pathol 2013;182:21-28.
27. Taub R, Greenbaum LE, Peng Y. Transcriptional regulatory signals define cytokine-dependent and -independent pathways in liver regeneration. Semin Liver Dis 1999; 19: 117-27.
28. Ramadori G, Saile B. Inflammation, damage repair, immune cells, and liver fibrosis: specific or nonspecific, this is the question. Gastroenterology 2004; 127: 997-1000.
29. Tilg H, Vogel W, Tratkiewicz J et al. Pilot study of natural human interleukin-2 in patients with chronic hepatitis B. Immunomodulatory and antiviral effects. J Hepatol 1993; 19(2):259-67.
30. Artillo S, Pastore G, Alberti A, et al. Double-blind, randomized controlled trial of interleukin-2 treatment of chronic hepatitis B. J Med Virol 1998; 54:167-172
31. Ruiz-Moreno M, García R, Rua MJ, et al. Levamisole and interferon in children with chronic hepatitis B. Hepatology 1993; 18(2):264-9
32. Woltman AM, Ter Borg MJ, Binda RS et al. Alpha-galactosylceramide in chronic hepatitis B infection: results from a randomized placebo-controlled Phase I/II trial. Antivir Ther 2009; 14(6), 809-18
33. Bertoletti A, Maini MK, Ferrari C. The host-pathogen interaction during HBV infection: immunological controversies. Antivir Ther 2010;15 Suppl 3:15-24.
34. Tan AT, Koh S, Goh W, Zhe HY, Gehring AJ, Lim SG, Bertoletti A. A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. .J Hepatol 2010;52(3):330-9
35. Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol 2013;4:57
36. Bertoletti A, Maini MK. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr Opin Microbiol 2000;3(4):387-92.
37. Pol S, Driss F, Michel ML, et al. Specific vaccine therapy in chronic hepatitis B infection. Lancet 1994; 344(8918): 342
38. Senturk H, Tabak F, Akdogan M, et al. Therapeutic vaccination in chronic hepatitis B. J Gastroenterol. Hepatol 2002; 17(1):72–76
39. Wang XY, Zhang XX, Yao X, et al. Serum HBeAg sero-conversion correlated with decrease of HBsAg and HBV DNA in chronic hepatitis B patients treated with a therapeutic vaccine. Vaccine 2010; 28(51), 8169-74
40. Wen YM, Wu XH, Hu DC, et al. Hepatitis B vaccine and anti-HBs complex as approach for vaccine therapy. Lancet 1995; 345(8964): 1575–1576.
41. Xu DZ, Zhao K, Guo LM, et al. A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients. PLoS ONE 2008; 3:e2565,
42. Vandepapelière P, Lau GK, Leroux-Roels G, et al. Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine 2007; 25(51); 8585-8597
43. Horiike N, Fazle Akbar SM, Michitaka K, et al. In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B. J Clin Virol 2005; 32(2),156-61
44. Wang XY, Zhang XX, Yao X, et al. Serum HBeAg sero-conversion correlated with decrease of HBsAg and HBV DNA in chronic hepatitis B patients treated with a therapeutic vaccine. Vaccine 2010; 28(51), 8169-8174
45. Hoa PT, Huy NT, Thu le T, et al. Randomized controlled study investigating viral suppression and serological response following pre-S1/pre-S2/S vaccine therapy combined with lamivudine treatment in HBeAg-positive patients with chronic hepatitis B. Antimicrob Agents Chemother 2009; 53(12): 5134-40
46. Yang FQ, Yu YY, Wang GQ, et al. A pilot randomized controlled trial of dual-plasmid HBV DNA vaccine mediated by in vivo electroporation in chronic hepatitis B patients under lamivudine chemotherapy. J Viral Hepat 2012; 19(8),581-93
47. Heathcote J, McHutchison J, Lee S, et al. A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group. Hepatology 1999; 30(2): 531–6.
48. Livingston BD, Alexander J, Crimi C, et al. Altered helper T lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans. J Immunol 1999; 161(5):3088-95
49. Al-Mahtab M, Akbar SM, Aguilar JC, Uddin MH, Khan MS, Rahman S. Therapeutic potential of a combined hepatitis B virus surface and core antigen vaccine in patients with chronic hepatitis B. Hepatol Int 2013; 7(4), 981-9
50. Akbar SM, Al-Mahtab M, Rahman S et al. A phase III clinical trial with a therapeutic vaccine containing both HBsAg and HBcAg administered via both mucosal and parenteral routes in patients with chronic hepatitis B. Presented at: 64th Annual Meeting of American Association for the Study of the Liver, Washington DC, USA, 1st November-5th November 2013. ** Only phase III clinical trial with HBsAg/HBcAg-based therapeutic vaccine in chronic hepatits B
51. Yang YF, Zhao W, Zhong YD, Xia HM, Shen L, Zhang N. Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta-analysis. J Viral Hepat 2009 ;16(4):265-71.
52. Moon JC, Kim SH, Kim IH, et al. Disease progression in chronic hepatitis B patients under long-term antiviral therapy. Gut Liver 2015; 9(3): 395-404
53. Chiang CJ, Yang YW, Chen JD, et al. Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan. Hepatology 2015; 61(4): 1154-1162
54. 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-.8
1. Iloeje UH, Yang HI, Chen CJ. Natural history of chronic hepatitis B: what exactly has REVEAL revealed? Liver Int 2012;32(9):1333-4
2. Hadziyannis SJ, Vassilopoulos D, Hadziyannis E. The natural course of chronic hepatitis B virus infection and its management. Adv Pharmacol 2013; 67: 247-91
3. Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatology 2014;60(6):2099-2108
4. 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(1):61-8
5. Al-Mahtab M, Akbar SM, Rahman S, Kamal M, Khan MSI. Biochemical, virological, immunological and histopathological features of 702 incidentally detected chronic hepatitis B virus carriers in Bangladesh. Digestion 2012;86(1):1-5
6. Farag MM, Tedjokusumo R, Flechtenmacher C, et al. Immune tolerance against HBV can be overcome in HBV transgenic mice by immunization with dendritic cells pulsed by HBVsvp. Vaccine 2012; 30(42): 6034-9
7. Buchmann P, Dembek C, Kuklick L ,et al. A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic mice. Vaccine. 2013;31(8):1197-203.
8. Akbar SM, Chen S, Al-Mahtab M, Abe M, Hiasa Y, Onji M.. Strong and multi-antigen specific immunity by hepatitis B core antigen (HBcAg)-based vaccines in a murine model of chronic hepatitis B: HBcAg is a candidate for a therapeutic vaccine against hepatitis B virus. Antiviral Res. 2012;96(1):59-64.
9. Chu CM, Chen YC, Tai DI, Liaw YF. Level of hepatitis B virus DNA in inactive carriers with persistently normal levels of alanine aminotransferase. Clin Gastroenterol Hepatol. 2010;8(6):535-40.
10. Kumar M, Sarin SK, Hissar S, et al. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology 2008;134(5): 1376-84
11. Tseng TC, Liu CJ, Yang HC, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology 2013;57(2):441-50
12. Ando K, Moriyama T, Guidotti LG, et al. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J Exp Med 1993; 178:1541–54
13. Maini MK, Boni C, Lee CK, et al. The role of virus- specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000; 191: 1269–80
14. Zheng Q, Zhu YY, Chen J, et al. Activated natural killer cells accelerate liver damage in patients with chronic hepatitis B virus infection. Clin Exp Immunol 2015;180(3):499-508
15. 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; 20: 667–680
16. Zhang Z, Zhang S, Zou Z, et al. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients. Hepatology 2011; 53: 73–85.
17. Zheng SJ, Wang P, Tsabary G, Chen YH. Critical roles of TRAIL inhepatic cell death and hepatic inflammation. J Clin Invest 2004; 113: 58–64
18. Zou Y, Chen T, Han M, et al. Increased killing of liver NK cells by Fas/Fas ligand and NKG2D/NKG2D ligand contributes to hepatocyte necrosis in virus-induced liver failure. J Immunol 2010; 184:466–75
19. Wu HL, Kao JH, Chen TC, et al. Serum cytokine/chemokine profiles in acute exacerbation of chronic hepatitis B: clinical and mechanistic implications. J Gastroenterol Hepatol. 2014;29(8):1629-36
20. Bayard F, Godon O, Nalpas B, et al. T-cell responses to hepatitis B splice-generated protein of hepatitis B virus and inflammatory cytokines/chemokines in chronic hepatitis B patients. ANRS study: HB EP 02 HBSP-FIBRO. J Viral Hepat. 2012 ;19(12):872-80.
21. Zhou Y, Wang S, Ma JW, et al. Hepatitis B virus protein X-induced expression of the CXC chemokine IP-10 is mediated through activation of NF-kappaB and increases migration of leukocytes. J Biol Chem 2010;285(16):12159-68.
22. Ishiyama, K., H. Ohdan, M. Ohira, H. Mitsuta, K. Arihiro, and T. Asahara. Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. Hepatology 2006; 43:362–72.
23. Peppa D, Gill US, Reynolds G, et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 2013; 210(1):99-114
24. Ramadori G, Saile B. Inflammation, damage repair, immune cells, and liver fibrosis: specific or nonspecific, this is the question. Gastroenterology 2004; 127: 997-1000.
25. Larrubia JR, Benito-Martínez S, Miquel-Plaza J, et al. Cytokines - their pathogenic and therapeutic role in chronic viral hepatitis. Rev Esp Enferm Dig 2009;101(5):343-51
26. Cobleigh MA, Robek MD. Protective and pathological properties of IL-22 in liver disease: Implication for viral hepatitis. Am J Pathol 2013;182:21-28.
27. Taub R, Greenbaum LE, Peng Y. Transcriptional regulatory signals define cytokine-dependent and -independent pathways in liver regeneration. Semin Liver Dis 1999; 19: 117-27.
28. Ramadori G, Saile B. Inflammation, damage repair, immune cells, and liver fibrosis: specific or nonspecific, this is the question. Gastroenterology 2004; 127: 997-1000.
29. Tilg H, Vogel W, Tratkiewicz J et al. Pilot study of natural human interleukin-2 in patients with chronic hepatitis B. Immunomodulatory and antiviral effects. J Hepatol 1993; 19(2):259-67.
30. Artillo S, Pastore G, Alberti A, et al. Double-blind, randomized controlled trial of interleukin-2 treatment of chronic hepatitis B. J Med Virol 1998; 54:167-172
31. Ruiz-Moreno M, García R, Rua MJ, et al. Levamisole and interferon in children with chronic hepatitis B. Hepatology 1993; 18(2):264-9
32. Woltman AM, Ter Borg MJ, Binda RS et al. Alpha-galactosylceramide in chronic hepatitis B infection: results from a randomized placebo-controlled Phase I/II trial. Antivir Ther 2009; 14(6), 809-18
33. Bertoletti A, Maini MK, Ferrari C. The host-pathogen interaction during HBV infection: immunological controversies. Antivir Ther 2010;15 Suppl 3:15-24.
34. Tan AT, Koh S, Goh W, Zhe HY, Gehring AJ, Lim SG, Bertoletti A. A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. .J Hepatol 2010;52(3):330-9
35. Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol 2013;4:57
36. Bertoletti A, Maini MK. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr Opin Microbiol 2000;3(4):387-92.
37. Pol S, Driss F, Michel ML, et al. Specific vaccine therapy in chronic hepatitis B infection. Lancet 1994; 344(8918): 342
38. Senturk H, Tabak F, Akdogan M, et al. Therapeutic vaccination in chronic hepatitis B. J Gastroenterol. Hepatol 2002; 17(1):72–76
39. Wang XY, Zhang XX, Yao X, et al. Serum HBeAg sero-conversion correlated with decrease of HBsAg and HBV DNA in chronic hepatitis B patients treated with a therapeutic vaccine. Vaccine 2010; 28(51), 8169-74
40. Wen YM, Wu XH, Hu DC, et al. Hepatitis B vaccine and anti-HBs complex as approach for vaccine therapy. Lancet 1995; 345(8964): 1575–1576.
41. Xu DZ, Zhao K, Guo LM, et al. A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients. PLoS ONE 2008; 3:e2565,
42. Vandepapelière P, Lau GK, Leroux-Roels G, et al. Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine 2007; 25(51); 8585-8597
43. Horiike N, Fazle Akbar SM, Michitaka K, et al. In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B. J Clin Virol 2005; 32(2),156-61
44. Wang XY, Zhang XX, Yao X, et al. Serum HBeAg sero-conversion correlated with decrease of HBsAg and HBV DNA in chronic hepatitis B patients treated with a therapeutic vaccine. Vaccine 2010; 28(51), 8169-8174
45. Hoa PT, Huy NT, Thu le T, et al. Randomized controlled study investigating viral suppression and serological response following pre-S1/pre-S2/S vaccine therapy combined with lamivudine treatment in HBeAg-positive patients with chronic hepatitis B. Antimicrob Agents Chemother 2009; 53(12): 5134-40
46. Yang FQ, Yu YY, Wang GQ, et al. A pilot randomized controlled trial of dual-plasmid HBV DNA vaccine mediated by in vivo electroporation in chronic hepatitis B patients under lamivudine chemotherapy. J Viral Hepat 2012; 19(8),581-93
47. Heathcote J, McHutchison J, Lee S, et al. A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group. Hepatology 1999; 30(2): 531–6.
48. Livingston BD, Alexander J, Crimi C, et al. Altered helper T lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans. J Immunol 1999; 161(5):3088-95
49. Al-Mahtab M, Akbar SM, Aguilar JC, Uddin MH, Khan MS, Rahman S. Therapeutic potential of a combined hepatitis B virus surface and core antigen vaccine in patients with chronic hepatitis B. Hepatol Int 2013; 7(4), 981-9
50. Akbar SM, Al-Mahtab M, Rahman S et al. A phase III clinical trial with a therapeutic vaccine containing both HBsAg and HBcAg administered via both mucosal and parenteral routes in patients with chronic hepatitis B. Presented at: 64th Annual Meeting of American Association for the Study of the Liver, Washington DC, USA, 1st November-5th November 2013. ** Only phase III clinical trial with HBsAg/HBcAg-based therapeutic vaccine in chronic hepatits B
51. Yang YF, Zhao W, Zhong YD, Xia HM, Shen L, Zhang N. Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta-analysis. J Viral Hepat 2009 ;16(4):265-71.
52. Moon JC, Kim SH, Kim IH, et al. Disease progression in chronic hepatitis B patients under long-term antiviral therapy. Gut Liver 2015; 9(3): 395-404
53. Chiang CJ, Yang YW, Chen JD, et al. Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan. Hepatology 2015; 61(4): 1154-1162
54. 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-.8