Advertisement

Antiviral Therapy for AECHB and Severe Hepatitis B (Liver Failure)

  • Qin Ning
  • Ting Wu
  • Hai-Bin Su
  • Ke Ma
  • Jun-Ying Qi
  • Ming Ni
  • Di Wu
Chapter

Abstract

This chapter describes the principles of antiviral therapy, treatment strategies, medications and recommendations for AECHB, HBV-ACLF, HBV-related liver cirrhosis, HBV-related HCC, and liver transplantation.
  1. 1.

    Severe exacerbation of chronic hepatitis B is closely related to continuous HBV replication. Therefore, inhibiting HBV replication to reduce viral load may block disease progression and improve the quality of life of these patients. ETV or TDF has been recommend first-line drug for the treatment of AECHB.

     
  2. 2.

    A hyperactive immune response due to continuous HBV replication is the main mechanism for development of severe hepatitis B. In addition to comprehensive treatment, early administration of potent nucleoside analogs can rapidly reduce HBV DNA concentration, relieve immune injury induced by HBV, and reduce liver inflammation and patient mortality. Antiviral agents have become important in the treatment of severe exacerbation of chronic hepatitis B.

     
  3. 3.

    Long-term antiviral treatment with nucleoside analogs can delay or reverse the progress of liver cirrhosis. Virologic response, viral resistance and adverse drug reactions should be closely monitored during treatment. The treatment should be optimized for maximum effect based on each patient’s responses.

     
  4. 4.

    Effective antiviral therapy can suppress HBV replication and reduce the incidence of HBV-related HCC. Patients with HBV-related HCC should receive individualized and optimal multidisciplinary comprehensive treatment. Anti-viral drugs with high efficacy, low resistance and low adverse drug reactions should be selected to improve the patient’s quality of life and prolong survival time.

     
  5. 5.

    Methods to prevent HBV reinfection after liver transplantation include passive immunization (HBIG), antiviral treatment (nucleoside analogs) and active immunization (hepatitis B vaccine).

     
  6. 6.

    Clinical trials involving sequential combination therapy with NUC and Peg-IFN have shown statistically significant decline in HBsAg levels on treatment and high rates of sustained post-treatment serologic response. Combination therapy with novel DAA and immunotherapeutic approach may hold promise to overcome both cccDNA persistence and immune escape, representing a critical step towards HBV cure.

     

References

  1. 1.
    Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association, Severe Liver Diseases and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure. Chin J Transplant (Electronic Edition). 2013;7:48–56.Google Scholar
  2. 2.
    Carosi G, Rizzetto M, Alberti A, Cariti G, Colombo M, Craxi A, Filice G, Levrero M, Mazzotta F, Pastore G, Piccinino F, Prati D, Raimondo G, Sagnelli E, Toti M, Brunetto M, Bruno R, Di Marco V, Ferrari C, Gaeta GB, Lampertico P, Marzano A, Pollicino T, Puoti M, Santantonio T, Smedile A. Treatment of chronic hepatitis B: update of the recommendations from the 2007 Italian Workshop. Dig Liver Dis. 2011;43:259–65.PubMedGoogle Scholar
  3. 3.
    Hou J, Wang G, Wang F, Cheng J, Ren H, Zhuang H, Sun J, Li L, Li J, Meng Q, Zhao J, Duan Z, Jia J, Tang H, Sheng J, Peng J, Lu F, Xie Q, Wei L, Chinese Society of Hepatology, Chinese Medical Association, Chinese Society of Infectious Diseases, Chinese Medical Association. Guideline of Prevention and Treatment for Chronic Hepatitis B (2015 Update). J Clin Transl Hepatol. 2017;5(4):297–318.PubMedPubMedCentralGoogle Scholar
  4. 4.
    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(2):370–98.Google Scholar
  5. 5.
    Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98.Google Scholar
  6. 6.
    Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Yuen MF, Lai CL. Treatment of chronic hepatitis B: evolution over two decades. J Gastroenterol Hepatol. 2011;26(Suppl 1):138–43.PubMedGoogle Scholar
  8. 8.
    World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection; 2015.Google Scholar
  9. 9.
    Committee of Experts on Antiviral Therapy for Special Patients with Chronic Hepatitis B. [Expert consensus on antiviral therapy for special patients with chronic hepatitis B: an update in 2014]. J Clin Hepatol. 2014;30:580–7.Google Scholar
  10. 10.
    Borentain P, Colson P, Coso D, Bories E, Charbonnier A, Stoppa AM, Auran T, Loundou A, Motte A, Ressiot E, Norguet E, Chabannon C, Bouabdallah R, Tamalet C, Gerolami R. Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer. J Viral Hepat. 2010;17:807–15.PubMedGoogle Scholar
  11. 11.
    Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Mullhaupt B, Clavien PA. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg. 2009;96(9):975–81.PubMedGoogle Scholar
  12. 12.
    Huang TS, Shyu YC, Chen HY, Yuan SS, Shih JN, Chen PJ. A systematic review and meta-analysis of adjuvant interferon therapy after curative treatment for patients with viral hepatitis-related hepatocellular carcinoma. J Viral Hepat. 2013;20:729–43.PubMedGoogle Scholar
  13. 13.
    Kuzuya T, Katano Y, Kumada T, Toyoda H, Nakano I, Hirooka Y, Itoh A, Ishigami M, Hayashi K, Honda T, Goto H. Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma. J Gastroenterol Hepatol. 2007;22(11):1929–35.PubMedGoogle Scholar
  14. 14.
    Nagamatsu H, Itano S, Nagaoka S, Akiyoshi J, Matsugaki S, Kurogi J, Tajiri N, Yamasaki S, Koga H, Torimura T, Kumashiro R, Sata M. Prophylactic lamivudine administration prevents exacerbation of liver damage in HBe antigen positive patients with hepatocellular carcinoma undergoing transhepatic arterial infusion chemotherapy. Am J Gastroenterol. 2004;99:2369–75.PubMedGoogle Scholar
  15. 15.
    Nagano H, Monden M. [FAIT (FU arterial infusion and interferon therapy) for hepatocellular carcinoma]. Nihon Rinsho. 2006;64:1314–8.Google Scholar
  16. 16.
    Cholongitas E, Goulis J, Akriviadis E, Papatheodoridis GV. Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis b virus recurrence after liver transplantation: a systematic review. Liver Transpl. 2011;17:1176–90.PubMedGoogle Scholar
  17. 17.
    Cholongitas E, Papatheodoridis GV. High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review. Am J Transplant. 2013;13:353–62.PubMedGoogle Scholar
  18. 18.
    Fung J, Chan SC, Cheung C, Yuen MF, Chok KS, Sharr W, Chan AC, Cheung TT, Seto WK, Fan ST, Lai CL, Lo CM. Oral nucleoside/nucleotide analogs without hepatitis B immune globulin after liver transplantation for hepatitis B. Am J Gastroenterol. 2013;108:942–8.PubMedGoogle Scholar
  19. 19.
    Fung J, Cheung C, Chan SC, Yuen MF, Chok KS, Sharr W, Dai WC, Chan AC, Cheung TT, Tsang S, Lam B, Lai CL, Lo CM. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology. 2011;141:1212–9.PubMedGoogle Scholar
  20. 20.
    Perrillo R, Buti M, Durand F, Charlton M, Gadano A, Cantisani G, Loong CC, Brown K, Hu W, Lopez-Talavera JC, Llamoso C. Entecavir and hepatitis B immune globulin in patients undergoing liver transplantation for chronic hepatitis B. Liver Transpl. 2013;19(8):887–95.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Roque-Afonso AM, Feray C, Samuel D, Simoneau D, Roche B, Emile JF, Gigou M, Shouval D, Dussaix E. Antibodies to hepatitis B surface antigen prevent viral reactivation in recipients of liver grafts from anti-HBC positive donors. Gut. 2002;50:95–9.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Saab S, Waterman B, Chi AC, Tong MJ. Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: a systematic review. Liver Transpl. 2010;16:300–7.PubMedGoogle Scholar
  23. 23.
    Seehofer D, Rayes N, Naumann U, Neuhaus R, Muller AR, Tullius SG, Berg T, Steinmuller T, Bechstein WO, Neuhaus P. Preoperative antiviral treatment and postoperative prophylaxis in HBV-DNA positive patients undergoing liver transplantation. Transplantation. 2001;72:1381–5.PubMedGoogle Scholar
  24. 24.
    Teperman LW, Poordad F, Bzowej N, Martin P, Pungpapong S, Schiano T, Flaherty J, Dinh P, Rossi S, Subramanian GM, Spivey J. Randomized trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation. Liver Transpl. 2013;19:594–601.PubMedGoogle Scholar
  25. 25.
    Terrault N, Roche B, Samuel D. Management of the hepatitis B virus in the liver transplantation setting: a European and an American perspective. Liver Transpl. 2005;11:716–32.PubMedGoogle Scholar
  26. 26.
    Wang P, Tam N, Wang H, Zheng H, Chen P, Wu L, He X. Is hepatitis B immunoglobulin necessary in prophylaxis of hepatitis B recurrence after liver transplantation? A meta-analysis. PLoS One. 2014;9:e104480.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Yilmaz N, Shiffman ML, Todd Stravitz R, Sterling RK, Luketic VA, Sanyal AJ, Maluf D, Coterell A, Posner MP, Fisher RA. Prophylaxis against recurrence of hepatitis B virus after liver transplantation: a retrospective analysis spanning 20 years. Liver Int. 2008;28:72–8.PubMedGoogle Scholar
  28. 28.
    El Sherbini A, Omar A. Treatment of children with HBeAg-positive chronic hepatitis B: a systematic review and meta-analysis. Dig Liver Dis. 2014;46:1103–10.PubMedGoogle Scholar
  29. 29.
    Jonas MM, Block JM, Haber BA, Karpen SJ, London WT, Murray KF, Narkewicz MR, Rosenthal P, Schwarz KB, McMahon BJ. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology. 2010;52:2192–205.PubMedGoogle Scholar
  30. 30.
    Jonas MM, Mizerski J, Badia IB, Areias JA, Schwarz KB, Little NR, Greensmith MJ, Gardner SD, Bell MS, Sokal EM. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med. 2002;346:1706–13.PubMedGoogle Scholar
  31. 31.
    Komatsu H, Inui A, Sogo T, Tsunoda T, Fujisawa T. Chronic hepatitis B virus infection in children and adolescents in Japan. J Pediatr Gastroenterol Nutr. 2015;60:99–104.PubMedGoogle Scholar
  32. 32.
    Paganelli M, Stephenne X, Sokal EM. Chronic hepatitis B in children and adolescents. J Hepatol. 2012;57:885–96.PubMedGoogle Scholar
  33. 33.
    Sokal EM, Kelly DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, Vegnente A, Little NR, Gardener SD, Jonas MM. Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology. 2006;43:225–32.PubMedGoogle Scholar
  34. 34.
    Ahn J, Salem SB, Cohen SM. Evaluation and management of hepatitis B in pregnancy: a survey of current practices. Gastroenterol Hepatol (N Y). 2010;6:570–8.Google Scholar
  35. 35.
    Brown RS Jr, Verna EC, Pereira MR, Tilson HH, Aguilar C, Leu CS, Buti M, Fagan EA. Hepatitis B virus and human immunodeficiency virus drugs in pregnancy: findings from the Antiretroviral Pregnancy Registry. J Hepatol. 2012;57:953–9.PubMedGoogle Scholar
  36. 36.
    Buchanan C, Tran TT. Management of chronic hepatitis B in pregnancy. Clin Liver Dis. 2010;14:495–504.PubMedGoogle Scholar
  37. 37.
    Chu M, Cho SM, Choe BH, Cho MH, Kwon S, Lee WK. Virologic responses to add-on adefovir dipivoxil treatment versus entecavir monotherapy in children with lamivudine-resistant chronic hepatitis B. J Pediatr Gastroenterol Nutr. 2012;55:648–52.PubMedGoogle Scholar
  38. 38.
    Della Corte C, Nobili V, Comparcola D, Cainelli F, Vento S. Management of chronic hepatitis B in children: an unresolved issue. J Gastroenterol Hepatol. 2014;29:912–9.PubMedGoogle Scholar
  39. 39.
    Deng M, Zhou X, Gao S, Yang SG, Wang B, Chen HZ, Ruan B. The effects of telbivudine in late pregnancy to prevent intrauterine transmission of the hepatitis B virus: a systematic review and meta-analysis. Virol J. 2012;9:185.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Fan L, Owusu-Edusei K Jr, Schillie SF, Murphy TV. Antiviral treatment among pregnant women with chronic hepatitis B. Infect Dis Obstet Gynecol. 2014;2014:546165.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Han GR, Cao MK, Zhao W, Jiang HX, Wang CM, Bai SF, Yue X, Wang GJ, Tang X, Fang ZX. A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol. 2011;55:1215–21.PubMedGoogle Scholar
  42. 42.
    Licata A, Ingrassia D, Serruto A, Soresi M, Giannitrapani L, Montalto G, Craxi A, Almasio PL. Clinical course and management of acute and chronic viral hepatitis during pregnancy. J Viral Hepat. 2015;22:515–23.PubMedGoogle Scholar
  43. 43.
    Petersen J. HBV treatment and pregnancy. J Hepatol. 2011;55:1171–3.PubMedGoogle Scholar
  44. 44.
    Tran TT. Management of hepatitis B in pregnancy: weighing the options. Cleve Clin J Med. 2009;76(Suppl 3):S25–9.PubMedGoogle Scholar
  45. 45.
    Wen WH, Chang MH, Zhao LL, Ni YH, Hsu HY, Wu JF, Chen PJ, Chen DS, Chen HL. Mother-to-infant transmission of hepatitis B virus infection: significance of maternal viral load and strategies for intervention. J Hepatol. 2013;59:24–30.PubMedGoogle Scholar
  46. 46.
    Bellecave P, Gouttenoire J, Gajer M, Brass V, Koutsoudakis G, Blum HE, Bartenschlager R, Nassal M, Moradpour D. Hepatitis B and C virus coinfection: a novel model system reveals the absence of direct viral interference. Hepatology. 2009;50:46–55.PubMedGoogle Scholar
  47. 47.
    Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol. 2008;23:512–20.PubMedGoogle Scholar
  48. 48.
    Collins JM, Raphael KL, Terry C, Cartwright EJ, Pillai A, Anania FA, Farley MM. Hepatitis B reactivation during successful treatment of hepatitis C with sofosbuvir and simeprevir. Clin Infect Dis. 2015;61:1304–6.PubMedGoogle Scholar
  49. 49.
    Kruse RL, Kramer JR, Tyson GL, Duan Z, Chen L, El-Serag HB, Kanwal F. Clinical outcomes of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients. Hepatology. 2014;60:1871–8.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Liu CJ. Treatment of patients with dual hepatitis C virus and hepatitis B virus infection: resolved and unresolved issues. J Gastroenterol Hepatol. 2014;29:26–30.PubMedGoogle Scholar
  51. 51.
    Liu CJ, Chen PJ. Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection. World J Gastroenterol. 2014;20:2955–61.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Liu CJ, Chen PJ, Chen DS. Dual chronic hepatitis B virus and hepatitis C virus infection. Hepatol Int. 2009;3:517–25.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Sun YT, Zhang YX, Tang H, Mao Q, Wang XZ, Zhang LY, Chen H, Zhong YN, Lin SM, Zhang DZ. Clinical characteristics and current management of hepatitis B and C in China. World J Gastroenterol. 2014;20:13582–90.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Luetkemeyer AF, Charlebois ED, Hare CB, Black D, Smith A, Havlir DV, Peters MG. Resistance patterns and response to entecavir intensification among HIV-HBV-coinfected adults with persistent HBV viremia. J Acquir Immune Defic Syndr. 2011;58:e96–9.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Matthews GV, Seaberg EC, Avihingsanon A, Bowden S, Dore GJ, Lewin SR, Sasadeusz J, Revill PA, Littlejohn M, Hoy JF, Finlayson R, Ruxrungtham K, Saulynas M, Locarnini S, Thio CL. Patterns and causes of suboptimal response to tenofovir-based therapy in individuals coinfected with HIV and hepatitis B virus. Clin Infect Dis. 2013;56:e87–94.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Piroth L, Pol S, Lacombe K, Miailhes P, Rami A, Rey D, Loustau-Ratti V, Morlat P, Goderel I, Sene D, Rosenthal E, Carrat F, Cacoub P. Management and treatment of chronic hepatitis B virus infection in HIV positive and negative patients: the EPIB 2008 study. J Hepatol. 2010;53:1006–12.PubMedGoogle Scholar
  57. 57.
    Sherman M. Strategies for managing coinfection with hepatitis B virus and HIV. Cleve Clin J Med. 2009;76(Suppl 3):S30–3.PubMedGoogle Scholar
  58. 58.
    Soriano V, de Mendoza C, Fernandez-Montero JV, Labarga P, Barreiro P. Management and treatment of chronic hepatitis B in HIV-positive patients. Ann Med. 2014;46:290–6.PubMedGoogle Scholar
  59. 59.
    Thio CL. Hepatitis B and human immunodeficiency virus coinfection. Hepatology. 2009;49:S138–45.PubMedGoogle Scholar
  60. 60.
    Tsai MS, Chang SY, Lo YC, Yang CJ, Sun HY, Liu WC, Wu PY, Hung CC. Hepatitis B virus (HBV) coinfection accelerates immunologic progression in patients with primary HIV infection in an area of hyperendemicity for HBV infection. J Infect Dis. 2013;208:1184–6.PubMedGoogle Scholar
  61. 61.
    Chuang TW, Hung CH, Huang SC, Lee CM. Complete remission of nephrotic syndrome of hepatitis B virus-associated membranous glomerulopathy after lamivudine monotherapy. J Formos Med Assoc. 2007;106:869–73.PubMedGoogle Scholar
  62. 62.
    Ikee R, Ishioka K, Oka M, Maesato K, Moriya H, Hidaka S, Ohtake T, Kobayashi S. Hepatitis B virus-related membranous nephropathy treated with entecavir. Nephrology (Carlton). 2010;15:266.Google Scholar
  63. 63.
    Ochi A, Ishimura E, Ichii M, Ohno Y, Nakatani S, Kobayashi I, Shima H, Tsuda A, Shidara K, Mori K, Tamori A, Inaba M. Successful treatment of hepatitis B virus-associated membranous nephropathy with entecavir and immunosuppressive agents. Nephrology (Carlton). 2014;19:595–6.Google Scholar
  64. 64.
    Okuse C, Yotsuyanagi H, Yamada N, Ikeda H, Takahashi H, Suzuki M, Kondo S, Kimura K, Koike J, Itoh F. Successful treatment of hepatitis B virus-associated membranous nephropathy with lamivudine. Clin Nephrol. 2006;65:53–6.PubMedGoogle Scholar
  65. 65.
    Shah HH, Patel C, Jhaveri KD. Complete remission of hepatitis B virus-associated nephrotic syndrome from IgA nephropathy following peginterferon therapy. Ren Fail. 2013;35:295–8.PubMedGoogle Scholar
  66. 66.
    Xu G, Duang Z, Wu X, Zou H, Fang X, Tu W. Treatment of hepatitis B virus-associated membranous nephritis patients in Chinese: an open parallel controlled trial. Clin Chem Lab Med. 2011;49:1077–8.PubMedGoogle Scholar
  67. 67.
    Yi Z, Jie YW, Nan Z. The efficacy of anti-viral therapy on hepatitis B virus-associated glomerulonephritis: a systematic review and meta-analysis. Ann Hepatol. 2011;10:165–73.PubMedGoogle Scholar
  68. 68.
    Ho EY, Yau T, Rousseau F, Heathcote EJ, Lau GK. Preemptive adefovir versus lamivudine for prevention of hepatitis B reactivation in chronic hepatitis B patients undergoing chemotherapy. Hepatol Int. 2015;9:224–30.PubMedGoogle Scholar
  69. 69.
    Hsu PI, Lai KH, Cheng JS, Kao SS, Li YR, Sun WC, Chen WC, Lin KH, Shin CA, Chiang PH, Li YD, Ou WT, Chen HC, Yu HC. Prevention of acute exacerbation of chronic hepatitis B infection in cancer patients receiving chemotherapy in a hepatitis B virus endemic area. Hepatology. 2015;62:387–96.PubMedGoogle Scholar
  70. 70.
    Huang H, Li X, Zhu J, Ye S, Zhang H, Wang W, Wu X, Peng J, Xu B, Lin Y, Cao Y, Li H, Lin S, Liu Q, Lin T. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA. 2014;312:2521–30.PubMedGoogle Scholar
  71. 71.
    Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, Csako G. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148:519–28.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Masarone M, De Renzo A, La Mura V, Sasso FC, Romano M, Signoriello G, Rosato V, Perna F, Pane F, Persico M. Management of the HBV reactivation in isolated HBcAb positive patients affected with Non Hodgkin Lymphoma. BMC Gastroenterol. 2014;14:31.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Yeo W, Chan HL. Hepatitis B virus reactivation associated with anti-neoplastic therapy. J Gastroenterol Hepatol. 2013;28:31–7.PubMedGoogle Scholar
  74. 74.
    Deutsch M, Dourakis S, Manesis EK, Gioustozi A, Hess G, Horsch A, Hadziyannis S. Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon alfa therapy. Hepatology. 1997;26:206–10.PubMedGoogle Scholar
  75. 75.
    Kozielewicz D, Zalesna A, Dybowska D. Can pegylated interferon alpha 2a cause development of thyroid disorders in patients with chronic hepatitis B? Expert Opin Drug Saf. 2014;13:1009–14.PubMedGoogle Scholar
  76. 76.
    Nonchev BI. Cases of interferon-alpha and interferon-beta-induced thyroiditis. Folia Med (Plovdiv). 2010;52:5–12.Google Scholar
  77. 77.
    Yang R, Shan Z, Li Y, Fan C, Li C, Teng W. Prevalence of thyroid autoantibodies in hepatitis C and hepatitis B infection in China. Intern Med. 2011;50:811–5.PubMedGoogle Scholar
  78. 78.
    Keeffe EB, Dieterich DT, Pawlotsky JM, Benhamou Y. Chronic hepatitis B: preventing, detecting, and managing viral resistance. Clin Gastroenterol Hepatol. 2008;6:268–74.PubMedGoogle Scholar
  79. 79.
    Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, Liaw YF, Mizokami M, Kuiken C. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology. 2007;46:254–65.PubMedGoogle Scholar
  80. 80.
    Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane EJ, Jacobson IM, Lim SG, Naoumov N, Marcellin P, Piratvisuth T, Zoulim F. Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol. 2007;5(8):890–7.PubMedGoogle Scholar
  81. 81.
    Lampertico P, Vigano M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology. 2005;42:1414–9.PubMedGoogle Scholar
  82. 82.
    Guicciardi ME, Gores GJ. Apoptosis: a mechanism of acute and chronic liver injury. Gut. 2005;54:1024–33.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Chan HL, Tsang SW, Hui Y, Leung NW, Chan FK, Sung JJ. The role of lamivudine and predictors of mortality in severe flare-up of chronic hepatitis B with jaundice. J Viral Hepat. 2002;9:424–8.PubMedGoogle Scholar
  84. 84.
    Tsang SW, Chan HL, Leung NW, Chau TN, Lai ST, Chan FK, Sung JJ. Lamivudine treatment for fulminant hepatic failure due to acute exacerbation of chronic hepatitis B infection. Aliment Pharmacol Ther. 2001;15:1737–44.PubMedGoogle Scholar
  85. 85.
    Tsubota A, Arase Y, Suzuki Y, Suzuki F, Sezaki H, Hosaka T, Akuta N, Someya T, Kobayashi M, Saitoh S, Ikeda K, Kumada H. Lamivudine monotherapy for spontaneous severe acute exacerbation of chronic hepatitis B. J Gastroenterol Hepatol. 2005;20:426–32.PubMedGoogle Scholar
  86. 86.
    Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, Leduc R, Peltekian K, Wong F, Margulies M, Heathcote EJ. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology. 2000;31:207–10.PubMedGoogle Scholar
  87. 87.
    Yoshiba M. [Recent advances in the treatment of fulminant hepatitis B]. Nihon Rinsho. 2004;62(Suppl 8):280–3.Google Scholar
  88. 88.
    Chien RN, Lin CH, Liaw YF. The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B. J Hepatol. 2003;38:322–7.PubMedGoogle Scholar
  89. 89.
    Wong VW, Chan HL. Severe acute exacerbation of chronic hepatitis B: a unique presentation of a common disease. J Gastroenterol Hepatol. 2009;24:1179–86.PubMedGoogle Scholar
  90. 90.
    Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. Hepatology. 2011;53:774–80.PubMedGoogle Scholar
  91. 91.
    Gao HB, Xu M, Shi HY, Xiao L, Zhang FC. [Effect of HBV DNA on prognosis of the different clinical stages of chronic severe hepatitis B]. J Clin Hepatol. 2010;13:116–8.Google Scholar
  92. 92.
    Ma K, Guo W, Han MF, Chen G, Chen T, Wu ZG, Yang DF, Huang JQ, Huang YC, Zhao XP, Tian DY, Song JX, Qi JY, Ning Q. Entecavir treatment prevents disease progression in hepatitis B virus-related acute-on-chronic liver failure: establishment of a novel logistical regression model. Hepatol Int. 2012;6:735–43.PubMedGoogle Scholar
  93. 93.
    Lin BL, Xie DY, Zhang XH, Xie JQ, Zhang SQ, Chong YT, Gao ZL. [Therapeutic efficacy and related factors of entecavir treatment for patients with acute on chronic hepatitis B liver failure]. Chin J Clin Infect Dis. 2011;4:21–4.Google Scholar
  94. 94.
    Hu JH, Wang HF, He WP, Liu XY, Du N, Huang K, Ding JB, Duan XZ, Chen J, Chen JM. [Lamivudine and entecavir significantly improved the prognosis of early-to-mid stage hepatitis B related acute on chronic liver failure]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2010;24:205–8.Google Scholar
  95. 95.
    Tillmann HL, Zachou K, Dalekos GN. Management of severe acute to fulminant hepatitis B: to treat or not to treat or when to treat? Liver Int. 2012;32:544–53.PubMedGoogle Scholar
  96. 96.
    Organization Committee of 13th Asia-Pacific Congress of Clinical Microbiology and Infection. Microbiology and Infection Consensus Guidelines for diagnosis and treatment of liver failure. Hepatobiliary Pancreat Dis Int. 2013;12:346–54.Google Scholar
  97. 97.
    Sarin SV, Kedarisetty CK, Abbas Z, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014. Hepatol Int. 2014;8:453–71.Google Scholar
  98. 98.
    Lee HC. Acute liver failure related to hepatitis B virus. Hepatol Res. 2008;38:S9–S13.PubMedGoogle Scholar
  99. 99.
    Liu XY, Hu JH, Wang HF, et al. Etiological analysis of 1977 patients with acute liver failure, subacute liver failure and acute-on-chronic liver failure. Chin J Hepatol. 2008;16:772–775 (in Chinese).Google Scholar
  100. 100.
    Liu XY, Hu JH, Wang HF, et al. Analysis of prognostic factors for patients with acute-on-chronic liver failure. Chin J Hepatol. 2009;17:607–610 (in Chinese).Google Scholar
  101. 101.
    Lee WM, Larson AM, Stravitz RT. AASLD position paper: the management of acute liver failure: update 2011. Hepatology. 2012;55:965–7.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Philips CA, Sarin SV. Potent antiviral therapy improves survival in acute on chronic liver failure due to hepatitis B virus reactivation. World J Gastroenterol. 2014;20:16037–52.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Zhang AM, Wang HF, Wang HB, et al. Association between HBV genotype and chronic/severe liver disease with HBV infection in Chinese patients. Chin J Exp Clin Virol. 2010;24:178–180 (in Chinese).Google Scholar
  104. 104.
    Yan T, Li K, Li F, et al. T1846 and A/G1913 are associated with acute on chronic liver failure in patients infected with hepatitis B virus genotypes B and C. J Gastroenterol. 2011;46:391–400.Google Scholar
  105. 105.
    Ren X, Xu Z, Liu Y, et al. Hepatitis B virus genotype and basal core promoter/precore mutations are associated with hepatitis B-related acute-on-chronic liver failure without pre-existing liver cirrhosis. J Viral Hepat. 2010;17:887–95.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Imamura T, Yokosuka O, Kurihara T, et al. Distribution of hepatitis B viral genotypes and mutations in the core promoter and precore regions in acute forms of liver disease in patients from Chiba, Japan. Gut. 2003;52:1630–7.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Alexopoulou A, Karayiannis P. HBeAg negative variants and their role in the natural history of chronic hepatitis B virus infection. World J Gastroenterol. 2014;20:7644–52.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Laleman W, Verbeke L, Meersseman P, et al. Acute-on chronic liver failure: current concepts on definition, pathogenesis, pathogenesis, clinical manifestations and potential therapeutic interventions. Expert Rev Gastroenterol Hepatol. 2011;5:523–37.PubMedGoogle Scholar
  109. 109.
    Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management. J Hepatol. 2014;61:1407–17.Google Scholar
  110. 110.
    Maruyama T, Iino S, Koike K, et al. Serology of acute exacerbation in chronic hepatitis B virus infection. Gastroenterology. 1993;105:1141–51.Google Scholar
  111. 111.
    Chu CM, Liaw YF. Intrahepatic distribution of HBsAg and HBcAg in chronic hepatitis B virus infection: hepatocyte with cytoplasmic/membranous HBcAg as a possible target for immune hepatocytolysis. Gastroenterology. 1987;92:220–5.PubMedGoogle Scholar
  112. 112.
    Chu CM, Shyu WC, Kuo RW, et al. HLA class I antigen display on hepatocyte membrane in chronic hepatitis B virus infection: its role in the pathogenesis of chronic type B hepatitis. Hepatology. 1988;8:712–7.PubMedGoogle Scholar
  113. 113.
    Liaw YF. Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy. J Gastroenterol Hepatol. 2003;18:246–52.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Liaw YF, Tsai SL. Pathogenesis and clinical significance of spontaneous exacerbation and remissions in chronic HBV infection. Viral Hepat Rev. 1997;3:143–54.Google Scholar
  115. 115.
    Tillmann HL, Hadem J, Leifeld L, et al. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat. 2006;13:256–63.PubMedGoogle Scholar
  116. 116.
    Jochum C, Gieseler RK, Gawlista I, et al. Hepatitis B-associated acute liver failure: immediate treatment with entecavir inhibits hepatitis B virus replication and potentially its sequelae. Digestion. 2009;80:235–40.PubMedGoogle Scholar
  117. 117.
    Huang K, Hu JH, Wang HF, et al. Survival and prognostic factors in hepatitis B virus-related acute-on-chronic liver failure. World J Gastroenterol. 2011;17:3448–52.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Garg H, Kumar A, Garg V, et al. Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure. Dig Liver Dis. 2012;44:166–71.PubMedGoogle Scholar
  119. 119.
    Kumar M, Sharma BC, Sarin SK. Hepatitis E virus as an etiology of acute exacerbation of previously unrecognized asymptomatic patients with hepatitis B virus-related chronic liver disease. J Gastroenterol Hepatol. 2008;23:883–7.PubMedGoogle Scholar
  120. 120.
    Hu JH, Wang HF, He WP, et al. Lamivudine and entecavir significantly improved the prognosis of early-to-mid stage hepatitis B related acute on chronic liver failure. Chin J Exp Clin Virol. 2010;24:205–208 (in Chinese).Google Scholar
  121. 121.
    Yan Y, Mai L, Zheng Y, et al. What MELD score mandates use of entecavir for ACLF-HBV HBeAg-negative patients? World J Gastroenterol. 2012;18:4604–9.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Hu JH, Huang K, Wang HF, et al. Survival analysis of 190 patients with HBV-related acute-on-chronic liver failure. Infect Dis Inf. 2010;23:83–86 (in Chinese).Google Scholar
  123. 123.
    Chung GE, Lee JH, Kim YJ. Does antiviral therapy reduce complications of cirrhosis? World J Gastroenterol. 2014;20:7306–11.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Brown A, Goodman Z. Hepatitis B-associated fibrosis and fibrosis/cirrhosis regression with nucleoside and nucleotide analogs. Expert Rev Gastroenterol Hepatol. 2012;6:187–98.PubMedGoogle Scholar
  125. 125.
    Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol. 2000;33:301–7.PubMedGoogle Scholar
  126. 126.
    Liaw YF, Sung JJ, Chow WC. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351(15):1521–31.Google Scholar
  127. 127.
    Fontana RJ, Hann HW, Perrillo RP, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology. 2002;123(3):719–27.PubMedGoogle Scholar
  128. 128.
    Chan HL, Tsang SW, Hui Y, et al. The role of lamivudine and predictors of mortality in severe flare-up of chronic hepatitis B with jaundice. J Viral Hepat. 2002;9:424–8.PubMedGoogle Scholar
  129. 129.
    Zhang L, Hao C, Liu J, et al. Meta-analysis of the short-term effects of lamivudine treatment for severe chronic hepatitis B. Virol J. 2013;10:134–46.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Tsubota A, Arase Y, Suzuki Y, et al. Lamivudine monotherapy for spontaneous severe acute exacerbation of chronic hepatitis B. J Gastroenterol Hepatol. 2005;20:426–32.Google Scholar
  131. 131.
    Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003;38:1419–27.PubMedGoogle Scholar
  132. 132.
    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(6):1743–51.PubMedGoogle Scholar
  133. 133.
    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(10):1001–10.PubMedGoogle Scholar
  134. 134.
    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(10):1011–20.PubMedGoogle Scholar
  135. 135.
    Zhang X, An Y, Jiang X, et al. Entecavir versus lamivudine therapy for patients with chronic hepatitis B-associated liver failure: a meta-analysis. Hepat Mon. 2014;14:e19164.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Chen C, Lin C, Hu T, et al. Entecavir vs. lamivudine in chronic hepatitis B patients with severe acute exacerbation and hepatic decompensation. J Hepatol. 2014;60:1127–34.PubMedGoogle Scholar
  137. 137.
    Shouval D. The pros and cons of lamivudine vs. entecavir in decompensated or severe acute exacerbation of chronic hepatitis B. J Hepatol. 2014;60:1108–9.PubMedGoogle Scholar
  138. 138.
    Wang L, Chen H, Fan C, et al. Efficacy and safety of telbivudine therapy in liver failure patients with chronic hepatitis B virus infection. J Med Virol. 2013;85:1907–12.PubMedGoogle Scholar
  139. 139.
    Chan HL, Chen YC, Gane EJ, et al. Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naïve patients with HBV-related decompensated cirrhosis. J Viral Hepat. 2012;19(10):732–43.PubMedGoogle Scholar
  140. 140.
    Chen T, He Y, Liu X, et al. Nucleoside analogues improve the short-term and long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure. Clin Exp Med. 2012;12:159–64.Google Scholar
  141. 141.
    Yu JW, Sun LJ, Zhao YH, et al. The study of efficacy of lamivudine in patients with severe acute hepatitis B. Dig Dis Sci. 2010;55:775–83.PubMedGoogle Scholar
  142. 142.
    Di Marco V, Di Stefano R, Ferraro D, et al. HBV-DNA suppression and disease course in HBV cirrhosis patients on long-term lamivudine therapy. Antivir Ther. 2005;10:431–9.PubMedGoogle Scholar
  143. 143.
    Di Marco V, Marzano A, Lampertico P, et al. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology. 2004;40:883–91.PubMedGoogle Scholar
  144. 144.
    Ono A, Suzuki F, Kawamura Y, et al. Long-term continuous entecavir therapy in nucleos(t)ide-naïve chronic hepatitis B patients. J Hepatol. 2012;57:508–14.PubMedGoogle Scholar
  145. 145.
    Tujios SR, Lee WM. Update in the management of chronic hepatitis B. Curr Opin Gastroenterol. 2013;29:250–6.PubMedGoogle Scholar
  146. 146.
    Liaw YF, Kao JH, Piratvisuth T, Chan HLY, Chien RN, Liu CJ, Gane E, Locarnini S, Lim SG, Han KH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;3:531–61.Google Scholar
  147. 147.
    Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, Tobias H. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6(12):1315–41.PubMedGoogle Scholar
  148. 148.
    Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295(1):65–73.PubMedGoogle Scholar
  149. 149.
    Hann HW, Fontana RJ, Wright T, Everson G, Baker A, Schiff ER, Riely C, Anschuetz G, Gardner SD, Brown N, Griffiths D, United States Lamivudine Compassionate Use Study Group. A United States compassionate use study of lamivudine treatment in nontransplantation candidates with decompensated hepatitis B virus-related cirrhosis. Liver Transpl. 2003;9(1):49–56.PubMedGoogle Scholar
  150. 150.
    Huang Y, Wu H, Wu S, Fu D, Ma Y, Shen X. A meta-analysis of nucleos(t)ide analogues in patients with decompensated cirrhosis due to hepatitis B. Dig Dis Sci. 2013;58(3):815–23.PubMedGoogle Scholar
  151. 151.
    Yeon JE, Yoo W, Hong SP, Chang YJ, Yu SK, Kim JH, Seo YS, Chung HJ, Moon MS, Kim SO, Byun KS, Lee CH. Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil. Gut. 2006;55(10):1488–95.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Kim SB, Kim SU, Kim BK, Park JY, Kim DY, Ahn SH, Han KH. Outcome of adefovir add-on lamivudine rescue therapy of up to 5 years in patients with lamivudine-resistant chronic hepatitis B. J Gastroenterol Hepatol. 2016;31:241–7.  https://doi.org/10.1111/jgh.13046.. [Epub ahead of print].CrossRefPubMedGoogle Scholar
  153. 153.
    Woo HY, Choi JY, Yoon SK, Suh DJ, Paik SW, Han KH, Um SH, Kim BI, Lee HJ, Cho M, Lee CK, Kim DJ, Hwang JS. Rescue therapy with adefovir in decompensated liver cirrhosis patients with lamivudine-resistant hepatitis B virus. Clin Mol Hepatol. 2014;20(2):168–76.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, Heathcote EJ, Manns M, Bzowej N, Niu J, Han SH, Hwang SG, Cakaloglu Y, Tong MJ, Papatheodoridis G, Chen Y, Brown NA, Albanis E, Galil K, Naoumov NV, GLOBE Study Group. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009;136(2):486–95.PubMedGoogle Scholar
  155. 155.
    Matthews SJ. Telbivudine for the management of chronic hepatitis B virus infection. Clin Ther. 2007;29(12):2635–53.PubMedGoogle Scholar
  156. 156.
    Sun J, Xie Q, Tan D, Ning Q, Niu J, Bai X, Fan R, Chen S, Cheng J, Yu Y, Wang H, Xu M, Shi G, Wan M, Chen X, Tang H, Sheng J, Dou X, Shi J, Ren H, Wang M, Zhang H, Gao Z, Chen C, Ma H, Jia J, Hou J. The 104-week efficacy and safety of telbivudine-based optimization strategy in chronic hepatitis B patients: a randomized, controlled study. Hepatology. 2014;59(4):1283–92.PubMedGoogle Scholar
  157. 157.
    Yao G, Chen C, Lu W, Ren H, Tan D, Wang Y, Xu D, Jiang Z, Liu J, Xu D, Macdonald L, AI463023 Study Group. Efficacy and safety of entecavir compared to lamivudine in nucleoside-naïve patients with chronic hepatitis B: a randomized double-blind trial in China. Hepatol Int. 2007;1(3):365–72.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, Suh DJ. Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol. 2010;52(2):176–82.PubMedGoogle Scholar
  159. 159.
    Zoutendijk R, Reijnders JG, Zoulim F, Brown A, Mutimer DJ, Deterding K, Hofmann WP, Petersen J, Fasano M, Buti M, Berg T, Hansen BE, Sonneveld MJ, Wedemeyer H, Janssen HL, VIRGIL Surveillance Study Group. Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut. 2013;62(5):760–5.PubMedGoogle Scholar
  160. 160.
    Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Schall RA, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468–75.PubMedGoogle Scholar
  161. 161.
    Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, Chang TT, Horban A, Wang C, Kwan P, Buti M, Prieto M, Berg T, Kitrinos K, Peschell K, Mondou E, Frederick D, Rousseau F, Schiff ER. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53(1):62–72.PubMedGoogle Scholar
  162. 162.
    Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL, Heathcote EJ, Little NR, Griffiths DA, Gardner SD, Castiglia M. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125(6):1714–22.PubMedGoogle Scholar
  163. 163.
    Sung JJ, Lai JY, Zeuzem S, Chow WC, Heathcote EJ, Perrillo RP, Brosgart CL, Woessner MA, Scott SA, Gray DF, Gardner SD. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol. 2008;48(5):728–35.PubMedGoogle Scholar
  164. 164.
    Gu EL, Yu YQ, Wang JL, Ji YY, Ma XY, Xie Q, Pan HY, Wu SM, Li J, Chen CW, Xu XW, Wang YE, Yao GB, Wang H, Zhang WH. Response-guided treatment of cirrhotic chronic hepatitis B patients: multicenter prospective study. World J Gastroenterol. 2015;21(2):653–60.PubMedPubMedCentralGoogle Scholar
  165. 165.
    Gish RG, Trinh H, Leung N, Chan FK, Fried MW, Wright TL, Wang C, Anderson J, Mondou E, Snow A, Sorbel J, Rousseau F, Corey L. Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study. J Hepatol. 2005;43(1):60–6.PubMedGoogle Scholar
  166. 166.
    Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, Gurel S, Caruntu FA, Flaherty JF, Massetto B, Dinh P, Corsa A, Subramanian GM, McHutchison JG, Husa P, Gane E. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2014;146(4):980–8.PubMedGoogle Scholar
  167. 167.
    Berg T, Zoulim F, Moeller B, Trinh H, Marcellin P, Chan S, Kitrinos KM, Dinh P, Flaherty JF Jr, McHutchison JG, Manns M. Long-term efficacy and safety of emtricitabine plus tenofovir DF vs. tenofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients. J Hepatol. 2014;60(4):715–22.PubMedGoogle Scholar
  168. 168.
    Ha NB, Ha NB, Garcia RT, Trinh HN, Chaung KT, Nguyen HA, Nguyen KK, Levitt BS, Nguyen MH. Medication nonadherence with long-term management of patients with hepatitis B e antigen-negative chronic hepatitis B. Dig Dis Sci. 2011;56(8):2423–31.PubMedGoogle Scholar
  169. 169.
    Hongthanakorn C, Chotiyaputta W, Oberhelman K, Fontana RJ, Marrero JA, Licari T, Lok AS. Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice. Hepatology. 2011;53(6):1854–63.PubMedGoogle Scholar
  170. 170.
    Wursthorn K, Jung M, Riva A, Goodman ZD, Lopez P, Bao W, Manns MP, Wedemeyer H, Naoumov NV. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology. 2010;52(5):1611–20.PubMedGoogle Scholar
  171. 171.
    Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, Lim SG, Wu PC, Dent JC, Edmundson S, Condreay LD, Chien RN, Asia Hepatitis Lamivudine Study Group. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology. 2001;33(6):1527–32.PubMedGoogle Scholar
  172. 172.
    Perrella A, Lanza AG, Pisaniello D, DiCostanzo G, Calise F, Cuomo O. Telbivudine prophylaxis for hepatitis B virus recurrence after liver transplantation improves renal function. Transplant Proc. 2014;46(7):2319–21.PubMedGoogle Scholar
  173. 173.
    Buti M, Tsai N, Petersen J, Flisiak R, Gurel S, Krastev Z, Schall RA, Flaherty JF, Martins EB, Charuworn P, Kitrinos KM, Subramanian GM, Gane E, Marcellin P. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci. 2015;60(5):1457–64.PubMedGoogle Scholar
  174. 174.
    Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, Borroto-Esoda K, Frederick D, Rousseau F. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008;48(3):750–8.PubMedGoogle Scholar
  175. 175.
    Lampertico P, Viganò M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133(5):1445–51.PubMedGoogle Scholar
  176. 176.
    Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, Han KH, Chao YC, Lee SD, Harris M, Yang J, Colonno R, Brett-Smith H. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133(5):1437–44.PubMedGoogle Scholar
  177. 177.
    Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, Chen Y, Heathcote EJ, Rasenack J, Bzowej N, Naoumov NV, Di Bisceglie AM, Zeuzem S, Moon YM, Goodman Z, Chao G, Constance BF, Brown NA, Globe Study Group. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007;357(25):2576–88.PubMedGoogle Scholar
  178. 178.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.PubMedGoogle Scholar
  179. 179.
    Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol. 2014;28(5):753–70.PubMedGoogle Scholar
  180. 180.
    Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118(12):3030–44.PubMedGoogle Scholar
  181. 181.
    Franceschi S, Raza SA. Epidemiology and prevention of hepatocellular carcinoma. Cancer Lett. 2009;286(1):5–8.PubMedGoogle Scholar
  182. 182.
    Chen G, Lin W, Shen F, Iloeje UH, London WT, Evans AA. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am J Gastroenterol. 2006;101(8):1797–803.PubMedGoogle Scholar
  183. 183.
    Liaw YF, Leung N, Kao JH, et al., Chronic Hepatitis B Guideline Working Party of the Asian-Pacific Association for the Study of the Liver. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2(3):263–83.PubMedPubMedCentralGoogle Scholar
  184. 184.
    European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50(2):227–42.Google Scholar
  185. 185.
    Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50(3):1–36.Google Scholar
  186. 186.
    Badvie S. Hepatocellular carcinoma. Postgrad Med J. 2000;76(891):4–11.PubMedPubMedCentralGoogle Scholar
  187. 187.
    Liu CJ, Kao JH. Hepatitis B virus-related hepatocellular carcinoma: epidemiology and pathogenic role of viral factors. J Chin Med Assoc. 2007;70(4):141–5.PubMedGoogle Scholar
  188. 188.
    Tennant BC, Toshkov IA, Peek SF, Jacob JR, Menne S, Hornbuckle WE, Schinazi RD, Korba BE, Cote PJ, Gerin JL. Hepatocellular carcinoma in the woodchuck model of hepatitis B virus infection. Gastroenterology. 2004;127(5 Suppl 1):S283–93.PubMedGoogle Scholar
  189. 189.
    Bréchot C, Gozuacik D, Murakami Y, Paterlini-Bréchot P. Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin Cancer Biol. 2000;10(3):211–31.PubMedGoogle Scholar
  190. 190.
    Hino O, Tabata S, Hotta Y. Evidence for increased in vitro recombination with insertion of human hepatitis B virus DNA. Proc Natl Acad Sci USA. 1991;88(20):9248–52.PubMedGoogle Scholar
  191. 191.
    Tsuei DJ, Chang MH, Chen PJ, Hsu TY, Ni YH. Characterization of integration patterns and flanking cellular sequences of hepatitis B virus in childhood hepatocellular carcinomas. J Med Virol. 2002;68(4):513–21.PubMedGoogle Scholar
  192. 192.
    Yoo YG, Na TY, Seo HW, Seong JK, Park CK, Shin YK, Lee MO. Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene. 2008;27(24):3405–13.PubMedGoogle Scholar
  193. 193.
    Han HK, Han CY, Cheon EP, Lee J, Kang KW. Role of hypoxia-inducible factor-alpha in hepatitis-B-virus X protein-mediated MDR1 activation. Biochem Biophys Res Commun. 2007;357(2):567–73.PubMedGoogle Scholar
  194. 194.
    Fujii R, Zhu C, Wen Y, Marusawa H, Bailly-Maitre B, Matsuzawa S, Zhang H, Kim Y, Bennett CF, Jiang W, Reed JC. HBXIP, cellular target of hepatitis B virus oncoprotein, is a regulator of centrosome dynamics and cytokinesis. Cancer Res. 2006;66(18):9099–107.PubMedGoogle Scholar
  195. 195.
    Kuang SY, Jackson PE, Wang JB, Lu PX, Muñoz A, Qian GS, Kensler TW, Groopman JD. Specific mutations of hepatitis B virus in plasma predict liver cancer development. Proc Natl Acad Sci U S A. 2004;101(10):3575–80.PubMedPubMedCentralGoogle Scholar
  196. 196.
    Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene. 2006;25(27):3778–86.PubMedGoogle Scholar
  197. 197.
    Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 2006;25(27):3787–800.PubMedGoogle Scholar
  198. 198.
    Kuo CY, Wang JC, Hsu SL, et al. HBx inhibits the growth of CCL13-HBX-stable cells via the GSK-3beta/beta-catenin cascade. Intervirology. 2008;51(2):130–6.PubMedGoogle Scholar
  199. 199.
    Liu X, Wang L, Zhang S, et al. Mutations in the C-terminus of the X protein of hepatitis B virus regulate Wnt-5a expression in hepatoma Huh7 cells: cDNA microarray and proteomic analyses. Carcinogenesis. 2008;29(6):1207–14.PubMedPubMedCentralGoogle Scholar
  200. 200.
    Rossmanith W, Schulte-Hermann R. Biology of transforming growth factor beta in hepatocarcinogenesis. Microsc Res Tech. 2001;52(4):430–6.PubMedGoogle Scholar
  201. 201.
    Fransvea E, Mazzocca A, Antonaci S, Giannelli G. Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma. Hepatology. 2009;49(3):839–50.PubMedGoogle Scholar
  202. 202.
    Oishi N, Shilagardi K, Nakamoto Y, Honda M, Kaneko S, Murakami S. Hepatitis B virus X protein overcomes oncogenic RAS-induced senescence in human immortalized cells. Cancer Sci. 2007;98(10):1540–8.PubMedGoogle Scholar
  203. 203.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.PubMedGoogle Scholar
  204. 204.
    Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, Naito M, Enomoto K, Watanabe S, Mak TW, Nakano T. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 2004;113(12):1774–83.PubMedPubMedCentralGoogle Scholar
  205. 205.
    Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002;285(1–2):1–24.PubMedGoogle Scholar
  206. 206.
    Bromberg JF. Activation of STAT proteins and growth control. Bioessays. 2001;23(2):161–9.PubMedGoogle Scholar
  207. 207.
    Yun C, Cho H, Kim SJ, Lee JH, Park SY, Chan GK, Cho H. Mitotic aberration coupled with centrosome amplification is induced by hepatitis B virus X oncoprotein via the Ras-mitogen-activated protein/extracellular signal-regulated kinase-mitogen-activated protein pathway. Mol Cancer Res. 2004;2(3):159–69.PubMedGoogle Scholar
  208. 208.
    Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, Factor VM, Thorgeirsson SS. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130(4):1117–28.PubMedGoogle Scholar
  209. 209.
    Griner EM, Kazanietz MG. Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer. 2007;7(4):281–94.PubMedGoogle Scholar
  210. 210.
    Wu TT, Hsieh YH, Wu CC, Hsieh YS, Huang CY, Liu JY. Overexpression of protein kinase C alpha mRNA in human hepatocellular carcinoma: a potential marker of disease prognosis. Clin Chim Acta. 2007;382(1–2):54–8.PubMedGoogle Scholar
  211. 211.
    Liu Y, Xu L, Zeng Q, Wang J, Wang M, Xi D, Wang X, Yang D, Luo X, Ning Q. Downregulation of FGL2/prothrombinase delays HCCLM6 xenograft tumour growth and decreases tumour angiogenesis. Liver Int. 2012;32(10):1585–95.PubMedGoogle Scholar
  212. 212.
    Su K, Chen F, Yan WM, Zeng QL, Xu L, Xi D, Pi B, Luo XP, Ning Q. Fibrinogen-like protein 2/fibroleukin prothrombinase contributes to tumor hypercoagulability via IL-2 and IFN-gamma. World J Gastroenterol. 2008;14(39):5980–9.PubMedPubMedCentralGoogle Scholar
  213. 213.
    Chang MH, You SL, Chen CJ, Liu CJ, Lee CM, Lin SM, Chu HC, Wu TC, Yang SS, Kuo HS, Chen DS, Taiwan Hepatoma Study Group. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009;101(19):1348–55.PubMedGoogle Scholar
  214. 214.
    Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008;28(9):1067–77.PubMedGoogle Scholar
  215. 215.
    Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA levels and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97(4):265–72.PubMedGoogle Scholar
  216. 216.
    Giannelli G, Bergamini C, Marinosci F, et al. Antifibrogenic effect of IFN-alpha2b on hepatic stellate cell activation by human hepatocytes. J Interferon Cytokine Res. 2006;26(5):301–8.PubMedGoogle Scholar
  217. 217.
    Tasci I, Mas MR, Vural SA, et al. Rat liver fibrosis regresses better with pegylated interferon alpha-2b and ursodeoxycholic acid treatment than spontaneously recovery. Liver Int. 2006;26(2):261–8.PubMedGoogle Scholar
  218. 218.
    Chan HL. Revisiting the treatment recommendations for chronic hepatitis B. Hepatology. 2009;49(2):700; author reply 701–2.PubMedGoogle Scholar
  219. 219.
    Tong MJ, Hsien C, Hsu L, Sun HE, Blatt LM. Treatment recommendations for chronic hepatitis B: an evaluation of current guidelines based on a natural history study in the United States. Hepatology. 2008;48(4):1070–8.PubMedGoogle Scholar
  220. 220.
    Yuen MF, Yuan HJ, Wong DK, Yuen JC, Wong WM, Chan AO, Wong BC, Lai KC, Lai CL. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut. 2005;54(11):1610–4.PubMedPubMedCentralGoogle Scholar
  221. 221.
    Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328(7446):983.PubMedPubMedCentralGoogle Scholar
  222. 222.
    El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264–73.PubMedPubMedCentralGoogle Scholar
  223. 223.
    Ye S. Expert consensus on antiviral therapy to treat hepatitis B/C virus-related hepatocellular carcinoma. Zhonghua Gan Zang Bing Za Zhi. 2014;22(5):321–6 (in Chinese).PubMedGoogle Scholar
  224. 224.
    Li N, Lai EC, Shi J, Guo WX, Xue J, Huang B, Lau WY, Wu MC, Cheng SQ. A comparative study of antiviral therapy after resection of hepatocellular carcinoma in the immune-active phase of hepatitis B virus infection. Ann Surg Oncol. 2010;17(1):179–85.PubMedGoogle Scholar
  225. 225.
    Kubo S, Hirohashi K, Tanaka H, Tsukamoto T, Shuto T, Yamamoto T, Ikebe T, Wakasa K, Nishiguchi S, Kinoshita H. Effect of viral status on recurrence after liver resection for patients with hepatitis B virus-related hepatocellular carcinoma. Cancer. 2000;88(5):1016–24.PubMedGoogle Scholar
  226. 226.
    Kubo S, Hirohashi K, Tanaka H, Tsukamoto T, Shuto T, Higaki I, Takemura S, Yamamoto T, Nishiguchi S, Kinoshita H. Virologic and biochemical changes and prognosis after liver resection for hepatitis B virus-related hepatocellular carcinoma. Dig Surg. 2001;18(1):26–33.PubMedGoogle Scholar
  227. 227.
    Kim BK, Park JY, Kim DY, Kim JK, Kim KS, Choi JS, Moon BS, Han KH, Chon CY, Moon YM, Ahn SH. Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection. Liver Int. 2008;28(3):393–401.PubMedGoogle Scholar
  228. 228.
    An HJ, Jang JW, Bae SH, Choi JY, Cho SH, Yoon SK, Han JY, Lee KH, Kim DG, Jung ES. Sustained low hepatitis B viral load predicts good outcome after curative resection in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 2010;25(12):1876–82.PubMedGoogle Scholar
  229. 229.
    Sun HC, Zhang W, Qin LX, Zhang BH, Ye QH, Wang L, Ren N, Zhuang PY, Zhu XD, Fan J, Tang ZY. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol. 2007;47(5):684–90.PubMedGoogle Scholar
  230. 230.
    Qu LS, Jin F, Huang XW, Shen XZ. Interferon-α therapy after curative resection prevents early recurrence and improves survival in patients with hepatitis B virus-related hepatocellular carcinoma. J Surg Oncol. 2010;102(7):796–801.PubMedGoogle Scholar
  231. 231.
    Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, Zhou XD, Zhou J, Qiu SJ, Shen YF. Postoperative interferon alpha treatment postponed recurrence and improved OS in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol. 2006;132(7):458–65.PubMedGoogle Scholar
  232. 232.
    Someya T, Ikeda K, Saitoh S, Kobayashi M, Hosaka T, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Arase Y, Kumada H. Interferon lowers tumor recurrence rate after surgical resection or ablation of hepatocellular carcinoma: a pilot study of patients with hepatitis B virus-related cirrhosis. J Gastroenterol. 2006;41(12):1206–13.PubMedGoogle Scholar
  233. 233.
    Ikeda K, Arase Y, Kobayashi M, Someya T, Saitoh S, Suzuki Y, Suzuki F, Tsubota A, Akuta N, Kumada H. Consistently low hepatitis B virus DNA saves patients from hepatocellular carcinogenesis in HBV-related cirrhosis. A nested case-control study using 96 untreated patients. Intervirology. 2003;46(2):96–104.PubMedGoogle Scholar
  234. 234.
    Tang B, Kruger WD, Chen G, Shen F, Lin WY, Mboup S, London WT, Evans AA. Hepatitis B viremia is associated with increased risk of hepatocellular carcinoma in chronic carriers. J Med Virol. 2004;72(1):35–40.PubMedGoogle Scholar
  235. 235.
    Dunk AA, Ikeda T, Pignatelli M, Thomas HC. Human lymphoblastoid interferon. In vitro and in vivo studies in hepatocellular carcinoma. J Hepatol. 1986;2(3):419–29.PubMedGoogle Scholar
  236. 236.
    Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Tsubota A, Chayama K, Murashima N, Kumada H. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor—a prospective randomized study of hepatitis C virus-related liver cancer. Hepatology. 2000;32(2):228–32.PubMedGoogle Scholar
  237. 237.
    Wong JS, Wong GL, Tsoi KK, Wong VW, Cheung SY, Chong CN, Wong J, Lee KF, Lai PB, Chan HL. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther. 2011;33(10):1104–12.PubMedGoogle Scholar
  238. 238.
    Chung GE, Kim W, Lee JH, Kim YJ, Yoon JH, Lee JM, Lee JY, Kim SH, Kim D, Lee HS. Negative hepatitis B envelope antigen predicts intrahepatic recurrence in hepatitis B virus-related hepatocellular carcinoma after ablation therapy. J Gastroenterol Hepatol. 2011;26(11):1638–45.PubMedGoogle Scholar
  239. 239.
    Xia F, Lai EC, Lau WY, Ma K, Li X, Bie P, Qian C. High serum hyaluronic acid and HBV viral load are main prognostic factors of local recurrence after complete radiofrequency ablation of hepatitis B-related small hepatocellular carcinoma. Ann Surg Oncol. 2012;19(4):1284–91.PubMedGoogle Scholar
  240. 240.
    Goto T, Yoshida H, Tateishi R, Enooku K, Goto E, Sato T, Ohki T, Masuzaki R, Imamura J, Shiina S, Koike K, Omata M. Influence of serum HBV DNA load on recurrence of hepatocellular carcinoma after treatment with percutaneous radiofrequency ablation. Hepatol Int. 2011;5(3):767–73.PubMedGoogle Scholar
  241. 241.
    Lin SM, Lin CJ, Hsu CW, Tai DI, Sheen IS, Lin DY, Liaw YF. Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors. Cancer. 2004;100(2):376–82.PubMedGoogle Scholar
  242. 242.
    Yoshida H, Yoshida H, Goto E, Sato T, Ohki T, Masuzaki R, Tateishi R, Goto T, Shiina S, Kawabe T, Omata M. Safety and efficacy of lamivudine after radiofrequency ablation in patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Int. 2008;2(1):89–94.PubMedGoogle Scholar
  243. 243.
    Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991;100(1):182–8.PubMedGoogle Scholar
  244. 244.
    Yeo W, Chan PK, Zhong S, Ho WM, Steinberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol. 2000;62(3):299–307.PubMedGoogle Scholar
  245. 245.
    Liao CA, Lee CM, Wu HC, Wang MC, Lu SN, Eng HL. Lamivudine for the treatment of hepatitis B virus reactivation following chemotherapy for non-Hodgkin’s lymphoma. Br J Haematol. 2002;116(1):166–9.PubMedGoogle Scholar
  246. 246.
    Lim LL, Wai CT, Lee YM, Kong HL, Lim R, Koay E, et al. Prophylactic lamivudine prevents hepatitis B reactivation in chemotherapy patients. Aliment Pharmacol Ther. 2002;16(11):1939–44.PubMedGoogle Scholar
  247. 247.
    Leaw SJ, Yen CJ, Huang WT, Chen TY, Su WC, Tsao CJ. Preemptive use of interferon or lamivudine for hepatitis B reactivation in patients with aggressive lymphoma receiving chemotherapy. Ann Hematol. 2004;83(5):270–5.PubMedGoogle Scholar
  248. 248.
    Dai MS, Wu PF, Shyu RY, Lu JJ, Chao TY. Hepatitis B virus reactivation in breast cancer patients undergoing cytotoxic chemotherapy and the role of preemptive lamivudine administration. Liver Int. 2004;24(6):540–6.PubMedGoogle Scholar
  249. 249.
    Jang JW, Choi JY, Bae SH, Yoon SK, Chang UI, Kim CW, Cho SH, Han JY, Lee YS. A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology. 2006;43(2):233–40.PubMedGoogle Scholar
  250. 250.
    Zhu SL, Zhong JH, Ke Y, Xiao HM, Ma L, Chen J, You XM, Li LQ. Comparative efficacy of postoperative transarterial chemoembolization with or without antiviral therapy for hepatitis B virus-related hepatocellular carcinoma. Tumour Biol. 2015;36:6277–84. [Epub ahead of print].PubMedGoogle Scholar
  251. 251.
    Kim JH, Park JW, Kim TH, Koh DW, Lee WJ, Kim CM. Hepatitis B virus reactivation after three-dimensional conformal radiotherapy in patients with hepatitis B virus-related hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2007;69(3):813–9.PubMedGoogle Scholar
  252. 252.
    Huang W, Zhang W, Fan M, Lu Y, Zhang J, Li H, Li B. Risk factors for hepatitis B virus reactivation after conformal radiotherapy in patients with hepatocellular carcinoma. Cancer Sci. 2014;105(6):697–703.PubMedPubMedCentralGoogle Scholar
  253. 253.
    Sherman M. Recurrence of hepatocellular carcinoma. N Engl J Med. 2008;359(19):2045–7.PubMedGoogle Scholar
  254. 254.
    Bruix J, Sherman M, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208–36.PubMedGoogle Scholar
  255. 255.
    Samuel D, Feray C, Bismum H. Hepatitis viruses and liver transplantation. J Gastroenterol Hepatol. 1997;12:S335–41.PubMedGoogle Scholar
  256. 256.
    Villamil FG. Hepatitis B: progress in the last 15 years. Liver Transplant. 2002;8(10 Suppl 1):S59–66.Google Scholar
  257. 257.
    Degertekin B, Han SH, Keeffe EB, Schiff ER, Luketic VA, Brown RS Jr, Emre S, Soldevila-Pico C, Reddy KR, Ishitani MB, Tran TT, Pruett TL, Lok AS, NIH HBV-OLT Study Group. Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation. Am J Transplant. 2010;10(8):1823–33.PubMedPubMedCentralGoogle Scholar
  258. 258.
    Marzano A, Salizzoni M, Debernardi-Venon W, Smedile A, Franchello A, Ciancio A, et al. Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with lamivudine and passive immunoprophylaxis. J Hepatol. 2001;34:903–10.PubMedGoogle Scholar
  259. 259.
    Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H, et al. Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology. 1998;28:585–9.PubMedGoogle Scholar
  260. 260.
    Rosenau J, Bahr MJ, Tillmann HL, Trautwein C, Klempnauer J, Manns MP, et al. Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B reinfection after liver transplantation possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection. J Hepatol. 2001;34(6):895–902.PubMedGoogle Scholar
  261. 261.
    Han SH, Ofman J, Holt C, King K, Kunder G, Chen P, et al. An efficacy and cost-effectiveness analysis of combination hepatitis B immune globulin and lamivudine to prevent recurrent hepatitis B after orthotopic liver transplantation compared with hepatitis B immune globulin monotherapy. Liver Transpl. 2000;6(6):741–8.PubMedGoogle Scholar
  262. 262.
    Steinmuller T, Seehofer D, Rayes N, Muller AR, Settmacher U, Jonas S, et al. Increasing applicability of liver transplantation for patients with hepatitis B-related liver disease. Hepatology. 2002;35:1528–35.PubMedGoogle Scholar
  263. 263.
    Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, Bismuth H. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med. 1993;329(25):1842–7.PubMedGoogle Scholar
  264. 264.
    Seehofer D, Berg T. Prevention of hepatitis B recurrence after liver transplantation. Transplantation. 2005;80(1 Suppl):S120–4.PubMedGoogle Scholar
  265. 265.
    Olivera-Martínez MA, Gallegos-Orozco JF. Recurrent viral liver disease (hepatitis B and C) after liver transplantation. Arch Med Res. 2007;38(6):691–701.PubMedGoogle Scholar
  266. 266.
    Müller R, Gubernatis G, Farle M, Niehoff G, Klein H, Wittekind C, Tusch G, Lautz HU, Böker K, Stangel W, et al. Liver transplantation in HBs antigen (HBsAg) carriers. Prevention of hepatitis B virus (HBV) recurrence by passive immunization. J Hepatol. 1991;13(1):90–6.PubMedGoogle Scholar
  267. 267.
    Samuel D, Bismuth A, Mathieu D, Arulnaden JL, Reynes M, Benhamou JP, Brechot C, Bismuth H. Passive immunoprophylaxis after liver transplantation in HBsAg-positive patients. Lancet. 1991;337(8745):813–5.PubMedGoogle Scholar
  268. 268.
    McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC, Caldwell SH, Pruett TL. Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization. Transplantation. 1996;61(9):1358–64.PubMedGoogle Scholar
  269. 269.
    Sawyer RG, McGory RW, Gaffey MJ, McCullough CC, Shephard BL, Houlgrave CW, Ryan TS, Kuhns M, McNamara A, Caldwell SH, Abdulkareem A, Pruett TL. Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization. Ann Surg. 1998;227(6):841–50.PubMedPubMedCentralGoogle Scholar
  270. 270.
    Terrault NA, Zhou S, Combs C, Hahn JA, Lake JR, Roberts JP, Ascher NL, Wright TL. Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulin. Hepatology. 1996;24(6):1327–33.PubMedGoogle Scholar
  271. 271.
    Fontana RJ, Keeffe EB, Carey W, Fried M, Reddy R, Kowdley KV, Soldevila-Pico C, McClure LA, Lok AS, National Institutes of Health Hepatitis B Virus Orthotopic Liver Transplantation Study Group. Effect of lamivudine treatment on survival of 309 North American patients awaiting liver transplantation for chronic hepatitis B. Liver Transpl. 2002;8(5):433–9.PubMedGoogle Scholar
  272. 272.
    Grellier L, Mutimer D, Ahmed M, Brown D, Burroughs AK, Rolles K, McMaster P, Beranek P, Kennedy F, Kibbler H, McPhillips P, Elias E, Dusheiko G. Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis. Lancet. 1996;348(9036):1212–5.PubMedGoogle Scholar
  273. 273.
    Mutimer D, Pillay D, Dragon E, Tang H, Ahmed M, O’Donnell K, Shaw J, Burroughs N, Rand D, Cane P, Martin B, Buchan S, Boxall E, Barmat S, Gutekunst K, McMaster P, Elias E. High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation. J Hepatol. 1999;30(4):715–21.PubMedGoogle Scholar
  274. 274.
    Marzano A, Salizzoni M, Debernardi-Venon W, Smedile A, Franchello A, Ciancio A, Gentilcore E, Piantino P, Barbui AM, David E, Negro F, Rizzetto M. Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with lamivudine and passive immunoprophylaxis. J Hepatol. 2001;34(6):903–10.PubMedGoogle Scholar
  275. 275.
    Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H, Goss JA, Schmidt P, Pakrasi A, Artinian L, Murray NG, Imagawa DK, Holt C, Goldstein LI, Stribling R, Busuttil RW. Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology. 1998;28(2):585–9.PubMedGoogle Scholar
  276. 276.
    Roche B, Feray C, Gigou M, Roque-Afonso AM, Arulnaden JL, Delvart V, Dussaix E, Guettier C, Bismuth H, Samuel D. HBV DNA persistence 10 years after liver transplantation despite successful anti-HBS passive immunoprophylaxis. Hepatology. 2003;38(1):86–95.PubMedGoogle Scholar
  277. 277.
    Rosenau J, Tillmann HL, Bahr MJ, Trautwein C, Boeker KH, Nashan B, Klempnauer J, Manns MP. Successful hepatitis B reinfection prophylaxis with lamivudine and hepatitis B immune globulin in patients with positive HBV-DNA at time of liver transplantation. Transplant Proc. 2001;33(7–8):3637–8.PubMedGoogle Scholar
  278. 278.
    Terrault NA, Vyas G. Hepatitis B immune globulin preparations and use in liver transplantation. Clin Liver Dis. 2003;7(3):537–50.PubMedGoogle Scholar
  279. 279.
    Hooman N, Rifai K, Hadem J, Vaske B, Philipp G, Priess A, Klempnauer J, Tillmann HL, Manns MP, Rosenau J. Antibody to hepatitis B surface antigen trough levels and half-lives do not differ after intravenous and intramuscular hepatitis B immunoglobulin administration after liver transplantation. Liver Transpl. 2008;14(4):435–42.PubMedGoogle Scholar
  280. 280.
    Angus PW, McCaughan GW, Gane EJ, Crawford DH, Harley H. Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B. Liver Transpl. 2000;6(4):429–33.PubMedGoogle Scholar
  281. 281.
    Gane EJ, Angus PW, Strasser S, Crawford DH, Ring J, Jeffrey GP, GW MC, Australasian Liver Transplant Study Group. Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation. Gastroenterology. 2007;132(3):931–7.PubMedGoogle Scholar
  282. 282.
    Hu TH, Chen CL, Lin CC, Wang CC, Chiu KW, Yong CC, Liu YW, Eng HL. Section 14. Combination of entecavir plus low-dose on-demand hepatitis B immunoglobulin is effective with very low hepatitis B recurrence after liver transplantation. Transplantation. 2014;97(Suppl 8):S53–9.PubMedGoogle Scholar
  283. 283.
    Na GH, Kim DG, Han JH, Kim EY, Lee SH, Hong TH, You YK, Choi JY. Prevention and risk factors of hepatitis B recurrence after living donor liver transplantation. J Gastroenterol Hepatol. 2014;29(1):151–6.PubMedGoogle Scholar
  284. 284.
    Jiménez-Pérez M, Sáez-Gómez AB, MongilPoce L, Lozano-Rey JM, de la Cruz-Lombardo J, Rodrigo-López JM. Efficacy and safety of entecavir and/or tenofovir for prophylaxis and treatment of hepatitis B recurrence post-liver transplant. Transplant Proc. 2010;42(8):3167–8.PubMedGoogle Scholar
  285. 285.
    Buti M, Mas A, Prieto M, Casafont F, González A, Miras M, Herrero JI, Jardi R, Esteban R. Adherence to lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence. Transplantation. 2007;84(5):650–4.PubMedGoogle Scholar
  286. 286.
    Buti M, Mas A, Prieto M, Casafont F, González A, Miras M, Herrero JI, Jardí R, Cruz de Castro E, García-Rey C. A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation. J Hepatol. 2003;38(6):811–7.PubMedGoogle Scholar
  287. 287.
    Neff GW, Kemmer N, Kaiser TE, Zacharias VC, Alonzo M, Thomas M, Buell J. Combination therapy in liver transplant recipients with hepatitis B virus without hepatitis B immune globulin. Dig Dis Sci. 2007;52(10):2497–500.PubMedGoogle Scholar
  288. 288.
    Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology. 2008;48(5):1460–6.PubMedGoogle Scholar
  289. 289.
    Gane EJ, Patterson S, Strasser SI, McCaughan GW, Angus PW. Combination of lamivudine and adefovir without hepatitis B immune globulin is safe and effective prophylaxis against hepatitis B virus recurrence in hepatitis B surface antigen-positive liver transplant candidates. Liver Transpl. 2013;19(3):268–74.PubMedGoogle Scholar
  290. 290.
    Sánchez-Fueyo A, Rimola A, Grande L, Costa J, Mas A, Navasa M, Cirera I, Sánchez-Tapias JM, Rodés J. Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation. Hepatology. 2000;31(2):496–501.PubMedGoogle Scholar
  291. 291.
    Albeniz Arbizu E, BarcenaMarugan R, Oton Nieto E, Carrera Alonso E, Garcia Gonzalez M, Moreno Garcia J, de Vicente LE, Nuño Vazquez-Garza J, Martin DP. Prophylaxis of recurrent hepatitis B virus by vaccination after liver transplant: preliminary results. Transplant Proc. 2003;35(5):1848–9.PubMedGoogle Scholar
  292. 292.
    Angelico M, Di Paolo D, Trinito MO, Petrolati A, Araco A, Zazza S, Lionetti R, Casciani CU, Tisone G. Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis. Hepatology. 2002;35(1):176–81.PubMedGoogle Scholar
  293. 293.
    Lo CM, Liu CL, Chan SC, Lau GK, Fan ST. Failure of hepatitis B vaccination in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B. J Hepatol. 2005;43(2):283–7.PubMedGoogle Scholar
  294. 294.
    Castells L, Esteban R. Hepatitis B vaccination in liver transplant candidates. Eur J Gastroenterol Hepatol. 2001;13(4):359–61.PubMedGoogle Scholar
  295. 295.
    Di Paolo D, Lenci I, Cerocchi C, Tariciotti L, Monaco A, Brega A, Lotti L, Tisone G, Angelico M. One-year vaccination against hepatitis B virus with a MPL-vaccine in liver transplant patients for HBV-related cirrhosis. Transpl Int. 2010;23(11):1105–12.PubMedGoogle Scholar
  296. 296.
    Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann H, Samuel D, Zeuzem S, Villeneuve JP, Arterburn S, Borroto-Esoda K, Brosgart C, Chuck S, Adefovir Dipivoxil Study 45 International Investigators Group. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl. 2007;13(3):349–60.PubMedGoogle Scholar
  297. 297.
    Lok AS. How to diagnose and treat hepatitis B virus antiviral drug resistance in the liver transplant setting. Liver Transpl. 2008;14(Suppl 2):S8–S14.PubMedPubMedCentralGoogle Scholar
  298. 298.
    Nkongolo S, Ni Y, Lempp FA, Kaufman C, Lindner T, Esser-Nobis K, Lohmann V, Mier W, Mehrle S, Urban S. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol. 2014;60(4):723–31.PubMedGoogle Scholar
  299. 299.
    Urban S, Bartenschlager R, Kubitz R, Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology. 2014;147(1):48–64.PubMedGoogle Scholar
  300. 300.
    Ko C, Park WJ, Park S, Kim S, Windisch MP, Ryu WS. The FDA approved drug irbesartan inhibits HBV-infection in HepG2 cells stably expressing sodium taurocholate co-transporting polypeptide. Antivir Ther. 2015;20:835–42.  https://doi.org/10.3851/IMP2965.CrossRefPubMedGoogle Scholar
  301. 301.
    Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. J Hepatol. 2009;51(3):581–92.PubMedGoogle Scholar
  302. 302.
    Lampertico P, Liaw YF. New perspectives in the therapy of chronic hepatitis B. Gut. 2012;61(Suppl 1):i18–24.PubMedGoogle Scholar
  303. 303.
    Scaglione SJ, Lok AS. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology. 2012;142(6):1360–1368.e1.PubMedGoogle Scholar
  304. 304.
    Chan HL, Wong VW, Tse AM, Tse CH, Chim AM, Chan HY, Wong GL, Sung JJ. Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response. Clin Gastroenterol Hepatol. 2007;5(12):1462–8.PubMedGoogle Scholar
  305. 305.
    Moucari R, Mackiewicz V, Lada O, Ripault MP, Castelnau C, Martinot-Peignoux M, Dauvergne A, Asselah T, Boyer N, Bedossa P, Valla D, Vidaud M, Nicolas-Chanoine MH, Marcellin P. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology. 2009;49(4):1151–7.PubMedGoogle Scholar
  306. 306.
    Martinot-Peignoux M, Lapalus M, Asselah T, Marcellin P. HBsAg quantification: useful for monitoring natural history and treatment outcome. Liver Int. 2014;34(Suppl 1):97–107.PubMedGoogle Scholar
  307. 307.
    Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359(23):2442–55.PubMedGoogle Scholar
  308. 308.
    Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, Lu ZM, Piratvisuth T, Germanidis G, Yurdaydin C, Diago M, Gurel S, Lai MY, Button P, Pluck N, Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. 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(12):1206–17.PubMedGoogle Scholar
  309. 309.
    Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, Chang WY, Berg T, Flisiak R, McCloud P, Pluck N, Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352(26):2682–95.PubMedGoogle Scholar
  310. 310.
    Thimme R, Dandri M. Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepatitis B? J Hepatol. 2013;58(2):205–9.PubMedGoogle Scholar
  311. 311.
    Wu D, Han M, Ning Q. An integration of deep viral suppression with sequential immune modulation (cocktail therapy) to restore antiviral capacity: the future of chronic hepatitis B? J Hepatol. 2015;62(1):240–1.PubMedGoogle Scholar
  312. 312.
    Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association, Hou JL, Lai W. The guideline of prevention and treatment for chronic hepatitis B: a 2015 update. Zhonghua Gan Zang Bing Za Zhi. 2015;23(12):888–905 (in Chinese).Google Scholar
  313. 313.
    Piccolo P, Lenci I, Demelia L, Bandiera F, Piras MR, Antonucci G, Nosotti L, Mari T, De Santis A, Ponti ML, Sorbello O, Iacomi F, Angelico M. A randomized controlled trial of pegylated interferon-alpha2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B. Antivir Ther. 2009;14(8):1165–74.PubMedGoogle Scholar
  314. 314.
    Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, So TM, Gerken G, de Man RA, Niesters HG, Zondervan P, Hansen B, Schalm SW, HBV 99-01 Study Group, Rotterdam Foundation for Liver Research. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365(9454):123–9.PubMedGoogle Scholar
  315. 315.
    Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, Longerich T, Schirmacher P, Metzler F, Zankel M, Fischer C, Currie G, Brosgart C, Petersen J. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology. 2006;44(3):675–84.PubMedGoogle Scholar
  316. 316.
    Marcellin P, Wursthorn K, Wedemeyer H, Chuang WL, Lau G, Avila C, Peng CY, Gane E, Lim SG, Fainboim H, Foster GR, Safadi R, Rizzetto M, Manns M, Bao W, Trylesinski A, Naoumov N. Telbivudine plus pegylated interferon alfa-2a in a randomized study in chronic hepatitis B is associated with an unexpected high rate of peripheral neuropathy. J Hepatol. 2015;62(1):41–7.PubMedGoogle Scholar
  317. 317.
    Marcellin P, Ahn SH, Ma X, Caruntu FA, Tak WY, Elkashab M, Chuang WL, Lim SG, Tabak F, Mehta R, Petersen J, Foster GR, Lou L, Martins EB, Dinh P, Lin L, Corsa A, Charuworn P, Subramanian GM, Reiser H, Reesink HW, Fung S, Strasser SI, Trinh H, Buti M, Gaeta GB, Hui AJ, Papatheodoridis G, Flisiak R, Chan HL, Study 149 Investigators. Combination of tenofovir disoproxil fumarate and peginterferon alfa-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology. 2016;150(1):134–44.PubMedGoogle Scholar
  318. 318.
    Kittner JM, Sprinzl MF, Grambihler A, Weinmann A, Schattenberg JM, Galle PR, Schuchmann M. Adding pegylated interferon to a current nucleos(t)ide therapy leads to HBsAg seroconversion in a subgroup of patients with chronic hepatitis B. J Clin Virol. 2012;54(1):93–5.PubMedGoogle Scholar
  319. 319.
    Ouzan D, Pénaranda G, Joly H, Khiri H, Pironti A, Halfon P. Add-on peg-interferon leads to loss of HBsAg in patients with HBeAg-negative chronic hepatitis and HBV DNA fully suppressed by long-term nucleotide analogs. J Clin Virol. 2013;58(4):713–7.PubMedGoogle Scholar
  320. 320.
    Brouwer WP, Xie Q, Sonneveld MJ, Zhang N, Zhang Q, Tabak F, Streinu-Cercel A, Wang JY, Idilman R, Reesink HW, Diculescu M, Simon K, Voiculescu M, Akdogan M, Mazur W, Reijnders JG, Verhey E, Hansen BE, Janssen HL, ARES Study Group. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: a multicenter randomized trial (ARES study). Hepatology. 2015;61(5):1512–22.PubMedGoogle Scholar
  321. 321.
    Xie Q, Zhou H, Bai X, Wu S, Chen JJ, Sheng J, et al. A randomized, open-label clinical study of combined pegylated interferon Alfa-2a (40KD) and entecavir treatment for hepatitis B “e” antigen-positive chronic hepatitis B. Clin Infect Dis. 2014;59:1714–23.PubMedGoogle Scholar
  322. 322.
    Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, Tang H, Sheng J, Zhao M. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol. 2014;61(4):777–84.PubMedGoogle Scholar
  323. 323.
    Han M, Jiang J, Hou J, Tan D, Sun Y, Zhao M, Ning Q. Sustained immune control in HBeAg-positive patients who switched from entecavir therapy to pegylated interferon-α2a: 1 year follow-up of the OSST study. Antivir Ther. 2016;21:337–44.  https://doi.org/10.3851/IMP3019. [Epub ahead of print].CrossRefPubMedGoogle Scholar
  324. 324.
    Moucari R, Boyer N, Ripault MP, Castelnau C, Mackiewicz V, Dauvergne A, Valla D, Vidaud M, Chanoine MH, Marcellin P. Sequential therapy with adefovir dipivoxil and pegylated interferon alfa-2a for HBeAg-negative patients. J Viral Hepat. 2011;18(8):580–6.PubMedGoogle Scholar
  325. 325.
    Sarin SK, Kumar M, Kumar R, Kazim SN, Guptan RC, Sakhuja P, Sharma BC. Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients. Am J Gastroenterol. 2005;100(11):2463–71.PubMedGoogle Scholar
  326. 326.
    Boglione L, D’Avolio A, Cariti G, Milia MG, Simiele M, De Nicolò A, Ghisetti V, Di Perri G. Sequential therapy with entecavir and PEG-INF in patients affected by chronic hepatitis B and high levels of HBV-DNA with non-D genotypes. J Viral Hepat. 2013;20(4):e11–9.PubMedGoogle Scholar
  327. 327.
    Hu P, Shang J, Zhang W, Gong G, Li YG, Chen XJ, Jiang JN, Xie Q, Dou X, Sun Y, Li YF, Liu Y, Liu G, Mao D, Chi X, Tang H, Ou Li X, Xie Y, Chen XP, Jiang JJ, Zhao P, Hou JL, Gao Z, Fan H, Ding J, Ren H. Predictive value of baseline and on-treatment qHBsAg level in HBeAg positive CHB patients who switched from NUCs to pegylated interferon a-2a: a further analysis from NEW SWITCH study. In: EASL, 2015, O116.Google Scholar
  328. 328.
    Höner Zu Siederdissen C, Cornberg M. The role of HBsAg levels in the current management of chronic HBV infection. Ann Gastroenterol. 2014;27(2):105–12.PubMedPubMedCentralGoogle Scholar
  329. 329.
    Piratvisuth T, Marcellin P, Popescu M, Kapprell HP, Rothe V, Lu ZM. Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. Hepatol Int. 2013;7(2):429–36.PubMedGoogle Scholar
  330. 330.
    Lin CL, Kao JH. Review article: novel therapies for hepatitis B virus cure—advances and perspectives. Aliment Pharmacol Ther. 2016;44(3):213–22.PubMedGoogle Scholar
  331. 331.
    Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012;1:e00049.PubMedPubMedCentralGoogle Scholar
  332. 332.
    Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, Iwamoto M, Nakajima S, Tsukuda S, Borroto-Esoda K, Sugiyama M, Tanaka Y, Kanai Y, Kusuhara H, Mizokami M, Wakita T. Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP). Hepatology. 2014;59(5):1726–37.PubMedPubMedCentralGoogle Scholar
  333. 333.
    Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, Alexandrov A, Urban S, Petersen J, Lütgehetmann M, Dandri M. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol. 2013;58(5):861–7.PubMedGoogle Scholar
  334. 334.
    Kaneko M, Watashi K, Kamisuki S, Matsunaga H, Iwamoto M, Kawai F, Ohashi H, Tsukuda S, Shimura S, Suzuki R, Aizaki H, Sugiyama M, Park SY, Ito T, Ohtani N, Sugawara F, Tanaka Y, Mizokami M, Sureau C, Wakita T. A novel tricyclic polyketide, vanitaracin A, specifically inhibits the entry of hepatitis B and D viruses by targeting sodium taurocholate cotransporting polypeptide. J Virol. 2015;89(23):11945–53.PubMedPubMedCentralGoogle Scholar
  335. 335.
    Yan H, Liu Y, Sui J, Li W. NTCP opens the door for hepatitis B virus infection. Antiviral Res. 2015;121:24–30.PubMedGoogle Scholar
  336. 336.
    Kennedy EM, Kornepati AV, Cullen BR. Targeting hepatitis B virus cccDNA using CRISPR/Cas9. Antiviral Res. 2015;123:188–92.PubMedGoogle Scholar
  337. 337.
    Ramanan V, Shlomai A, Cox DB, Schwartz RE, Michailidis E, Bhatta A, Scott DA, Zhang F, Rice CM, Bhatia SN. CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus. Sci Rep. 2015;5:10833.PubMedPubMedCentralGoogle Scholar
  338. 338.
    Pollicino T, Belloni L, Raffa G, Pediconi N, Squadrito G, Raimondo G, Levrero M. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology. 2006;130(3):823–37.PubMedGoogle Scholar
  339. 339.
    Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl MF, Koppensteiner H, Makowska Z, Volz T, Remouchamps C, Chou WM, Thasler WE, Hüser N, Durantel D, Liang TJ, Münk C, Heim MH, Browning JL, Dejardin E, Dandri M, Schindler M, Heikenwalder M, Protzer U. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014;343(6176):1221–8.PubMedPubMedCentralGoogle Scholar
  340. 340.
    Delaney WE 4th, Edwards R, Colledge D, Shaw T, Furman P, Painter G, Locarnini S. 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(9):3057–60.PubMedGoogle Scholar
  341. 341.
    Feld JJ, Colledge D, Sozzi V, Edwards R, Littlejohn M, Locarnini SA. The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging. Antiviral Res. 2007;76(2):168–77.PubMedGoogle Scholar
  342. 342.
    Wu GY, Zheng XJ, Yin CC, Jiang D, Zhu L, Liu Y, Wei L, Wang Y, Chen HS. Inhibition of hepatitis B virus replication by Bay 41-4109 and its association with nucleocapsid disassembly. J Chemother. 2008;20(4):458–67.PubMedGoogle Scholar
  343. 343.
    Billioud G, Pichoud C, Puerstinger G, Neyts J, Zoulim F. The main hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication. Antiviral Res. 2011;92:271–6.PubMedGoogle Scholar
  344. 344.
    Bernstein E, Caudy AA, Hammond SM, Hannon GJ. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature. 2001;409:363–6.PubMedGoogle Scholar
  345. 345.
    Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 2000;404:293–6.PubMedGoogle Scholar
  346. 346.
    Wooddell CI, Rozema DB, Hossbach M, John M, Hamilton HL, Chu Q, Hegge JO, Klein JJ, Wakefield DH, Oropeza CE, Deckert J, Roehl I, Jahn-Hofmann K, Hadwiger P, Vornlocher HP, McLachlan A, Lewis DL. Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection. Mol Ther. 2013;21(5):973–85.PubMedPubMedCentralGoogle Scholar
  347. 347.
    Petersen J, Thompson AJ, Levrero M. Aiming for cure in HBV and HDV infection. J Hepatol. 2016;65:835–48. pii: S0168-8278(16)30257-4.  https://doi.org/10.1016/j.jhep.2016.05.043. [Epub ahead of print].PubMedGoogle Scholar
  348. 348.
    Mahtab MA, Bazinet M, Vaillant A. REP 9 AC: a potent HBsAg release inhibitor that elicits durable immunological control of chronic HBV infection. Hepatology. 2011;54(S1):478A.Google Scholar
  349. 349.
    Mahtab MA, Bazinet M, Patient R, Roingeard P, Vaillant A. Nucleic acid polymers REP 9 AC/REP 9 AC′ elicit sustained immunologic control of chronic HBV infection. Glob Antiviral J. 2011;7(Suppl 1):64A.Google Scholar
  350. 350.
    Bazinet M, Pântea V, Cebotarescu V, Cojuhari L, Jimbei P, Albrecht J, Schmid P, Krawczyk A, Karimzadeh H, Roggendorf M, Vaillant A. Update on the safety and efficacy of REP 2139 monotherapy and subsequent combination therapy with pegylated interferon alpha-2a in chronic HBV/HDV co-infection in Caucasian patients. J Hepatol. 2016;64:S584.Google Scholar
  351. 351.
    Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM, Fosdick A, Frey CR, Zheng J, Wolfgang G, Halcomb RL, Tumas DB. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology. 2013;144(7):1508–17, 1517.e1–10.PubMedPubMedCentralGoogle Scholar
  352. 352.
    Steuer HM, Daffis S, Lehar SM, Palazzo A, Tharinger H, Frey C, Pflanz S, Niu C, Chang CY, Jin MQ, Chen VL, Delaney WE, Peiser L, Fletcher SP, Nguyen MH. Functional activation of NK and CD8+ T cells in vitro by the toll-like receptor 7 agonist GS-9620. Hepatology. 2015;62:1187A.Google Scholar
  353. 353.
    Dahmen A, Herzog-Hauff S, Böcher WO, Galle PR, Löhr HF. Clinical and immunological efficacy of intradermal vaccine plus lamivudine with or without interleukin-2 in patients with chronic hepatitis B. J Med Virol. 2002;66(4):452–60.PubMedGoogle Scholar
  354. 354.
    Guptan RC, Thakur V, Kazim SN, Sarin SK. Efficacy of granulocyte-macrophage colony-stimulating factor or lamivudine combination with recombinant interferon in non-responders to interferon in hepatitis B virus-related chronic liver disease patients. J Gastroenterol Hepatol. 2002;17(7):765–71.PubMedGoogle Scholar
  355. 355.
    Shih C, Chou SF, Yang CC, Huang JY, Choijilsuren G, Jhou RS. Control and eradication strategies of hepatitis B virus. Trends Microbiol. 2016;24:739–749. pii: S0966-842X(16)30047-6.  https://doi.org/10.1016/j.tim.2016.05.006. [Epub ahead of print].PubMedGoogle Scholar
  356. 356.
    Liu J, Zhang E, Ma Z, Wu W, Kosinska A, Zhang X, Möller I, Seiz P, Glebe D, Wang B, Yang D, Lu M, Roggendorf M. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog. 2014;10(1):e1003856.PubMedPubMedCentralGoogle Scholar
  357. 357.
    Gaggar A, Coeshott C, Apelian D, Rodell T, Armstrong BR, Shen G, Subramanian GM, McHutchison JG. Safety, tolerability and immunogenicity of GS-4774, a hepatitis B virus-specific therapeutic vaccine, in healthy subjects: a randomized study. Vaccine. 2014;32(39):4925–31.PubMedGoogle Scholar
  358. 358.
    Martin P, Dubois C, Jacquier E, Dion S, Mancini-Bourgine M, Godon O, Kratzer R, Lelu-Santolaria K, Evlachev A, Meritet JF, Schlesinger Y, Villeval D, Strub JM, Van Dorsselaer A, Marchand JB, Geist M, Brandely R, Findeli A, Boukhebza H, Menguy T, Silvestre N, Michel ML, Inchauspé G. 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):1961–71.PubMedGoogle Scholar
  359. 359.
    Han MF, Wu D, Tan DM, Chen YP, Chen XY, Dou XG, Ma K, Sun L, Ning Q. Combination/sequential therapy with ETV, Peg-IFN alpha-2b and GMCSF enhanced HBsAg loss and appearance of HBsAb in NA suppressed CHB patients (the Anchor A study): an interim analysis. In: AASLD, Vol. 29, 2017.Google Scholar
  360. 360.
    Wu D, Ning Q. Toward a cure for hepatitis b virus infection: combination therapy involving viral suppression and immune modulation and long-term outcome. J Infect Dis. 2017;216(Suppl 8):S771–7.PubMedGoogle Scholar
  361. 361.
    Yang HC, Kao JH. Viral hepatitis. HBV cure—can we pin our hopes on immunotherapy? Nat Rev Gastroenterol Hepatol. 2015;12(3):129–31.PubMedGoogle Scholar

Copyright information

© Springer Nature B.V. and Huazhong University of Science and Technology Press 2019

Authors and Affiliations

  • Qin Ning
    • 1
  • Ting Wu
    • 1
  • Hai-Bin Su
    • 2
  • Ke Ma
    • 1
  • Jun-Ying Qi
    • 1
  • Ming Ni
    • 1
  • Di Wu
    • 1
  1. 1.Tongji Hospital of Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
  2. 2.Beijing 302 HospitalBeijingChina

Personalised recommendations