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Current hepatitis B treatment guidelines and future research directions

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Abstract

Hepatitis B virus (HBV) infection causes a tremendous clinical burden across the world with more than half a million people dying annually from HBV related disease. Significant advances have been made in HBV treatment in the past decade and several guidelines have been published by professional societies and expert panels. Although these recommendations have been valuable to help optimize HBV treatment, there is discordance in treatment criteria and many patients infected with HBV may fall outside of these recommendations. This paper systematically reviews the natural history of the disease and compares and contrasts the recommendations for initiation of treatment from the various societies. There is also discussion of special groups that require particular consideration and some of the open research questions and future research directions within the field.

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References

  1. WHO. “Hepatitis B.” World Health Organization, June 2013. Accessed 20 Feb. 2014. http://www.who.int/mediacentre/factsheets/fs204/en/

    Google Scholar 

  2. Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004; 350(11): 1118–1129

    CAS  PubMed  Google Scholar 

  3. Sorrell MF, Belongia EA, Costa J, Gareen IF, Grem JL, Inadomi JM, Kern ER, McHugh JA, Petersen GM, Rein MF, Strader DB, Trotter HT. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med 2009; 150(2): 104–110

    PubMed  Google Scholar 

  4. Gust ID. Epidemiology of hepatitis B infection in the Western Pacific and South East Asia. Gut 1996; 38(Suppl 2): S18–S23

    PubMed Central  PubMed  Google Scholar 

  5. Zuckerman AJ. More than third of world’s population has been infected with hepatitis B virus. BMJ 1999; 318(7192): 1213

    CAS  PubMed Central  PubMed  Google Scholar 

  6. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012; 57(1): 167–185

    Google Scholar 

  7. Mason A, Wick M, White H, Perrillo R. Hepatitis B virus replication in diverse cell types during chronic hepatitis B virus infection. Hepatology 1993; 18(4): 781–789

    CAS  PubMed  Google Scholar 

  8. Lee WM. Hepatitis B virus infection. N Engl J Med 1997; 337(24): 1733–1745

    CAS  PubMed  Google Scholar 

  9. Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med 2004; 116(12): 829–834

    CAS  PubMed  Google Scholar 

  10. Tong MJ, Hsu L, Hsien C, Kao JH, Durazo FA, Saab S, Blatt LM. A comparison of hepatitis B viral markers of patients in different clinical stages of chronic infection. Hepatol Int 2010; 4(2): 516–522

    PubMed Central  PubMed  Google Scholar 

  11. Chu CM, Liaw YF. Prevalence of and risk factors for hepatitis B viremia after spontaneous hepatitis B surface antigen seroclearance in hepatitis B carriers. Clin Infect Dis 2012; 54(1): 88–90

    CAS  PubMed  Google Scholar 

  12. Knöll A, Pietrzyk M, Loss M, Goetz WA, Jilg W. Solid-organ transplantation in HBsAg-negative patients with antibodies to HBV core antigen: low risk of HBV reactivation. Transplantation 2005; 79(11): 1631–1633

    PubMed  Google Scholar 

  13. Liaw YF, Kao JH, Piratvisuth T, Chan HLY, Chien RN, Liu CJ, Gane E, Locarnini S, Lim SG, Han KH, Amarapurkar D, Cooksley G, Jafri W, Mohamed R, Hou JL, Chuang WL, Lesmana LA, Sollano JD, Suh DJ, Omata M. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012; 6(3): 531–561

    Google Scholar 

  14. Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, Carey W, Brown RS Jr, Luketic VA, Terrault N, Lok AS. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology 2003; 125(2): 444–451

    PubMed  Google Scholar 

  15. Hunt CM, McGill JM, Allen MI, Condreay LD. Clinical relevance of hepatitis B viral mutations. Hepatology 2000; 31(5): 1037–1044

    CAS  PubMed  Google Scholar 

  16. Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology 2003; 124(2): 327–334

    CAS  PubMed  Google Scholar 

  17. Sato S, Suzuki K, Akahane Y, Akamatsu K, Akiyama K, Yunomura K, Tsuda F, Tanaka T, Okamoto H, Miyakawa Y, Mayumi M. Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med 1995; 122(4): 241–248

    CAS  PubMed  Google Scholar 

  18. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295(1): 65–73

    CAS  PubMed  Google Scholar 

  19. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130(3): 678–686

    PubMed  Google Scholar 

  20. 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): 1206–1217

    CAS  PubMed  Google Scholar 

  21. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L; BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006; 354(10): 1011–1020

    CAS  PubMed  Google Scholar 

  22. 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): 2576–2588

    CAS  PubMed  Google Scholar 

  23. 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): 2442–2455

    CAS  PubMed  Google Scholar 

  24. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W, Goodman Z, Chi YC, Zhang H, Hindes R, Iloeje U, Beebe S, Kreter B. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52(3): 886–893

    CAS  PubMed  Google Scholar 

  25. 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): 468–475

    CAS  PubMed  Google Scholar 

  26. Tong MJ, Pan CQ, Hann HW, Kowdley KV, Han SH, Min AD, Leduc TS. The management of chronic hepatitis B in Asian Americans. Dig Dis Sci 2011; 56(11): 3143–3162

    CAS  PubMed  Google Scholar 

  27. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50(3): 661–662

    PubMed  Google Scholar 

  28. 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): 1315–1341, quiz 1286

    CAS  PubMed  Google Scholar 

  29. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000-summary of a workshop. Gastroenterology 2001; 120(7): 1828–1853

    CAS  PubMed  Google Scholar 

  30. Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 2002; 36(6): 1408–1415

    CAS  PubMed  Google Scholar 

  31. 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): 1610–1614

    PubMed Central  PubMed  Google Scholar 

  32. Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, Kao JH, Chen DS. Role of hepatitis B viral load and basal core promoter mutation in hepatocellular carcinoma in hepatitis B carriers. J Infect Dis 2006; 193(9): 1258–1265

    CAS  PubMed  Google Scholar 

  33. 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): 1070–1078

    PubMed  Google Scholar 

  34. Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, Kao JH, Chen DS. Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: a casecontrol study. J Infect Dis 2006; 194(5): 594–599

    CAS  PubMed  Google Scholar 

  35. Liaw YF. Natural history of chronic hepatitis B virus infection and long-term outcome under treatment. Liver Int 2009; 29(Suppl 1): 100–107

    PubMed  Google Scholar 

  36. Han SH, Durazo FA, Saab S, Tong MJ. A proposed, evidencebased approach to the treatment of chronic Hepatitis B. J Clin Gastroenterol 2011; 45(3): 259–266

    PubMed  Google Scholar 

  37. Liaw YF. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia. J Hepatol 2009; 51(2): 403–410

    PubMed  Google Scholar 

  38. Hsu YS, Chien RN, Yeh CT, Sheen IS, Chiou HY, Chu CM, Liaw YF. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002; 35(6): 1522–1527

    PubMed  Google Scholar 

  39. Chu CM, Liaw YF. Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology 2007; 133(5): 1458–1465

    CAS  PubMed  Google Scholar 

  40. Chen YC, Chu CM, Liaw YF. Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B. Hepatology 2010; 51(2): 435–444

    PubMed  Google Scholar 

  41. Chu CM, Liaw YF. Incidence and risk factors of progression to cirrhosis in inactive carriers of hepatitis B virus. Am J Gastroenterol 2009; 104(7): 1693–1699

    PubMed  Google Scholar 

  42. Feld JJ, Ayers M, El-Ashry D, Mazzulli T, Tellier R, Heathcote EJ. Hepatitis B virus DNA prediction rules for hepatitis B e antigennegative chronic hepatitis B. Hepatology 2007; 46(4): 1057–1070

    CAS  PubMed  Google Scholar 

  43. Tseng TC, Liu CJ, Su TH, Wang CC, Chen CL, Chen PJ, Chen DS, Kao JH. Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis B e antigen seroconverters. Gastroenterology 2011; 141(2): 517–525, 525 e1–2

    CAS  PubMed  Google Scholar 

  44. Chan HL, Wong GL, Tse CH, Chan HY, Wong VW. Viral determinants of hepatitis B surface antigen seroclearance in hepatitis B e antigen-negative chronic hepatitis B patients. J Infect Dis 2011; 204(3): 408–414

    CAS  PubMed  Google Scholar 

  45. Tong MJ, Hsu L, Chang PW, Blatt LM. Evaluation of current treatment recommendations for chronic hepatitis B: a 2011 update. J Gastroenterol Hepatol 2011; 26(5): 829–835

    CAS  PubMed  Google Scholar 

  46. Jeng WJ, Sheen IS, Chen YC, Hsu CW, Chien RN, Chu CM, Liaw YF. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology 2013; 58(6): 1888–1896

    CAS  PubMed  Google Scholar 

  47. Reijnders JG, Janssen HL. Relapse of chronic hepatitis B after discontinuation of nucleos(t)ide analogs: is the glass half full or half empty? Hepatology 2013; 58(6): 1885–1887

    CAS  PubMed  Google Scholar 

  48. Tillmann HL, Hadem J, Leifeld L, Zachou K, Canbay A, Eisenbach C, Graziadei I, Encke J, Schmidt H, Vogel W, Schneider A, Spengler U, Gerken G, Dalekos GN, Wedemeyer H, Manns MP. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006; 13(4): 256–263

    CAS  PubMed  Google Scholar 

  49. Lee WM, Squires RH Jr, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: Summary of a workshop. Hepatology 2008; 47(4): 1401–1415

    PubMed Central  PubMed  Google Scholar 

  50. Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann HL, Samuel D, Zeuzem S, Lilly L, Rendina M, Villeneuve JP, Lama N, James C, Wulfsohn MS, Namini H, Westland C, Xiong S, Choy GS, Van Doren S, Fry J, Brosgart CL; Adefovir Dipovoxil Study 435 International Investigators Group. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 2003; 38(6): 1419–1427

    CAS  PubMed  Google Scholar 

  51. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351(15): 1521–1531

    CAS  PubMed  Google Scholar 

  52. Perrillo R, Tamburro C, Regenstein F, Balart L, Bodenheimer H, Silva M, Schiff E, Bodicky C, Miller B, Denham C, Brodeur C, Roach K, Albrecht J. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 1995; 109(3): 908–916

    CAS  PubMed  Google Scholar 

  53. Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, Anschuetz G, Davis R, Gardner SD, Brown NA. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 2002; 123(3): 719–727

    PubMed  Google Scholar 

  54. 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 Intrnational Investigators Group. Adefovir dipivoxil for waitlisted and post-liver transplantation patients with lamivudineresistant hepatitis B: final long-term results. Liver Transpl 2007; 13 (3): 349–360

    Google Scholar 

  55. 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): 176–182

    CAS  PubMed  Google Scholar 

  56. Papatheodoridis GV, Cholongitas E, Archimandritis AJ, Burroughs AK. Current management of hepatitis B virus infection before and after liver transplantation. Liver Int 2009; 29(9): 1294–1305

    CAS  PubMed  Google Scholar 

  57. John S, Andersson KL, Kotton CN, Hertl M, Markmann JF, Cosimi AB, Chung RT. Prophylaxis of hepatitis B infection in solid organ transplant recipients. Therap Adv Gastroenterol 2013; 6(4): 309–319

    PubMed Central  PubMed  Google Scholar 

  58. Carroll MB, Forgione MA. Use of tumor necrosis factor alpha inhibitors in hepatitis B surface antigen-positive patients: a literature review and potential mechanisms of action. Clin Rheumatol 2010; 29(9): 1021–1029

    PubMed  Google Scholar 

  59. Mastroianni CM, Lichtner M, Citton R, Del Borgo C, Rago A, Martini H, Cimino G, Vullo V. Current trends in management of hepatitis B virus reactivation in the biologic therapy era. World J Gastroenterol 2011; 17(34): 3881–3887

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Ferri C, Govoni M, Calabrese L. The A, B, Cs of viral hepatitis in the biologic era. Curr Opin Rheumatol 2010; 22(4): 443–450

    CAS  PubMed  Google Scholar 

  61. Iannitto E, Minardi V, Calvaruso G, Mulè A, Ammatuna E, Di Trapani R, Ferraro D, Abbadessa V, Craxí A, Di Stefano R. Hepatitis B virus reactivation and alemtuzumab therapy. Eur J Haematol 2005; 74(3): 254–258

    PubMed  Google Scholar 

  62. Pei SN, Chen CH, Lee CM, Wang MC, Ma MC, Hu TH, Kuo CY. Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients. Ann Hematol 2010; 89(3): 255–262

    CAS  PubMed  Google Scholar 

  63. Lee YH, Bae SC, Song GG. Hepatitis B virus reactivation in HBsAg-positive patients with rheumatic diseases undergoing antitumor necrosis factor therapy or DMARDs. Int J Rheum Dis 2013; 16(5): 527–531

    CAS  PubMed  Google Scholar 

  64. Liu CJ, Chen PJ, Chen DS, Kao JH. Hepatitis B virus reactivation in patients receiving cancer chemotherapy: natural history, pathogenesis, and management. Hepatol Int, 2013; 7(2): 316–326

    Google Scholar 

  65. Li HR, Huang JJ, Guo HQ, Zhang X, Xie Y, Zhu HL, Zhai LZ, Pu XX, Huang Y, Guo CC, Lin TY. Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy. J Viral Hepat 2011; 18(12): 877–883

    PubMed  Google Scholar 

  66. Ikeda M. Reactivation of hepatitis B virus in patients receiving chemotherapy. Jpn J Clin Oncol 2013; 43(1): 8–16

    PubMed  Google Scholar 

  67. Mandalà M, Fagiuoli S, Francisci D, Bruno R, Merelli B, Pasulo L, Tondini C, Labianca R, Roila F. Hepatitis B in immunosuppressed cancer patients: pathogenesis, incidence and prophylaxis. Crit Rev Oncol Hematol 2013; 87(1): 12–27

    PubMed  Google Scholar 

  68. Long M, Jia W, Li S, Jin L, Wu J, Rao N, Feng H, Chen K, Deng H, Liu F, Su F, Song E. A single-center, prospective and randomized controlled study: can the prophylactic use of lamivudine prevent hepatitis B virus reactivation in hepatitis B santigen seropositive breast cancer patients during chemotherapy? Breast Cancer Res Treat 2011; 127(3): 705–712

    CAS  PubMed  Google Scholar 

  69. Wedemeyer H, Yurdaydìn C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, Gürel S, Zeuzem S, Zachou K, Bozkaya H, Koch A, Bock T, Dienes HP, Manns MP; HIDIT Study Group. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011; 364(4): 322–331

    CAS  PubMed  Google Scholar 

  70. Soriano V, Puoti M, Bonacini M, Brook G, Cargnel A, Rockstroh J, Thio C, Benhamou Y. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV International Panel. AIDS 2005; 19(3): 221–240

    PubMed  Google Scholar 

  71. Jamma S, Hussain G, Lau DT. Current concepts of HBV/HCV coinfection: coexistence, but not necessarily in harmony. Curr Hepat Rep 2010; 9(4): 260–269

    PubMed Central  PubMed  Google Scholar 

  72. Rockstroh JK, Bhagani S, Benhamou Y, Bruno R, Mauss S, Peters L, Puoti M, Soriano V, Tural C; EACS Executive Committee. European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med 2008; 9(2): 82–88

    CAS  PubMed  Google Scholar 

  73. 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(1): 46–55

    CAS  PubMed  Google Scholar 

  74. Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol 2008; 23(4): 512–520

    PubMed  Google Scholar 

  75. Liu CJ, Chuang WL, Lee CM, Yu ML, Lu SN, Wu SS, Liao LY, Chen CL, Kuo HT, Chao YC, Tung SY, Yang SS, Kao JH, Liu CH, Su WW, Lin CL, Jeng YM, Chen PJ, Chen DS, Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses. Gastroenterology 2009; 136(2): 496–504 e3

    Google Scholar 

  76. Potthoff A, Wedemeyer H, Boecher WO, Berg T, Zeuzem S, Arnold J, Spengler U, Gruengreiff K, Kaeser T, Schuchmann M, Bergk A, Forestier N, Deterding K, Manns MP, Trautwein C; Hep-Net B/C Co-infection Study Group. The HEP-NET B/C coinfection trial: a prospective multicenter study to investigate the efficacy of pegylated interferon-alpha2b and ribavirin in patients with HBV/HCV co-infection. J Hepatol 2008; 49(5): 688–694

    CAS  PubMed  Google Scholar 

  77. Jonas MM, Block JM, Haber BA, Karpen SJ, London WT, Murray KF, Narkewicz MR, Rosenthal P, Schwarz KB, McMahon BJ; Hepatitis B Foundation. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology 2010; 52(6): 2192–2205

    PubMed  Google Scholar 

  78. Murray KF, Szenborn L, Wysocki J, Rossi S, Corsa AC, Dinh P, McHutchison J, Pang PS, Luminos LM, Pawlowska M, Mizerski J. Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology 2012; 56(6): 2018–2026

    CAS  PubMed  Google Scholar 

  79. Evans AA, London WT, Gish RG, Cohen C, Block TM. Chronic HBV infection outside treatment guidelines: is treatment needed? Antivir Ther 2013; 18(2): 229–235

    CAS  PubMed  Google Scholar 

  80. Liaw YF. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology 2011; 53(6): 2121–2129

    CAS  PubMed  Google Scholar 

  81. Nguyen T, Thompson AJ, Bowden S, Croagh C, Bell S, Desmond PV, Levy M, Locarnini SA. Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J Hepatol 2010; 52(4): 508–513

    CAS  PubMed  Google Scholar 

  82. Chan HL, Wong VW, Wong GL, Tse CH, Chan HY, Sung JJ. A longitudinal study on the natural history of serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology 2010; 52(4): 1232–1241

    CAS  PubMed  Google Scholar 

  83. Jaroszewicz J, Calle Serrano B, Wursthorn K, Deterding K, Schlue J, Raupach R, Flisiak R, Bock CT, Manns MP, Wedemeyer H, Cornberg M. Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective. J Hepatol 2010; 52(4): 514–522

    CAS  PubMed  Google Scholar 

  84. Jung YK, Kim JH, Lee YS, Lee HJ, Yoon E, Jung ES, Hong SK, Joo MK, Yeon JE, Park JJ, Kim JS, Bak YT, Byun KS. Change in serum hepatitis B surface antigen level and its clinical significance in treatment-naïve, hepatitis B e antigen-positive patients receiving entecavir. J Clin Gastroenterol 2010; 44(9): 653–657

    CAS  PubMed  Google Scholar 

  85. Brunetto MR, Moriconi F, Bonino F, Lau GK, Farci P, Yurdaydin C, Piratvisuth T, Luo K, Wang Y, Hadziyannis S, Wolf E, McCloud P, Batrla R, Marcellin P. Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009; 49(4): 1141–1150

    CAS  PubMed  Google Scholar 

  86. Wiegand J, Wedemeyer H, Finger A, Heidrich B, Rosenau J, Michel G, Bock CT, Manns MP, Tillmann HL. A decline in hepatitis B virus surface antigen (HBsAg) predicts clearance, but does not correlate with quantitative HBeAg or HBV DNA levels. Antivir Ther 2008; 13(4): 547–554

    CAS  PubMed  Google Scholar 

  87. Seto WK, Wong DK, Fung J, Huang FY, Lai CL, Yuen MF. Reduction of hepatitis B surface antigen levels and hepatitis B surface antigen seroclearance in chronic hepatitis B patients receiving 10 years of nucleoside analogue therapy. Hepatology 2013; 58(3): 923–931

    CAS  PubMed  Google Scholar 

  88. Arase Y, Ikeda K, Suzuki F, Suzuki Y, Saitoh S, Kobayashi M, Akuta N, Someya T, Hosaka T, Sezaki H, Kobayashi M, Kumada H. Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B. Am J Med 2006; 119(1): 71e9–16

    Google Scholar 

  89. Manesis EK, Hadziyannis ES, Angelopoulou OP, Hadziyannis SJ. Prediction of treatment-related HBsAg loss in HBeAG-negative chronic hepatitis B: a clue from serum HBsAg levels. Antivir Ther 2007; 12(1): 73–82

    CAS  PubMed  Google Scholar 

  90. Sonneveld MJ, Hansen BE, Piratvisuth T, Jia JD, Zeuzem S, Gane E, Liaw YF, Xie Q, Heathcote EJ, Chan HL, Janssen HL. Response-guided peginterferon therapy in hepatitis B e antigenpositive chronic hepatitis B using serum hepatitis B surface antigen levels. Hepatology 2013; 58(3): 872–880

    CAS  PubMed  Google Scholar 

  91. Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, Kuo SF, Liu CH, Chen PJ, Chen DS, Kao JH. Determinants of spontaneous surface antigen loss in hepatitis B e antigen-negative patients with a low viral load. Hepatology 2012; 55(1): 68–76

    PubMed  Google Scholar 

  92. Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL. Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using ontreatment hepatitis B surface antigen decline. Hepatology 2010; 52(4): 1251–1257

    CAS  PubMed  Google Scholar 

  93. Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology 2012; 143(3): 629–636 e1

    CAS  PubMed  Google Scholar 

  94. da Silva LC, Nova ML, Ono-Nita SK, Pinho JR, Sitnik R, Santos VA, Carrilho FJ. Simultaneous quantitation of serum HBV DNA and HBeAg can distinguish between slow and fast viral responses to antiviral therapy in patients with chronic hepatitis B. Rev Inst Med Trop Sao Paulo 2009; 51(5): 261–268

    PubMed  Google Scholar 

  95. Heijtink RA, Kruining J, Honkoop P, Kuhns MC, Hop WC, Osterhaus AD, Schalm SW. Serum HBeAg quantitation during antiviral therapy for chronic hepatitis B. J Med Virol 1997; 53(3): 282–287

    CAS  PubMed  Google Scholar 

  96. Lee JM, Ahn SH, Kim HS, Park H, Chang HY, Kim Y, Hwang SG, Rim KS, Chon CY, Han KH, Park JY. Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir. Hepatology 2011; 53(5): 1486–1493

    PubMed  Google Scholar 

  97. Matthews GV, Ali RJ, Avihingsanon A, Amin J, Hammond R, Bowden S, Lewin SR, Sasadeusz J, Littlejohn M, Locarnini SL, Ruxrungtham K, Dore GJ. Quantitative HBsAg and HBeAg predict hepatitis B seroconversion after initiation of HAART in HIV-HBV coinfected individuals. PLoS ONE 2013; 8(4): e61297

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Perrillo R, Mimms L, Schechtman K, Robbins D, Campbell C. Monitoring of antiviral therapy with quantitative evaluation of HBeAg: a comparison with HBV DNA testing. Hepatology 1993; 18(6): 1306–1312

    CAS  PubMed  Google Scholar 

  99. Thompson AJ, Nguyen T, Iser D, Ayres A, Jackson K, Littlejohn M, Slavin J, Bowden S, Gane EJ, Abbott W, Lau GK, Lewin SR, Visvanathan K, Desmond PV, Locarnini SA. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010; 51(6): 1933–1944

    CAS  PubMed  Google Scholar 

  100. Zhang X, Lin SM, Ye F, Chen TY, Liu M, Chen YR, Zheng SQ, Zhao YR, Zhang SL. An early decrease in serum HBeAg titre is a strong predictor of virological response to entecavir in HBeAgpositive patients. J Viral Hepat 2011; 18(7): e184–e190

    CAS  PubMed  Google Scholar 

  101. Cai D, Mills C, Yu W, Yan R, Aldrich CE, Saputelli JR, Mason WS, Xu X, Guo JT, Block TM, Cuconati A, Guo H. Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation. Antimicrob Agents Chemother 2012; 56(8): 4277–4288

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Palumbo GBL, Pediconi N, Levrero M. Targeting the cccDNA by epigenetic drugs inhibits HBV transcription and replication. in The Liver Meeting 2013. 2013; Washington, DC: AASLD

    Google Scholar 

  103. Block TM, Gish R, Guo H, Mehta A, Cuconati A, Thomas London W, Guo JT. Chronic hepatitis B: what should be the goal for new therapies? Antiviral Res 2013; 98(1): 27–34

    CAS  PubMed Central  PubMed  Google Scholar 

  104. 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): 861–867

    CAS  PubMed  Google Scholar 

  105. Michel ML, Deng Q, Mancini-Bourgine M. Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: perspectives and challenges. J Hepatol 2011; 54(6): 1286–1296

    CAS  PubMed  Google Scholar 

  106. Pol S, Nalpas B, Driss F, Michel ML, Tiollais P, Denis J, Brécho C; Multicenter study group. Efficacy and limitations of a specific immunotherapy in chronic hepatitis B. J Hepatol 2001; 34(6): 917–921

    CAS  PubMed  Google Scholar 

  107. Mancini-Bourgine M, Fontaine H, Scott-Algara D, Pol S, Bréchot C, Michel ML. Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers. Hepatology 2004; 40(4): 874–882

    CAS  PubMed  Google Scholar 

  108. Akbar SM, Furukawa S, Horiike N, Abe M, Hiasa Y, Onji M. Safety and immunogenicity of hepatitis B surface antigen-pulsed dendritic cells in patients with chronic hepatitis B. J Viral Hepat 2011; 18(6): 408–414

    CAS  PubMed  Google Scholar 

  109. Engels B, Uckert W. Redirecting T lymphocyte specificity by T cell receptor gene transfer-a new era for immunotherapy. Mol Aspects Med 2007; 28(1): 115–142

    CAS  PubMed  Google Scholar 

  110. 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): 1508–1517, 1517 e1–10

    CAS  PubMed  Google Scholar 

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  1. Division of Gastroenterology and Hepatology, University of California, Irvine, School of Medicine, Orange, CA, 92868, USA

    Jonathan Skupsky & Ke-Qin Hu

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Skupsky, J., Hu, KQ. Current hepatitis B treatment guidelines and future research directions. Front. Med. 8, 145–157 (2014). https://doi.org/10.1007/s11684-014-0335-1

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