Skip to main content

Advertisement

SpringerLink
Log in

Systematic Review of the Literature on Comparative Effectiveness of Antiviral Treatments for Chronic Hepatitis B Infection

  • Reviews
  • Published:
Journal of General Internal Medicine Aims and scope Submit manuscript

Abstract

OBJECTIVES

To evaluate the comparative effectiveness of antiviral drugs in adults with chronic hepatitis B monoinfection for evidence-based decision-making.

METHODS

A systematic review of randomized controlled clinical trials (RCTs) published in English. Results after interferon and nucleos(t)ides analog therapies were synthesized with random-effects meta-analyses and number needed to treat (NNT).

RESULTS

Despite sustained improvements in selected biomarkers, no one drug regimen improved all intermediate outcomes. In 16 underpowered RCTs, drug treatments did not reduce mortality, liver cancer, or cirrhosis. Sustained HBV DNA clearance was achieved in one patient when two were treated with adefovir (NNT from 1 RCT = 2 95%CI 1;2) or interferon alfa-2b (NNT from 2 RCTs = 2 95%CI 2;4), 13 with lamivudine (NNT from 1 RCT = 13 95%CI 7;1000), and 11 with peginterferon alfa-2a vs. lamivudine (NNT from 1 RCT = 11 95%CI 7;25). Sustained HBeAg seroconversion was achieved in one patient when eight were treated with interferon alfa-2b (NNT from 2 RCTs = 8 95%CI 5;33) or 10—with peginterferon alfa-2b vs. interferon alfa-2b (NNT from 1 RCT = 10 95%CI 5;1000). Greater benefits and safety after entecavir vs. lamivudine or pegylated interferon alfa-2b vs. interferon alfa-2b require future investigation of clinical outcomes. Adverse events were common and more frequent after interferon. Treatment utilization for adverse effects is unknown.

CONCLUSIONS

Individual clinical decisions should rely on comparative effectiveness and absolute rates of intermediate outcomes and adverse events. Future research should clarify the relationship of intermediate and clinical outcomes and cost-effectiveness of drugs for evidence-based policy and clinical decisions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health consensus development conference statement: management of hepatitis B. Hepatology. 2009;49(5 Suppl):S4–12.

    Article  PubMed  Google Scholar 

  2. Wilt TJ, Shamliyan T, Shaukat A, et al. Management of chronic hepatitis B. Evid Rep Technol Assess (Full Rep). 2008;174:1–671.

    Google Scholar 

  3. Feld JJ, Wong DK, Heathcote EJ. Endpoints of therapy in chronic hepatitis B. Hepatology. 2009;49(5 Suppl):S96–102.

    Article  CAS  PubMed  Google Scholar 

  4. Shamliyan TA, MacDonald R, Shaukat A, et al. Antiviral therapy for adults with chronic hepatitis B: a systematic review for a National Institutes of Health Consensus Development Conference. Ann Intern Med. 2009;150(2):111–24.

    PubMed  Google Scholar 

  5. Reichen J. ACP Journal Club. Review: evidence is insufficient to evaluate effectiveness of antiviral therapies for chronic hepatitis B. Ann Intern Med. 2009;150(10):JC5–6.

    CAS  PubMed  Google Scholar 

  6. National Institutes of Health (U.S.). NIH consensus development conference management of hepatitis B. [Bethesda, Md.: National Institutes of Health; 2008: Retieved October 1, 2010 http://videocast.nih.gov/launch.asp?14714 Retrieved October 1, 2010 http://videocast.nih.gov/launch.asp?14712 Retrieved October 1, 2010 http://videocast.nih.gov/launch.asp?14719

  7. Chen CJ, Yang HI, Iloeje UH. Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology. 2009;49(5 Suppl):S72–84.

    Article  CAS  PubMed  Google Scholar 

  8. Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology. 2009;49(5 Suppl):S103–11.

    Article  CAS  PubMed  Google Scholar 

  9. Dienstag JL. Benefits and risks of nucleoside analog therapy for hepatitis B. Hepatology. 2009;49(5 Suppl):S112–21.

    Article  CAS  PubMed  Google Scholar 

  10. Higgins J, Green S, Cochrane Collaboration. Cochrane Handbook for Systematic Reviews of Interventions. Chichester: Wiley-Blackwell; 2008.

    Book  Google Scholar 

  11. Sox HC, Greenfield S. Comparative effectiveness research: a report from the Institute of Medicine. Ann Intern Med. 2009;151(3):203–5.

    PubMed  Google Scholar 

  12. Slutsky J, Atkins D, Chang S, Sharp BA. AHRQ series paper 1: comparing medical interventions: AHRQ and the effective health-care program. J Clin Epidemiol. 2010;63(5):481–3.

    Article  PubMed  Google Scholar 

  13. Helfand M, Balshem H. AHRQ series paper 2: principles for developing guidance: AHRQ and the effective health-care program. J Clin Epidemiol. 2010;63(5):484–90.

    Article  PubMed  Google Scholar 

  14. Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20(3 Suppl):21–35.

    Article  CAS  PubMed  Google Scholar 

  15. Cochrane Collaboration. The Cochrane library. Retrieved October 1, 2010 from http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME

  16. United States. Food and Drug Administration. MedWatch. MedWatch online voluntary reporting form (3500). [Rockville, Md.]: Food and Drug Administration, MedWatch; 2002. Retrieved October 1, 2010 from http://purl.access.gpo.gov/GPO/LPS39966 and retrieved October 1, 2010 from http://purl.access.gpo.gov/GPO/LPS81658

  17. Fontaine H, Petitprez K, Roudot-Thoraval F, Trinchet JC. Guidelines for the diagnosis of uncomplicated cirrhosis. Gastroenterol Clin Biol. 2007;31(5):504–9.

    Article  PubMed  Google Scholar 

  18. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45(2):507–39.

    Article  CAS  PubMed  Google Scholar 

  19. Pungpapong S, Kim WR, Poterucha JJ. Natural history of hepatitis B virus infection: an update for clinicians. Mayo Clin Proc. 2007;82(8):967–75.

    Article  CAS  PubMed  Google Scholar 

  20. West S, King V, Carey TS, et al. Systems to rate the strength of scientific evidence. Evid Rep Technol Assess. 2002;47:1–11.

    Google Scholar 

  21. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999;354(9193):1896–900.

    Article  CAS  PubMed  Google Scholar 

  22. Whitehead A. Meta-analysis of Controlled Clinical Trials. Chichester: John Wiley & Sons; 2002.

    Book  Google Scholar 

  23. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  CAS  PubMed  Google Scholar 

  24. Viechtbauer W. Confidence intervals for the amount of heterogeneity in meta-analysis. Stat Med. Feb 6 2006.

  25. Knapp G, Biggerstaff BJ, Hartung J. Assessing the amount of heterogeneity in random-effects meta-analysis. Biom J. 2006;48(2):271–85.

    Article  PubMed  Google Scholar 

  26. Thornton A, Lee P. Publication bias in meta-analysis: its causes and consequences. J Clin Epidemiol. 2000;53(2):207–16.

    Article  CAS  PubMed  Google Scholar 

  27. Atkins D, Briss PA, Eccles M, et al. Systems for grading the quality of evidence and the strength of recommendations II: pilot study of a new system. BMC Health Serv Res. 2005;5(1):25.

    Article  PubMed  Google Scholar 

  28. Atkins D, Eccles M, Flottorp S, et al. Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches The GRADE Working Group. BMC Health Serv Res. 2004;4(1):38.

    Article  PubMed  Google Scholar 

  29. Egger M, Smith GD, Altman DG. Systematic Reviews in Health Care. London: NetLibrary, Inc. BMJ Books; 2001.

    Book  Google Scholar 

  30. Ebrahim S. The use of numbers needed to treat derived from systematic reviews and meta-analysis. Caveats and pitfalls. Eval Health Prof. 2001;24(2):152–64.

    Article  CAS  PubMed  Google Scholar 

  31. Altman DG. Confidence intervals for the number needed to treat. Br Med J (Clinical research). 1998;317(7168):1309–12.

    CAS  Google Scholar 

  32. Chou R, Aronson N, Atkins D, et al. AHRQ series paper 4: assessing harms when comparing medical interventions: AHRQ and the effective health-care program. J Clin Epidemiol. 2010;63(5):502–12.

    Article  PubMed  Google Scholar 

  33. Wallace BC, Schmid CH, Lau J, Trikalinos TA. Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol. 2009;9:80.

    Article  PubMed  Google Scholar 

  34. Red book 2008 pharmacy’s fundamental reference. 2008 ed. Montvale, N.J.: Thomson; 2008.

  35. You JH, Chan FW. Pharmacoeconomics of entecavir treatment for chronic hepatitis B. Expert Opin Pharmacother. 2008;9(15):2673–81.

    Article  CAS  PubMed  Google Scholar 

  36. Jones J, Shepherd J, Baxter L, et al. Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation. Health Technol Assess. 2009;13(35):1–172. iii.

    CAS  Google Scholar 

  37. Janssen HL, Gerken G, Carreno V, et al. Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology. 1999;30(1):238–43.

    Article  CAS  PubMed  Google Scholar 

  38. Schalm SW, Heathcote J, Cianciara J, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut. 2000;46(4):562–8.

    Article  CAS  PubMed  Google Scholar 

  39. Barbaro G, Zechini F, Pellicelli AM, et al. Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial. J Hepatol. 2001;35(3):406–11.

    Article  CAS  PubMed  Google Scholar 

  40. Perrillo RP, Lai CL, Liaw YF, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002;36(1):186–94.

    Article  CAS  PubMed  Google Scholar 

  41. Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology. 2002;36(6):1425–30.

    CAS  PubMed  Google Scholar 

  42. Chung YH, Song BC, Lee GC, et al. Individualization of interferon therapy using serum hepatitis B virus DNA to reduce viral relapse in patients with chronic hepatitis B: a randomized controlled trial. Eur J Gastroenterol Hepatol. 2003;15(5):489–93.

    CAS  PubMed  Google Scholar 

  43. Schiff ER, Dienstag JL, Karayalcin S, et al. Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol. 2003;38(6):818–26.

    Article  CAS  PubMed  Google Scholar 

  44. Yalcin K, Degertekin H, Yildiz F, Celik Y. Comparison of 12-month courses of interferon-alpha-2b-lamivudine combination therapy and interferon-alpha-2b monotherapy among patients with untreated chronic hepatitis B. Clin Infect Dis. 2003;36(12):1516–22.

    Article  CAS  PubMed  Google Scholar 

  45. Niederau C, Heintges T, Niederau M, Stremmel W, Strohmeyer G. Prospective randomized controlled trial of sequential treatment with corticoids and alpha-interferon versus treatment with interferon alone in patients with chronic active hepatitis B. Eur J Med. 1992;1(7):396–402.

    CAS  PubMed  Google Scholar 

  46. Robson SC, Brice E, van Rensburg C, Kannemeyer J, Hift RJ, Kirsch RE. Safety and efficacy of interferon alpha-2b following prednisone withdrawal in the treatment of chronic viral hepatitis B. A case-controlled, randomised study. S Afr Med J. 1992;82(5):317–20.

    CAS  PubMed  Google Scholar 

  47. Akarca US, Ersoz G, Gunsar F, et al. Interferon-lamivudine combination is no better than lamivudine alone in anti-HBe-positive chronic hepatitis B. Antivir Ther. 2004;9(3):325–34.

    CAS  PubMed  Google Scholar 

  48. Jang MK, Chung YH, Choi MH, et al. Combination of alpha-interferon with lamivudine reduces viral breakthrough during long-term therapy. J Gastroenterol Hepatol. 2004;19(12):1363–8.

    Article  CAS  PubMed  Google Scholar 

  49. Lok AS, Wu PC, Lai CL, et al. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology. 1992;102(6):2091–7.

    CAS  PubMed  Google Scholar 

  50. Economou M, Manolakopoulos S, Trikalinos TA, et al. Interferon-alpha plus lamivudine vs lamivudine reduces breakthroughs, but does not affect sustained response in HBeAg negative chronic hepatitis B. World J Gastroenterol. 2005;11(37):5882–7.

    CAS  PubMed  Google Scholar 

  51. Sarin SK, Kumar M, Kumar R, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  52. Shi M, Wang RS, Zhang H, et al. Sequential treatment with lamivudine and interferon-alpha monotherapies in hepatitis B e antigen-negative Chinese patients and its suppression of lamivudine-resistant mutations. J Antimicrob Chemother. 2006;58(5):1031–5.

    Article  CAS  PubMed  Google Scholar 

  53. Scotto G, Palumbo E, Fazio V, Cibelli DC, Saracino A, Angarano G. Efficacy and tolerability of lamivudine alone versus lamivudine plus alpha-interferon for treatment of chronic active hepatitis B in patients with a precore-mutant variant. Infez Med. 2006;14(3):145–51.

    PubMed  Google Scholar 

  54. Lu HY, Zhuang LW, Yu YY, et al. Intrahepatic HBV DNA as a predictor of antivirus treatment efficacy in HBeAg-positive chronic hepatitis B patients. World J Gastroenterol. 2007;13(20):2878–82.

    CAS  PubMed  Google Scholar 

  55. Akyuz F, Kaymakoglu S, Demir K, et al. Lamivudine monotherapy and lamivudine plus interferon alpha combination therapy in HBeAg negative chronic hepatitis B not responding to previous interferon alpha monotherapy. Acta Gastroenterol Belg. 2007;70(1):20–4.

    PubMed  Google Scholar 

  56. Perez V, Tanno H, Villamil F, Fay O. Recombinant interferon alfa-2b following prednisone withdrawal in the treatment of chronic type B hepatitis. J Hepatol. 1990;11(Suppl 1):S113–7.

    Article  PubMed  Google Scholar 

  57. Hadziyannis S, Bramou T, Makris A, Moussoulis G, Zignego L, Papaioannou C. Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B. J Hepatol. 1990;11(Suppl 1):S133–6.

    Article  PubMed  Google Scholar 

  58. Muller R, Baumgarten R, Markus R, et al. Treatment of chronic hepatitis B with interferon alfa-2b. J Hepatol. 1990;11(Suppl 1):S137–40.

    Article  PubMed  Google Scholar 

  59. Waked I, Amin M, Abd el Fattah S, Osman LM, Sabbour MS. Experience with interferon in chronic hepatitis B in Egypt. J Chemother. 1990;2(5):310–8.

    CAS  PubMed  Google Scholar 

  60. Perrillo RP, Schiff ER, Davis GL, et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med. 1990;323(5):295–301.

    Article  CAS  PubMed  Google Scholar 

  61. Zarski JP, Causse X, Cohard M, Cougnard J, Trepo C. A randomized, controlled trial of interferon alfa-2b alone and with simultaneous prednisone for the treatment of chronic hepatitis B. French Multicenter Group. J Hepatol. 1994;20(6):735–41.

    Article  CAS  PubMed  Google Scholar 

  62. Reichen J, Bianchi L, Frei PC, Male PJ, Lavanchy D, Schmid M. Efficacy of steroid withdrawal and low-dose interferon treatment in chronic active hepatitis B. Results of a randomized multicenter trial. Swiss Association for the Study of the Liver. J Hepatol. 1994;20(2):168–74.

    Article  CAS  PubMed  Google Scholar 

  63. Di Bisceglie AM, Fong TL, Fried MW, et al. A randomized, controlled trial of recombinant alpha-interferon therapy for chronic hepatitis B. Am J Gastroenterol. 1993;88(11):1887–92.

    PubMed  Google Scholar 

  64. Perez V, Findor J, Tanno H, Sorda J. A controlled trial of high dose interferon, alone and after prednisone withdrawal, in the treatment of chronic hepatitis B: long term follow up. Gut. 1993;34(2 Suppl):S91–4.

    Article  CAS  PubMed  Google Scholar 

  65. Muller R, Baumgarten R, Markus R, et al. Low dose alpha interferon treatment in chronic hepatitis B virus infection. Gut. 1993;34(2 Suppl):S97–8.

    Article  CAS  PubMed  Google Scholar 

  66. Lopez-Alcorocho JM, Bartolome J, Cotonat T, Carreno V. Efficacy of prolonged interferon-alpha treatment in chronic hepatitis B patients with HBeAb: comparison between 6 and 12 months of therapy. J Viral Hepat. 1997;4(Suppl 1):27–32.

    Article  PubMed  Google Scholar 

  67. Lampertico P, Del Ninno E, Manzin A, et al. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology. 1997;26(6):1621–5.

    Article  CAS  PubMed  Google Scholar 

  68. Mutimer D, Naoumov N, Honkoop P, et al. Combination alpha-interferon and lamivudine therapy for alpha-interferon-resistant chronic hepatitis B infection: results of a pilot study. J Hepatol. 1998;28(6):923–9.

    Article  CAS  PubMed  Google Scholar 

  69. Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56(5):699–705.

    Article  CAS  PubMed  Google Scholar 

  70. Cooksley WG, Piratvisuth T, Lee SD, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepatitis. 2003;10(4):298–305.

    Article  CAS  Google Scholar 

  71. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351(12):1206–17.

    Article  CAS  PubMed  Google Scholar 

  72. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352(26):2682–95.

    Article  CAS  PubMed  Google Scholar 

  73. Cindoruk M, Karakan T, Unal S. Hepatic steatosis has no impact on the outcome of treatment in patients with chronic hepatitis B infection. J Clin Gastroenterol. 2007;41(5):513–7.

    Article  PubMed  Google Scholar 

  74. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348(9):800–7.

    Article  CAS  PubMed  Google Scholar 

  75. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med. 2005;352(26):2673–81.

    Article  CAS  PubMed  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348(9):808–16.

    Article  CAS  PubMed  Google Scholar 

  78. Zeng M, Mao Y, Yao G, et al. A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology. 2006;44(1):108–16.

    Article  CAS  PubMed  Google Scholar 

  79. Westland C, Delaney Wt, Yang H, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology. 2003;125(1):107–16.

    Article  CAS  PubMed  Google Scholar 

  80. Westland CE, Yang H, Delaney WEt, et al. Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology. 2003;38(1):96–103.

    Article  CAS  PubMed  Google Scholar 

  81. Izzedine H, Hulot JS, Launay-Vacher V, et al. Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies. Kidney Int. 2004;66(3):1153–8.

    Article  CAS  PubMed  Google Scholar 

  82. Perrillo R, Hann HW, Mutimer D, et al. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology. 2004;126(1):81–90.

    Article  CAS  PubMed  Google Scholar 

  83. Akyildiz M, Gunsar F, Ersoz G, et al. Adefovir dipivoxil alone or in combination with lamivudine for three months in patients with lamivudine resistant compensated chronic hepatitis B. Dig Dis Sci. 2007;52(12):3444–7.

    Article  CAS  PubMed  Google Scholar 

  84. Peters MG, Hann HWH, Martin P, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004;126(1):91–101.

    Article  CAS  PubMed  Google Scholar 

  85. Chan HL, Heathcote EJ, Marcellin P, et al. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann Intern Med. 2007;147(11):745–54.

    PubMed  Google Scholar 

  86. Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. American J Gastroenterol. 2006;101(2):297–303.

    Article  CAS  Google Scholar 

  87. Janssen HL, van Zonneveld M, Senturk H, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  88. Buster EH, Hansen BE, Buti M, et al. Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis. Hepatology. 2007;46(2):388–94.

    Article  CAS  PubMed  Google Scholar 

  89. ter Borg MJ, van Zonneveld M, Zeuzem S, et al. Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response. Hepatology. 2006;44(3):721–7.

    Article  PubMed  CAS  Google Scholar 

  90. Flink HJ, Hansen BE, Heathcote EJ, et al. Successful treatment with peginterferon alfa-2b of HBeAg-positive HBV non-responders to standard interferon or lamivudine. Am J Gastroenterol. 2006;101(11):2523–9.

    CAS  PubMed  Google Scholar 

  91. van Zonneveld M, Flink HJ, Verhey E, et al. The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation. Aliment Pharmacol Ther. 2005;21(9):1163–71.

    Article  PubMed  CAS  Google Scholar 

  92. Flink HJ, Sprengers D, Hansen BE, et al. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon {alpha}-2b therapy. Gut. 2005;54(11):1604–9.

    Article  CAS  PubMed  Google Scholar 

  93. van Zonneveld M, Zondervan PE, Cakaloglu Y, et al. Peg-interferon improves liver histology in patients with HBeAg-positive chronic hepatitis B: no additional benefit of combination with lamivudine. Liver Int. 2006;26(4):399–405.

    Article  PubMed  CAS  Google Scholar 

  94. Chan HL, Hui AY, Wong VW, Chim AM, Wong ML, Sung JJ. Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B. Hepatology. 2005;41(6):1357–64.

    Article  CAS  PubMed  Google Scholar 

  95. Chan HL, Leung NW, Hui AY, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med. 2005;142(4):240–50.

    CAS  PubMed  Google Scholar 

  96. Chan HL, Tse AM, Zhang MD, et al. Genetic polymorphisms of interleukin-1-beta in association with sustained response to anti-viral treatment in chronic hepatitis B in Chinese. Aliment Pharmacol Ther. 2006;23(12):1703–11.

    Article  CAS  PubMed  Google Scholar 

  97. Zhao H, Kurbanov F, Wan MB, et al. Genotype B and younger patient age associated with better response to low-dose therapy: a trial with pegylated/nonpegylated interferon-alpha-2b for hepatitis B e antigen-positive patients with chronic hepatitis B in China. Clin Infect Dis. 2007;44(4):541–8.

    Article  CAS  PubMed  Google Scholar 

  98. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354(10):1011.

    Article  CAS  PubMed  Google Scholar 

  99. 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.

    Article  CAS  PubMed  Google Scholar 

  100. Lai CL, Rosmawati M, Lao J, et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology. 2002;123(6):1831–8.

    Article  CAS  PubMed  Google Scholar 

  101. Chang TT, Gish RG, Hadziyannis SJ, et al. A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology. 2005;129(4):1198–209.

    Article  CAS  PubMed  Google Scholar 

  102. Sherman M, Yurdaydin C, Sollano J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130(7):2039–49.

    Article  CAS  PubMed  Google Scholar 

  103. Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133(5):1437–44.

    Article  CAS  PubMed  Google Scholar 

  104. Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology. 2005;129(2):528–36.

    CAS  PubMed  Google Scholar 

  105. Kweon YO, Goodman ZD, Dienstag JL, et al. Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol. 2001;35(6):749–55.

    Article  CAS  PubMed  Google Scholar 

  106. Ke CZ, Chen Y, Gong ZJ, et al. Dynamic changes of HBV DNA in serum and peripheral blood mononuclear cells of chronic hepatitis patients after lamivudine treatment. World J Gastroenterol. 2006;12(25):4061–3.

    CAS  PubMed  Google Scholar 

  107. Yuen MF, Chow DH, Tsui K, et al. Liver histology of Asian patients with chronic hepatitis B on prolonged lamivudine therapy. Aliment Pharmacol Ther. 2005;21(7):841–9.

    Article  CAS  PubMed  Google Scholar 

  108. Yao GB. Management of hepatitis B in China. J Med Virol. 2000;61(3):392–7.

    Article  CAS  PubMed  Google Scholar 

  109. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351(15):1521–31.

    Article  CAS  PubMed  Google Scholar 

  110. Liaw YF, Leung NW, Chang TT, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology. 2000;119(1):172–80.

    Article  CAS  PubMed  Google Scholar 

  111. Leung NW, Lai CL, Chang TT, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  112. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124(1):105–17.

    Article  CAS  PubMed  Google Scholar 

  113. Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341(17):1256–63.

    Article  CAS  PubMed  Google Scholar 

  114. Honkoop P, de Man RA, Niesters HG, et al. Quantitative hepatitis B virus DNA assessment by the limiting-dilution polymerase chain reaction in chronic hepatitis B patients: evidence of continuing viral suppression with longer duration and higher dose of lamivudine therapy. J Viral Hepatitis. 1998;5(5):307–12.

    Article  CAS  Google Scholar 

  115. Nevens F, Main J, Honkoop P, et al. Lamivudine therapy for chronic hepatitis B: a six-month randomized dose-ranging study. Gastroenterology. 1997;113(4):1258–63.

    Article  CAS  PubMed  Google Scholar 

  116. Chan HL, Wang H, Niu J, Chim AM, Sung JJ. Two-year lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B: a double-blind, placebo-controlled trial. Antivir Ther. 2007;12(3):345–53.

    CAS  PubMed  Google Scholar 

  117. Yao G, Wang B, Cui Z, Yao J, Zeng M. A randomized double-blind placebo-controlled study of lamivudine in the treatment of patients with chronic hepatitis B virus infection. Chin Med J (Engl). 1999;112(5):387–91.

    CAS  Google Scholar 

  118. Kim YJ, Kim BG, Jung JO, Yoon JH, Lee HS. High rates of progressive hepatic functional deterioration whether lamivudine therapy is continued or discontinued after emergence of a lamivudine-resistant mutant: a prospective randomized controlled study. J Gastroenterol. 2006;41(3):240–9.

    Article  CAS  PubMed  Google Scholar 

  119. Tassopoulos NC, Volpes R, Pastore G, et al. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B.Lamivudine Precore Mutant Study Group. Hepatology. 1999;29(3):889–96.

    Article  CAS  PubMed  Google Scholar 

  120. Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007;357(25):2576–88.

    Article  CAS  PubMed  Google Scholar 

  121. Hou J, Yin YK, Xu D, et al. Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: Results at 1 year of a randomized, double-blind trial. Hepatology. 2008;47(2):447–54.

    Article  CAS  PubMed  Google Scholar 

  122. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359(23):2442–55.

    Article  CAS  PubMed  Google Scholar 

  123. Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998;339(2):61–8.

    Article  CAS  PubMed  Google Scholar 

  124. Taylor BC, Yuan JM, Shamliyan TA, Shaukat A, Kane RL, Wilt TJ. Clinical outcomes in adults with chronic hepatitis B in association with patient and viral characteristics: a systematic review of evidence. Hepatology. 2009;49(5 Suppl):S85–95.

    Article  PubMed  Google Scholar 

  125. McGinn TG, Guyatt GH, Wyer PC, Naylor CD, Stiell IG, Richardson WS. Users' guides to the medical literature: XXII: how to use articles about clinical decision rules. Evidence-Based Medicine Working Group. JAMA. 2000;284(1):79–84.

    Article  CAS  PubMed  Google Scholar 

  126. McAlister FA, Straus SE, Guyatt GH, Haynes RB. Users' guides to the medical literature: XX. Integrating research evidence with the care of the individual patient. Evidence-Based Medicine Working Group. JAMA. 2000;283(21):2829–36.

    Article  CAS  PubMed  Google Scholar 

  127. Chalmers I. Well informed uncertainties about the effects of treatments. Br Med J (Clinical research). 2004;328(7438):475–6.

    Article  Google Scholar 

  128. Ghany MG, Doo EC. Antiviral resistance and hepatitis B therapy. Hepatology. 2009;49(5 Suppl):S174–84.

    Article  CAS  PubMed  Google Scholar 

  129. Hoofnagle JH. Reactivation of hepatitis B. Hepatology. 2009;49(5 Suppl):S156–65.

    Article  CAS  PubMed  Google Scholar 

  130. Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology. 2009;49(5 Suppl):S185–95.

    Article  CAS  PubMed  Google Scholar 

  131. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. Feb 2009;50(2):227-242.

    Google Scholar 

  132. Belongia EA, Costa J, Gareen IF, et al. NIH consensus development statement on management of hepatitis B. NIH Consens State Sci Statements. 2008;25(2):1–29.

    CAS  PubMed  Google Scholar 

  133. Dusheiko GM. Cost-effectiveness of oral treatments for chronic hepatitis B. J Hepatol. Aug 6 2009.

  134. Buti M, Brosa M, Casado MA, Rueda M, Esteban R. Modeling the cost-effectiveness of different oral antiviral therapies in patients with chronic hepatitis B. J Hepatol. May 20 2009.

Download references

Acknowledgements

We would like to thank AHRQ Task Order Officer Shilpa Amin, MD, MBSC for her guidance throughout the project. We also want to thank librarians Judith Stanke and Dr. Del Reed for their contributions to the literature search; Maureen Carlyle and Marilyn Eells for their excellent technical assistance in preparation of the full evidence report and this manuscript; Rebecca Schultz for her assistance in formatting the tables, and Nancy Russell, MLS for her assistance with proofreading the manuscript.

Grant Support

This project was funded under Contract No. 290-02-0009 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the paper should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Conflict of Interest

None disclosed.

Author information

Authors and Affiliations

  1. Division of Health Policy and Management, Minnesota Evidence-based Practice Center, University of Minnesota School of Public Health, 420 Delaware Street SE, D330-5 Mayo (MMC 729), Minneapolis, MN, 55455, USA

    Tatyana A. Shamliyan MD, MS & Robert L. Kane MD

  2. Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA

    Jian-Min Yuan MD, PhD

  3. Minneapolis VA Center for Chronic Disease Outcomes Research, Minneapolis, MN, USA

    Roderick MacDonald MS & Timothy J. Wilt MD, MPH

  4. University of Minnesota Medical School and the Minneapolis VA Medical Center Section of Gastroenterology, Minneapolis, MN, USA

    Aasma Shaukat MD, MPH

  5. University of Minnesota Medical School and the Minneapolis VA Medical Center Section of Infectious Diseases, Minneapolis, MN, USA

    James R. Johnson MD

  6. University of Minnesota Medical School and the Minneapolis VA Medical Center Section of General Medicine, Minneapolis, MN, USA

    Timothy J. Wilt MD, MPH

Authors
  1. Tatyana A. Shamliyan MD, MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James R. Johnson MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roderick MacDonald MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aasma Shaukat MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian-Min Yuan MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert L. Kane MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Timothy J. Wilt MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatyana A. Shamliyan MD, MS.

Additional information

Corporate names, city, and state of manufacturers of brand-name materials

STATA software (The Statistics/Data Analysis StataCorp. Stata statistical software: Release 9.2. College Station, Texas, USA)

Adefovir (Hepsera, Gilead Sciences, Foster City, California)

Entecavir (Baraclude, Bristol-Myers Squibb, New York)

Interferon Alfa 2b (Intron A, Schering-Plough, Milan, Italy)

Interferon Alfa 2b (Intron A, Schering Plough, Kenilworth, New Jersey)

Interferon Alfa 2b (Intron A, Shering-Plough, Athens, Greece)

Interferon Alfa 2b (Intron A, Scherag, South Africa)

Interferon Alfa 2b (Schering-Plough, Shanghai, China)

Interferon Alfa 2b (Intron A, Essex, Switzerland)

Lamivudine (Glaxo Wellcome, Suzhou, China)

Lamivudine (Zeffix, GlaxoSmithKline, Greenford, United Kingdom)

Lamivudine (Epivir-HBV Glaxo-Wellcome Inc, Research Triangle Park, North Carolina)

Lamivudine (GSK, Athens, Greece)

Lamivudine (Zeffix, GlaxoSmithKline, Middlesex, UK)

Peginterferon alfa-2a (PEGASYS, F. Hoffmann-La Roche Ltd., Basel, Switzerland)

Peginterferon alfa-2b (PegIntron, Schering-Plough Corp., Kenilworth, New Jersey)

Telbivudine Idenix Pharmaceuticals Inc. (Cambridge, Massachusetts)

Tenofovir DF Gilead Sciences

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Appendix 1

Pooled analysis used to calculate number needed to treat (1/pooled absolute risk difference) and number of attributable per 1000 events (1000*pooled absolute risk difference) (DOC 596 kb)

Online Appendix 2

Rates (%) of the most common (>10%) adverse effects after antiviral drugs in adults with chronic hepatitis B (Pooled with random effect models from randomized controlled clinical trials) (DOC 109 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shamliyan, T.A., Johnson, J.R., MacDonald, R. et al. Systematic Review of the Literature on Comparative Effectiveness of Antiviral Treatments for Chronic Hepatitis B Infection. J GEN INTERN MED 26, 326–339 (2011). https://doi.org/10.1007/s11606-010-1569-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11606-010-1569-5

KEY WORDS

Search

Navigation