Current Hepatitis Reports

, Volume 11, Issue 4, pp 263–271 | Cite as

Interferon-based Therapy for e-antigen Negative Chronic Hepatitis B Virus Infection

  • Fayaz A. Handoo
  • Hamdan AlGhamdi
  • Faisal M. Sanai
  • Ibrahim H. Altraif
Global Perspectives: Middle East (SM Alavian and AI Sharara, Section Editors)

Abstract

The prevalence of the hepatitis B e antigen (HBeAg)-negative form of chronic hepatitis B (CHB) has increased over the years and is generally more difficult to treat. Pegylated interferon (PEG-IFN) offers a durable response, finite treatment duration and absence of viral resistance. On the other hand, the risk of viral relapse for patients discontinuing nucleos(t)ide analogues remains a major concern for this form of treatment, raising the spectre of drug resistance and safety with long-term use. PEG-IFN remains one of the first-line drugs for a select group of CHB patients, and with its dual immunomodulatory and antiviral effect offers a realistic chance of durable off-treatment response and HBsAg clearance. PEG-IFN could be offered to patients with a high pre-treatment likelihood of response. In this article we aim to discuss the indications and goals of antiviral therapy in HBeAg-negative patients, the safety and efficacy of IFN-based therapy, the predictors of response, and its potential future directions.

Keywords

Hepatitis B HBeAg-negative Peginterferon Treatment Durability Quantitative HBsAg HBV DNA Response predictors 

Abbreviations

HBV

Hepatitis B virus

CHB

Chronic hepatitis B

PEG-IFN

Pegylated interferon

HCC

Hepatocellular carcinoma

PPV

Positive predictive value

NPV

Negative predictive value

NA

Nucleos(t)ide analogues

ALT

Alanine aminotransferase

ULN

Upper limit of normal

HBsAg

Hepatitis B s antigen

HBeAg

Hepatitis B e antigen

AUC

Area under the curve

Notes

Disclosure

FA Handoo: none; H AlGhamdi: none, FM Sanai: board membership with Schering Plough, consultancy with Glaxo-Smith Kline, grants from Roche, receives honoraria and payment for development of educational presentations from Bristol Myers Squibb and Merck Sharpe & Dohme; IH Altraif: consultant for MSD-Merck, receives honoraria from Schering-Plough and royalties from GSK.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Goldstein ST, Zhou F, Hadler SC, et al. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol. 2005;34(6):1329–39.PubMedCrossRefGoogle Scholar
  2. 2.
    Lavanchy D. Worldwide epidemiology of HBV infection, disease burden and vaccine prevention. J Clin Virol. 2005;34 Suppl 1:S1–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Bosch FX, Ribes J, Cleries R, et al. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005;9:191–211.PubMedCrossRefGoogle Scholar
  4. 4.
    Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373:582–92.PubMedCrossRefGoogle Scholar
  5. 5.
    Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol. 2001;34:306–13.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73. 26:177–82.PubMedCrossRefGoogle Scholar
  7. 7.
    Hoofnagle JH, di Bisceglie AM. The treatment of chronic viral hepatitis. N Engl J Med. 1997;336:347–56.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    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 Hepat. 2003;10:298–305.PubMedCrossRefGoogle Scholar
  10. 10.
    Hyams KC. Risks of chronicity following acute hepatitis B infection: a review. Clin Infect Dis. 1995;20:992–1000.PubMedCrossRefGoogle Scholar
  11. 11.
    Lok AS, Lai CL, Wu PC, et al. Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B infection. Gastroenterology. 1987;92:1839–43.PubMedGoogle Scholar
  12. 12.
    Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989;2:588–91.PubMedCrossRefGoogle Scholar
  13. 13.
    Okamoto H, Tsuda F, Akahane Y, et al. Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol. 1994;68:8102–10.PubMedGoogle Scholar
  14. 14.
    Lok AS, Akarca U, Greene S, et al. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci USA. 1999;91:4077–81.CrossRefGoogle Scholar
  15. 15.
    Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2001;34:617–24.PubMedCrossRefGoogle Scholar
  16. 16.
    Fattovich G. Natural history of hepatitis B. J Hepatol. 2003;39 Suppl 1:S50–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Cao GW. Clinical relevance and public health significance of hepatitis B virus genomic variation. World J Gastroenterol. 2009;15:5761–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Abdo AA, Abdou AM, Akarca US, et al. A review of chronic hepatitis B epidemiology and management issues in selected countries in the Middle East. J Viral Hepat. 2012;19(1):9–22.CrossRefGoogle Scholar
  19. 19.
    Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology. 2003;46:329–38.PubMedCrossRefGoogle Scholar
  20. 20.
    • EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–85. The practice guidelines emphasize that patients with compensated cirrhosis and detectable HBV DNA must be considered for treatment even if ALT levels are normal. Google Scholar
  21. 21.
    Papatheodoridis GV, Manolakopoulos S, Liaw Y-F, et al. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol. 2012;57(1):196–202.Google Scholar
  22. 22.
    Poynard T, Morra R, Ingiliz P, et al. Assessment of liver fibrosis: noninvasive means. Saudi J Gastroenterol. 2008;14:163–73.PubMedCrossRefGoogle Scholar
  23. 23.
    Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–39.PubMedCrossRefGoogle Scholar
  24. 24.
    European Association for the study of the Liver. EASL Clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227–42.CrossRefGoogle Scholar
  25. 25.
    Liaw YF, Leung NW, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B:a 2008 update. Hepatol Int. 2008;2:263–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Yuen MF, Wong DK, Fung J, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008;135:1192–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Locarnini S. Molecular virology of hepatitis B virus. Semin Liver Dis. 2004;24 Suppl 1:3–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Feld JJ, Wong DK, Heathcote EJ. Endpoints of therapy in chronic hepatitis B. Hepatology. 2009;49:S96–S102.PubMedCrossRefGoogle Scholar
  29. 29.
    Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–86.PubMedCrossRefGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    Sung JJY, Tsoi KKF, Wong VWS, et al. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008;28:1067–77.PubMedCrossRefGoogle Scholar
  32. 32.
    • Marcellin P, Bonino F, Lau GK, et al. Sustained response of hepatitis B e antigen negative patients 3 years after treatment with peginterferon alpha-2a. Gastroenterology. 2009;136:2169–79. This is the first study to describe the durability of response to PEG-IFN therapy in HBeAg-negative patients. PubMedCrossRefGoogle Scholar
  33. 33.
    Peters M. Action of cytokines on the immune response and viral interactions: an overview. Hepatology. 1996;23:909–16.PubMedCrossRefGoogle Scholar
  34. 34.
    Fensterl V, Sen GC. Interferons and viral infections. Biofactors. 2009;35(1):14–20.PubMedCrossRefGoogle Scholar
  35. 35.
    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;351:1206–17.PubMedCrossRefGoogle Scholar
  36. 36.
    •• Marcellin P, Piratvisuth T, Brunetto M, et al. Increasing rates of HBsAg clearance and seroconversion in patients with HBeAg-negative disease treated with peginterferon alfa-2a ± lamivudine: results of 5-year post-treatment follow up. J Hepatol. 2009;50:S33. This important study reported continued increase in HBsAg clearance on long term follow up after 48 weeks of PEG-IFN therapy. Google Scholar
  37. 37.
    Heathcote JE, Gane EJ, de Man RA, et al. Three year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140:132–43.PubMedCrossRefGoogle Scholar
  38. 38.
    Zoutendijk R, Hansen BE, van Vuuren AJ, et al. Prediction of HBsAg loss using HBsAg decline after long term virological response to nucleos(t)ide analogue therapy for chronic hepatitis B. Hepatology. 2010;52(Suppl):509A.Google Scholar
  39. 39.
    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 randomized trial. Lancet. 2005;365:123–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Van Zonneveld M, Flink HJ, Verhey E, et al. The safety of pegylated interferon alfa-2b in the treatment of chronic hepatitis B; predictive factors for dose reduction and treatment discontinuation. Aliment Pharmacol Ther. 2005;21:1163–71.PubMedCrossRefGoogle Scholar
  41. 41.
    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;46:388–94.PubMedCrossRefGoogle Scholar
  42. 42.
    Janssen HL, Brouwer JT, Nevens F, et al. Fatal hepatic decompensation associated with interferon alfa. European concerted action on viral hepatitis. BMJ. 1993;306:107–8.PubMedCrossRefGoogle Scholar
  43. 43.
    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;56:699–705.PubMedCrossRefGoogle Scholar
  44. 44.
    Chan HLY, Wong VWS, Tse AM, et al. Serum hepatitis B surface antigen quantification can reflect hepatitis B virus in the liver and predict treatment response. Clin Gastroentrol Hepatol. 2007;5:1462–8.CrossRefGoogle Scholar
  45. 45.
    Guner R, Karahocagil M, Buyukberber M, et al. Correlation between intrahepatic hepatitis B virus cccDNA levels and other activity markers in patients with HBeAg-negative chronic hepatitis B infection. Eur J Gastroenterol Hepatol. 2011;23(12):1185–91.PubMedCrossRefGoogle Scholar
  46. 46.
    Al-Ashgar HI, Khan MQ, Aljumah A, et al. Efficacy of peginterferon α-2a and predictors of response in HBeAg-negative, genotype D-naive patients. Hepatol Int. 2011. doi:10.1007/s12072-011-9319-2.
  47. 47.
    Farci P, Marcellin P, Lu ZM, et al. On treatment predictors of sustained biochemical and virological response in patients with HBeAg-negative chronic hepatitis B treated with peginteron alpha-2a. Hepatology. 2005;42 Suppl 2:175 A.Google Scholar
  48. 48.
    Chan HYL, Wong VWS, Chim AML, et al. Treatment of patients with chronic hepatitis B who had failed previous antiviral treatment with Pegylated interferon alpha-2a. Antivir Ther. 2008;13:555–62.PubMedGoogle Scholar
  49. 49.
    Marcellin P, Brunetto M, Bonino F, et al. In patients with HBeAg-negative chronic hepatitis B HBsAg serum levels early during treatment with peginterferon alpha-2a predict HBsAg clearance 4 years posttreatment. Hepatology. 2008;48 Suppl 1:718A.Google Scholar
  50. 50.
    Peng CY, Lai HC, Li YF, et al. Early serum HBsAg level as a strong predictor of sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Aliment Pharmacol Ther. 2012;35(4):458–68.PubMedCrossRefGoogle Scholar
  51. 51.
    • Brunetto MR, Moriconi F, Bonino F, et al. Hepatitis B surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology. 2009;49(4):1141–50. This multinational trial studied the possible role of on treatment and end of therapy HBsAg quantification in predicting sustained off treatment response and HBsAg clearance with PEG-IFN. PubMedCrossRefGoogle Scholar
  52. 52.
    Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology. 2009;49:1151–7.PubMedCrossRefGoogle Scholar
  53. 53.
    •• Rijckborst V, Hansen BE, Cakaloglu Y, et al. Early on treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels. Hepatology. 2010;52:454–61. This study through the combination of failure of HBsAg drop and <2 log copies/ml HBV DNA decline at week 12 provides a solid stopping rule early on during treatment with PEG-IFN in those HBeAg-negative patients who most likely would be future nonresponders. PubMedCrossRefGoogle Scholar
  54. 54.
    Rijckborst V, Hansen BE, Ferenci P, et al. Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a. J Hepatol. 2012;56:1006–11.PubMedCrossRefGoogle Scholar
  55. 55.
    Marcellin P, Bonino F, Yurdaydin C, et al. Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients. Hepatol Int. 2012. doi:10.1007/s12072-012-9343-x.
  56. 56.
    Piccolo P, Lenci I, Demelia L, et al. A randomized controlled trial of pegylated interferon-alpha2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B. Antivir Ther. 2009;14:1165–74.PubMedCrossRefGoogle Scholar
  57. 57.
    Moucari R, Boyer N, Ripault MP, et al. Sequential therapy with adefovir dipivoxil and pegylated interferon alfa-2a for HBeAg-negative patients. J Viral Hepat. 2011;18(8):580–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Jaroszewicz J, Ho H, Markova A, et al. Hepatitis B surface antigen (HBsAg) decrease and serum interferon inducible protein-10 levels as predictive markers of HBsAg loss during treatment with nucleos(t)ide analogues. Antivir Ther. 2011;16(6):915–24.PubMedCrossRefGoogle Scholar
  59. 59.
    Sarin SK, Sood A, Kumar M, et al. Effect of lowering HBV DNA levels by initial antiviral therapy before adding immunomodulator on treatment of chronic hepatitis B. Am J Gastroenterol. 2007;102:96–104.PubMedCrossRefGoogle Scholar
  60. 60.
    •• Lampertico P, Viganò M, Di Costanzo GG, et al. Extended (2 years) treatment with peginterferon alfa-2a [40KD] improves sustained response rates in genotype D patients with HBeAg negative chronic hepatitis B. J Hepatol. 2010;52 Suppl 1:S45. This study suggests that in difficult-to-treat HBeAg-negative patients, such as those infected with genotype D, PEG-IFN can be safely extended to 96 weeks, to significantly increase the sustained virological response. CrossRefGoogle Scholar
  61. 61.
    Funk ML, Rosenberg DM, Lok ASF. World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promotor varients. J Viral Hepat. 2002;9:52–61.PubMedCrossRefGoogle Scholar
  62. 62.
    Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen negative chronic hepatitis B—natural history and treatment. Semin Liver Dis. 2006;26:130–41.PubMedCrossRefGoogle Scholar
  63. 63.
    Marcellin P, Buti M, Gane EJ, et al. Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis. Hepatology. 2011;54:1011A.CrossRefGoogle Scholar
  64. 64.
    Shouval D, Lai CL, Chang TT, et al. Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy. J Hepatol. 2009;50:289–95.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Fayaz A. Handoo
    • 1
  • Hamdan AlGhamdi
    • 1
  • Faisal M. Sanai
    • 1
    • 2
  • Ibrahim H. Altraif
    • 1
    • 3
  1. 1.Department of Hepatobiliary Sciences and Liver TransplantationKing Abdulaziz Medical City, King Fahad National Guard HospitalRiyadhKingdom of Saudi Arabia
  2. 2.Liver Disease Research CenterKing Saud UniversityRiyadhKingdom of Saudi Arabia
  3. 3.King Saud Bin Abdulaziz University for Health SciencesRiyadhKingdom of Saudi Arabia

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