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Future Therapy for Hepatitis B Virus: Role of Nucleos(t)ide Analogues and Pegylated Interferon Therapy

  • Hepatitis B (JK Lim, Section Editor)
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Abstract

Purpose of Review

The goal of chronic hepatitis B (CHB) therapy is an improvement in clinical outcomes, but surrogate markers include viral suppression, hepatitis B e-antigen (HBeAg) seroconversion, and, more recently, hepatitis B surface antigen (HBsAg) clearance, labeled as “functional cure.” The current therapy of CHB is based on two strategies: either a finite course of pegylated interferon (pegIFN) or an indefinite duration of oral nucleos(t)ide analogues (NAs). NAs with high antiviral potency and barrier to resistance have become the mainstay of therapy due to ease of use, tolerability, and cost. However, optimization of these two therapeutic modalities has not been fully explored to maximize outcomes, which include combination therapy.

Recent Findings

Initial randomized control trials with approved NAs and pegIFN as de novo combinations did not appear to show benefit compared to pegIFN alone, but meta-analyses now show that there are significant improvements in undetectable HBV DNA, HBeAg loss and seroconversion, and HBsAg loss. However, many patients remain on long-term NA therapy, and a strategy to increase HBeAg seroconversion and preferably HBsAg clearance are needed. Such strategies include switch (sequential) or add-on pegIFN to patients already on NAs. An add-on pegIFN strategy in HBeAg-negative CHB (PEGAN study) has shown 8% HBsAg clearance after 48 weeks of therapy, and a switch strategy (OSST study) showed a similar result—8.5% HBsAg clearance. However, the ultimate goal of HBsAg seroclearance remains still <10% despite these strategies.

Summary

It may be possible to improve these outcomes further by selecting patients with lower quantitative HBsAg (qHBsAg) levels and to predict outcomes based on on-treatment qHBsAg responses.

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References

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

  1. World Health Organization. WHO factsheet: hepatitis B: [updated 2014 July]. Available from: URL: http://www.who.int/mediacentre/factsheets/fs204/en.

  2. Stanaway JD, Flaxman AD, Naghavi M, Fitzmaurice C, Vos T, Abubakar et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet. 2016. doi:10.1016/S0140-6736(16)30579-7.

  3. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261–83. doi:10.1002/hep.28156.

    Article  PubMed  Google Scholar 

  4. European Association For The Study Of The Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167–85. doi:10.1016/j.jhep.2012.02.010.

    Article  Google Scholar 

  5. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98. doi:10.1007/s12072-015-9675-4.

    Article  CAS  PubMed  Google Scholar 

  6. Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology. 2009;49(5 Suppl):S103–11. doi:10.1002/hep.22956.

    Article  CAS  PubMed  Google Scholar 

  7. Lok AS, McMahon BJ, Brown Jr RS, Wong JB, Ahmed AT, Farah W, et al. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology. 2016;63(1):284–306. doi:10.1002/hep.28280.

    Article  CAS  PubMed  Google Scholar 

  8. • Zeisel MB, Lucifora J, Mason WS, Sureau C, Beck J, Levrero M, et al. Towards an HBV cure: state-of-the-art and unresolved questions--report of the ANRS workshop on HBV cure. Gut. 2015;64(8):1314–26. doi:10.1136/gutjnl-2014-308943. This review during the ANRS workshop summarised the current understanding of HBV host-interactions leading to viral persistence, as well as the roadblocks to be overcome to address unmet medical needs in the treatment of chronic HBV infection.

    Article  CAS  PubMed  Google Scholar 

  9. Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut. 2014;63(8):1325–32. doi:10.1136/gutjnl-2013-305517.

    Article  CAS  PubMed  Google Scholar 

  10. Govan L, Wu O, Xin Y, Hutchinson SJ, Hawkins N. Comparative effectiveness of antiviral treatment for hepatitis B: a systematic review and Bayesian network meta-analysis. Eur J Gastroenterol Hepatol. 2015;27(8):882–94. doi:10.1097/MEG.0000000000000376.

    Article  CAS  PubMed  Google Scholar 

  11. Woo G, Tomlinson G, Nishikawa Y, Kowgier M, Sherman M, Wong DK, et al. Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses. Gastroenterology. 2010;139(4):1218–29. doi:10.1053/j.gastro.2010.06.042.

    Article  CAS  PubMed  Google Scholar 

  12. Liang X, Fan R, Sun J, Shaikh J, Taneja A, Gupta S, et al. Effect of telbivudine versus other nucleos(t)ide analogs on HBeAg seroconversion and other outcomes in patients with chronic hepatitis B: a network meta-analysis. Adv Ther. 2016;33(4):519–31. doi:10.1007/s12325-016-0305-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang N, Hu HD, Sun H, Feng Q, Hu P, Liu Q, et al. Comparison of the forty-eight week efficacy between telbivudine and entecavir in HBeAg-positive Asian patients with chronic hepatitis B: a meta-analysis. Turk J Gastroenterol. 2013;24(3):230–40.

    Article  PubMed  Google Scholar 

  14. Su QM, Ye XG. Effects of telbivudine and entecavir for HBeAg-positive chronic hepatitis B: a meta-analysis. World J Gastroenterol. 2012;18(43):6290–301. doi:10.3748/wjg.v18.i43.6290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu H, Wang X, Wan G, Yang Z, Zeng H. Telbivudine versus entecavir for nucleos(t)ide-naive HBeAg-positive chronic hepatitis B: a meta-analysis. Am J Med Sci. 2014;347(2):131–8. doi:10.1097/MAJ.0b013e318286878d.

    Article  PubMed  Google Scholar 

  16. Chan HL, Shaikh J, Gupta S, Hamed K. Renal function in nucleos(t)ide analog-treated patients with chronic hepatitis B: a systematic literature review and network meta-analysis. Adv Ther. 2016;33(5):862–75. doi:10.1007/s12325-016-0337-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liaw YF, Lau GK, Kao JH, Gane E. Hepatitis B e antigen seroconversion: a critical event in chronic hepatitis B virus infection. Dig Dis Sci. 2010;55(10):2727–34. doi:10.1007/s10620-010-1179-4.

    Article  CAS  PubMed  Google Scholar 

  18. Hou JL, Jia JD, Wei L, Zhao W, Wang YM, Cheng M, et al. Efficacy and safety of entecavir treatment in a heterogeneous CHB population from a ‘real-world’ clinical practice setting in China. J Viral Hepat. 2013;20(11):811–20. doi:10.1111/jvh.12115.

    PubMed  Google Scholar 

  19. Buti M, Tsai N, Petersen J, Flisiak R, Gurel S, Krastev Z, et al. 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. doi:10.1007/s10620-014-3486-7.

    Article  CAS  PubMed  Google Scholar 

  20. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, 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 

  21. •• Marcellin P, Ahn SH, Ma X, Caruntu FA, Tak WY, Elkashab M, et al. Combination of tenofovir disoproxil fumarate and peginterferon alpha-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology. 2016;150(1):134–44 e10. doi:10.1053/j.gastro.2015.09.043. This open-label, randomized-controlled study demonstrated a significantly greater proportion of patients receiving TDF plus peginterferon for 48 weeks had HBsAg loss than those receiving TDF or peginterferon alone.

    Article  CAS  PubMed  Google Scholar 

  22. Buster EH, Flink HJ, Cakaloglu Y, Simon K, Trojan J, Tabak F, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008;135(2):459–67. doi:10.1053/j.gastro.2008.05.031.

    Article  CAS  PubMed  Google Scholar 

  23. Marcellin P, Bonino F, Lau GK, Farci P, Yurdaydin C, Piratvisuth T, et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a. Gastroenterology. 2009;136(7):2169–79 e1–4. doi:10.1053/j.gastro.2009.03.006.

    Article  CAS  PubMed  Google Scholar 

  24. Sonneveld MJ, Rijckborst V, Cakaloglu Y, Simon K, Heathcote EJ, Tabak F, et al. Durable hepatitis B surface antigen decline in hepatitis B e antigen-positive chronic hepatitis B patients treated with pegylated interferon-alpha2b: relation to response and HBV genotype. Antivir Ther. 2012;17(1):9–17. doi:10.3851/IMP1887.

    Article  CAS  PubMed  Google Scholar 

  25. Wang Z, Sun L, Wu Y, Xia Q. Extended duration versus standard duration of peginterferon alfa-2a in treatment of chronic hepatitis B: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2016;40(2):195–202. doi:10.1016/j.clinre.2015.06.022.

    Article  CAS  PubMed  Google Scholar 

  26. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, 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 

  27. Zhou J, Wu X, Wei W, You H, Jia J, Kong Y. A meta-analysis of the efficacy of interferon monotherapy or combined with different nucleos(t)ide analogues for chronic hepatitis B. Int J Environ Res Public Health. 2016;13(5). doi:10.3390/ijerph13070730.

  28. Wei W, Wu Q, Zhou J, Kong Y, You H. A better antiviral efficacy found in nucleos(t)ide analog (NA) combinations with interferon therapy than NA monotherapy for HBeAg positive chronic hepatitis B: a meta-analysis. Int J Environ Res Public Health. 2015;12(8):10039–55. doi:10.3390/ijerph120810039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, et al. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology. 2006;44(3):675–84.

    Article  CAS  PubMed  Google Scholar 

  30. Huang R, Hao Y, Zhang J, Wu C. Interferon-alpha plus adefovir combination therapy versus interferon-alpha monotherapy for chronic hepatitis B treatment: a meta-analysis. Hepatol Res. 2013;43(10):1040–51. doi:10.1111/hepr.12058.

    CAS  PubMed  Google Scholar 

  31. Xie QL, Zhu Y, Wu LH, Fu LL, Xiang Y. The efficacy and safety of entecavir and interferon combination therapy for chronic hepatitis B virus infection: a meta-analysis. PLoS ONE. 2015;10(7):e0132219. doi:10.1371/journal.pone.0132219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Marcellin P, Wursthorn K, Wedemeyer H, Chuang WL, Lau G, Avila C, et al. 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. doi:10.1016/j.jhep.2014.08.021.

    Article  CAS  PubMed  Google Scholar 

  33. Chan HL, Chan CK, Hui AJ, Chan S, Poordad F, Chang TT, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology. 2014;146(5):1240–8. doi:10.1053/j.gastro.2014.01.044.

    Article  CAS  PubMed  Google Scholar 

  34. Gish RG, Chang TT, Lai CL, de Man RA, Gadano A, Llamoso C, et al. Quantitative hepatitis B surface antigen analysis in hepatitis B e antigen-positive nucleoside-naive patients treated with entecavir. Antivir Ther. 2013;18(5):691–8. doi:10.3851/IMP2559.

    Article  CAS  PubMed  Google Scholar 

  35. Chen CH, Chiu YC, Lu SN, Lee CM, Wang JH, Hu TH, et al. Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues. World J Gastroenterol. 2014;20(24):7686–95. doi:10.3748/wjg.v20.i24.7686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. • Brouwer WP, Xie Q, Sonneveld MJ, Zhang N, Zhang Q, Tabak F, et al. 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. doi:10.1002/hep.27586. In this global investigator-initiated, open-label, multicenter, randomized trial, 24 weeks of Peg-IFN add-on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy.

    Article  CAS  PubMed  Google Scholar 

  37. Bourliere M, Rabiega P, Ganne-Carrie N, Serfaty L, Marcellin P, Pouget N et al. HBsAg clearance after addition of 48 weeks of pegIFN in HBeAg negative CHB patients on nucleos(t)ide therapy with undetectable HBV DNA for at least one year: final results from ANRS-HB06 pegan study: multicenter randomized controlled phase iii trial. European Association for Study of Liver; Vienna, Austria 2015.

  38. Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, et al. 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. doi:10.1016/j.jhep.2014.05.044.

    Article  CAS  PubMed  Google Scholar 

  39. Han M, Jiang J, Hou J, Tan D, Sun Y, Zhao M, et al. Sustained immune control in HBeAg-positive patients who switched from entecavir therapy to pegylated interferon-alpha2a: 1 year follow-up of the OSST study. Antivir Ther. 2016;21(4):337–44. doi:10.3851/IMP3019.

    Article  PubMed  Google Scholar 

  40. Ren H, Hu P, Chen X, Gong G, Shang J, Zhang W et al. Switching to PegIFN a–2a in NUC treated CHB patients (NEW SWITCH study): comparison 48 and 96 weeks. Asia Pacific Association for Study of Liver; Tokyo, Japan 2016. p. Abstract O-101.

  41. 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):629–36 e1. doi:10.1053/j.gastro.2012.05.039.

    Article  CAS  PubMed  Google Scholar 

  42. Chan HL, Wong GL, Chim AM, Chan HY, Chu SH, Wong VW. Prediction of off-treatment response to lamivudine by serum hepatitis B surface antigen quantification in hepatitis B e antigen-negative patients. Antivir Ther. 2011;16(8):1249–57. doi:10.3851/IMP1921.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore

    Guan-Huei Lee, David Hsingyu Chen & Seng-Gee Lim

  2. Faculty of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Guan-Huei Lee & Seng-Gee Lim

  3. Division of Gastroenterology and Hepatology, National University Hospital, 1E Lower Kent Ridge Road, Singapore, 119228, Singapore

    Guan-Huei Lee & Seng-Gee Lim

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Seng Gee Lim declares personal fee participation on advisory boards for Gilead Sciences, Novartis, Merck Sharpe and Dohme, Bristol Myer Squibb, AbbVie, and Abbott. He also received personal fees for the following speaker bureaus: Bristol Myers Squibb. Novartis, Gilead Sciences, Abbott, Merck Sharpe and Dohme, and Roche. He also received educational/research funding: Abbott, Novartis, Merck Sharpe and Dohme, and Gilead Sciences. Guan Huei Lee declares personal fee participation on advisory boards for Gilead Sciences. David Hsingyu Chen declares that he has no conflicts of interest.

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This article is part of the Topical Collection on Hepatitis B

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Lee, GH., Chen, D.H. & Lim, SG. Future Therapy for Hepatitis B Virus: Role of Nucleos(t)ide Analogues and Pegylated Interferon Therapy. Curr Hepatology Rep 15, 230–236 (2016). https://doi.org/10.1007/s11901-016-0325-7

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