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Adding interferon to lamivudine enhances the early virologic response and reversion of the precore mutation in difficult-to-treat HBV infection

  • Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

The virologic impact of adding interferon to antiviral nucleoside therapy was studied in Japanese patients having perinatally transmitted hepatitis B virus (HBV) genotype C.

Methods

Sixty-four patients including 41 positive for hepatitis B e antigen (HBeAg) were assigned to receive either (1) a combination of interferon-α (6 million units daily for 2 weeks, then three times weekly) plus lamivudine (100 mg daily) for 24 weeks followed by lamivudine alone for 28 weeks (n = 30) or (2) 52-week lamivudine monotherapy (n = 34).

Results

The combination treatment enhanced the early virologic response, and HBV clearance was more frequent at week 8 for patients with baseline HBV DNA ≤ 7 log copies/ml (90% vs. 33%, P = 0.013) and at week 24 for patients with baseline HBV DNA > 7 log copies/ml (75% vs. 40%, P = 0.080). In the combination arm, YMDD mutants emerged less often at week 52 (8% vs. 30%, P = 0.047). However, reversion of the precore mutation was more prominent with combination treatment than with monotherapy (McNemar test, P = 0.014 and P = 0.103, respectively). HBeAg seroconversion (P = 0.429) and sustained off-treatment HBV suppression to ≤5 log copies/ml (log-rank test, P = 0.195) were not improved.

Conclusions

Simultaneous commencement of treatment with interferon and a nucleoside analog may be worthy as a treatment option to augment the early virologic response and prevent drug resistance in difficult-to-treat patients. Combination treatment was also shown to enhance reversion of the precore mutation. Further studies are warranted to clarify the therapeutic implications of this phenomenon.

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References

  1. Santantonio T, Niro GA, Sinisi E, Leandro G, Insalata M, Guastadisegni A, et al. Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B patients: a controlled pilot study. J Hepatol 2002;36:799–804.

    Article  PubMed  CAS  Google Scholar 

  2. Hasan F, Al-Khaldi J, Asker H, Varghese R, Siddique I, Al-Shammali M, et al. Treatment of chronic hepatitis B with the sequential administration of interferon and lamivudine. Gastroenterol 2003;50:2040–2042.

    CAS  Google Scholar 

  3. Marcellin P, Lau GKK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alpha-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206–1217.

    Article  PubMed  CAS  Google Scholar 

  4. Lau GKK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon alpha-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682–2695.

    Article  PubMed  CAS  Google Scholar 

  5. Chan HLY, Leung NWY, Hui AY, Wong VWS, Liew CT, Chim AML, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-α2b and lamivudine with lamivudine alone. Ann Intern Med 2005;142:240–250.

    PubMed  CAS  Google Scholar 

  6. Yurdaydin C, Bozkaya H, Cetinkaya H, Sahin T, Karaoğuz D, Törüner M, et al. Lamivudine vs lamivudine and interferon combination treatment of HBeAg(-) chronic hepatitis B. J Viral Hepatitis 2005;12:262–268.

    Article  CAS  Google Scholar 

  7. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–435.

    Article  PubMed  CAS  Google Scholar 

  8. Mizokami M, Nakano T, Orito E, Tanaka Y, Sakugawa H, Mukaide M, et al. Hepatitis B virus genotype assignment using restriction fragment length polymorphism patterns. FEBS Lett 1999;450:66–71.

    Article  PubMed  CAS  Google Scholar 

  9. Aikawa T, Kanai K, Kako M, Kawasaki T, Hino K, Iwabuchi S, et al. Interferon-α2a for chronic hepatitis B with e antigen or antibody: comparable antiviral effects on wild-type virus and precore mutant. J Viral Hepatitis 1995;2:243–250.

    Article  CAS  Google Scholar 

  10. Aritomi T, Yatsuhashi H, Fujino T, Yamasaki K, Inoue O, Koga M, et al. Association of mutations in the core promoter and precore region of hepatitis virus with fulminant and severe acute hepatitis in Japan. J Gastroenterol Hepatol 1998;13:1125–1132.

    Article  PubMed  CAS  Google Scholar 

  11. Sypsa VA, Mimidis K, Tassopoulos NC, Chrysagis D, Vassiliadis T, Moulakakis A, et al. A viral kinetic study using pegylated interferon alpha-2b and/or lamivudine in patients with chronic hepatitis B/HBeAg negative. Hepatology 2005;42:77–85.

    Article  PubMed  CAS  Google Scholar 

  12. Yuen MF, Sablon E, Hui CK, Yuan HJ, Decraemer H, Lai CL. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology 2001;34:785–791.

    Article  PubMed  CAS  Google Scholar 

  13. Lok ASF, Hussain M, Cursano C, Margotti M, Gramenzi A, Grazi GL, et al. Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy. Hepatology 2000;32:1145–1153.

    Article  PubMed  CAS  Google Scholar 

  14. Cho SW, Hahm KB, Kim JH. Reversion from precore/core promoter mutants to wild-type hepatitis B virus during the course of lamivudine therapy. Hepatology 2000;32:1163–1169.

    Article  PubMed  CAS  Google Scholar 

  15. Ciancio A, Smedile A, Rizzetto M, Lagget M, Gerin J, Korba B. Identification of HBV DNA sequences that are predictive of response to lamivudine therapy. Hepatology 2004;39:64–73.

    Article  PubMed  CAS  Google Scholar 

  16. Chen CH, Lee CM, Lu SN, Changchien CS, Wang JC, Wang JH, et al. Comparison of sequence changes of precore and core promoter regions in HBeAg-positive chronic hepatitis B patients with and without HBeAg clearance in lamivudine therapy. J Hepatol 2006;44:76–82.

    Article  PubMed  CAS  Google Scholar 

  17. Lok ASF, Akarca U, Greene S. 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 1994;91:4077–4081.

    Article  PubMed  CAS  Google Scholar 

  18. Buckwold VE, Xu Z, Chen M, Yen TSB, Ou JH. Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol 1996;70:5845–5851.

    PubMed  CAS  Google Scholar 

  19. Parekh S, Zoulim F, Ahn SH, Tsai A, Li J, Kawai S, et al. Genome replication, virion secretion, and e antigen expression of naturally occurring hepatitis B virus core promoter mutants. J Virol 2003; 77:6601–6612.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan

    Nobukazu Yuki & Michio Kato

  2. SRL Inc., Hino, Japan

    Takayuki Nagaoka, Masao Omura & Kazumasa Hikiji

  3. Department of Medical Information, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan

    Kazuhiko Nukui

Authors
  1. Nobukazu Yuki
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  2. Takayuki Nagaoka
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  3. Kazuhiko Nukui
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  4. Masao Omura
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  5. Kazumasa Hikiji
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  6. Michio Kato
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Yuki, N., Nagaoka, T., Nukui, K. et al. Adding interferon to lamivudine enhances the early virologic response and reversion of the precore mutation in difficult-to-treat HBV infection. J Gastroenterol 43, 457–463 (2008). https://doi.org/10.1007/s00535-008-2174-9

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  • DOI: https://doi.org/10.1007/s00535-008-2174-9

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