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Dynamics of lamivudine-resistant hepatitis B virus strains in patients with entecavir rescue therapy

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Abstract

Entecavir rescue therapy is frequently used in patients with lamivudine-resistant hepatitis B virus (HBV) strains. The aim of this study was to investigate evolutionary patterns of HBV quasispecies during entecavir rescue therapy and evaluate their impacts on therapeutic efficacy. We enrolled 21 chronic hepatitis B patients who failed to respond to lamivudine therapy and were switched to entecavir treatment. Measurement of serum HBV DNA and sequence analysis of HBV reverse transcriptase were done up to 144 weeks. Four patients of this series showed a reversion to wild-type HBV after entecavir treatment and in three of them, a complete viral response (<2.6 log10 copies/ml) was achieved. An additional five patients developed entecavir genotypic resistance, with prior occurrence of lamivudine-resistant mutation (L180 M ± M204 V/I). A viral breakthrough was observed in four of the five patients with entecavir-resistant mutants. The remaining 12 patients of this series showed dominance of lamivudine-resistant mutants throughout the entecavir rescue therapy, and five of them achieved a complete viral response at the end of follow-up. The average HBV DNA level was significantly lower in patients with a reversion to wild-type HBV than in those without it (P < 0.05). In conclusion, reversion to wild-type HBV is a favorable indicator for response to entecavir rescue therapy in lamivudine-refractory patients with chronic hepatitis B. The presence of lamivudine-resistant mutations contributes to the development of entecavir resistance.

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References

  1. A.H. Malik, W.M. Lee, Chronic hepatitis B virus infection: treatment strategies for the next millennium. Ann. Intern. Med. 132, 723–731 (2000)

    Article  PubMed  CAS  Google Scholar 

  2. C.L. Lai, R.N. Chien, N.W. Leung, T.T. Chang, R. Guan, D.I. Tai et al., A one year trial of lamivudine for chronic hepatitis B. N. Engl. J. Med. 339, 61–68 (1998)

    Article  PubMed  CAS  Google Scholar 

  3. J.L. Dienstag, E.R. Schiff, T.L. Wright, R.P. Perrillo, H.W. Hann, Z. Goodman et al., Lamivudine as initial treatment for chronic hepatitis B in the United States. N. Engl. J. Med. 341, 1256–1263 (1999)

    Article  PubMed  CAS  Google Scholar 

  4. Y.F. Liaw, J.J. Sung, W.C. Chow, G. Farrell, C.Z. Lee, H. Yuen et al., Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N. Engl. J. Med. 351, 1521–1531 (2004)

    Article  PubMed  CAS  Google Scholar 

  5. G.V. Papatheodoridis, E. Dimou, K. Dimakopoulos, S. Manolakopoulos, I. Rapti, G. Kitis et al., Outcome of hepatitis Be antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology 42, 121–129 (2005)

    Article  PubMed  CAS  Google Scholar 

  6. C.L. Lai, J. Dienstag, E. Schiff, N.W. Leung, M. Atkins, C. Hunt et al., Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin. Infect. Dis. 36, 687–696 (2003)

    Article  PubMed  CAS  Google Scholar 

  7. H.J. Kim, J.H. Park, D.I. Park, Y.K. Cho, C.I. Sohn, W.K. Jeon et al., Rescue therapy for lamivudine-resistant chronic hepatitis B: comparison between entecavir 1.0 mg monotherapy, adefovir monotherapy and adefovir add-on lamivudine combination therapy. J. Gastroenterol. Hepatol. 25, 1374–1380 (2010)

    Article  PubMed  CAS  Google Scholar 

  8. O. Lada, Y. Benhamou, A. Cahour, C. Katlama, T. Poynard, V. Thibault, In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antivir Ther 9, 353–363 (2004)

    PubMed  CAS  Google Scholar 

  9. F. van Bömmel, T. Wünsche, S. Mauss, P. Reinke, A. Bergk, D. Schürmann, B. Wiedenmann, T. Berg, Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 40, 1421–1425 (2004)

    Article  PubMed  Google Scholar 

  10. M. Sherman, C. Yurdaydin, H. Simsek et al., Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology 48, 99–108 (2008)

    Article  PubMed  CAS  Google Scholar 

  11. S. Levine, D. Hernandez, G. Yamanaka, S. Zhang, R. Rose, S. Weinheimer et al., Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro. Antimicrob. Agents Chemother. 46, 2525–2532 (2002)

    Article  PubMed  CAS  Google Scholar 

  12. R.J. Colonno, R. Rose, C.J. Baldick, S. Levine, K. Pokornowski, C.F. Yu et al., Entecavir resistance is rare in nucleoside naive patients with hepatitis B. Hepatology 44, 1656–1665 (2006)

    Article  PubMed  CAS  Google Scholar 

  13. D.J. Tenney, R.E. Rose, C.J. Baldick, S.M. Levine, K.A. Pokornowski, A.W. Walsh et al., Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob. Agents Chemother. 51, 902–911 (2007)

    Article  PubMed  CAS  Google Scholar 

  14. S. Ijaz, C. Arnold, S. Dervisevic, J. Mechurova, N. Tatman, R.S. Tedder, N.V. Naoumov, Dynamics of lamivudine-resistant hepatitis B virus during adefovir monotherapy versus lamivudine plus adefovir combination therapy. J. Med. Virol. 80, 1160–1170 (2008)

    Article  PubMed  CAS  Google Scholar 

  15. J.J. Guo, Q.L. Li, X.F. Shi, D.Z. Zhang, A.Z. Zeng, T. Feng et al., Dynamics of hepatitis B virus resistance to entecavir in a nucleoside/nucleotide-naïve patient. Antiviral Res. 81, 180–183 (2009)

    Article  PubMed  CAS  Google Scholar 

  16. A. Snow-Lampart, B. Chappell, M. Curtis, Y. Zhu, F. Myrick, J. Schawalder et al., No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus. Hepatology 53, 763–773 (2011)

    Article  PubMed  CAS  Google Scholar 

  17. K.P. Fischer, K.S. Gutfreund, D.L. Tyrrell, Lamivudine resistance in hepatitis B: mechanisms and clinical implications. Drug Resist Updat 4, 118–128 (2001)

    Article  PubMed  CAS  Google Scholar 

  18. F. van Bömmel, B. Zöllner, C. Sarrazin, U. Spengler, D. Hüppe, B. Möller et al., Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology 44, 318–325 (2006)

    Article  PubMed  Google Scholar 

  19. P. Zhao, C. Wang, L. Huang, D. Xu, T. Li, Comparison of rescue strategies in lamivudine-resistant patients with chronic hepatitis B. Antiviral Res. 96, 100–104 (2012)

    Article  PubMed  CAS  Google Scholar 

  20. S.Y. Ko, W.H. Choe, S.Y. Kwon, J.H. Kim, J.W. Seo, K.H. Kim et al., Long-term impact of entecavir monotherapy in chronic hepatitis B patients with a partial virologic response to entecavir therapy. Scand. J. Gastroenterol. 47, 1362–1367 (2012)

    Article  PubMed  CAS  Google Scholar 

  21. A. Ono, F. Suzuki, Y. Kawamura, H. Sezaki, T. Hosaka, N. Akuta et al., Long-term continuous entecavir therapy in nucleos(t)ide-naïve chronic hepatitis B patients. J. Hepatol. 57, 508–514 (2012)

    Article  PubMed  CAS  Google Scholar 

  22. D.J. Tenney, S.M. Levine, R.E. Rose, A.W. Walsh, S.P. Weinheimer, L. Discotto, M. Plym et al., Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob. Agents Chemother. 48, 3498–3507 (2004)

    Article  PubMed  CAS  Google Scholar 

  23. H.J. Yuan, W.M. Lee, Molecular mechanisms of resistance to antiviral therapy in patients with chronic hepatitis B. Curr. Mol. Med. 7, 185–197 (2007)

    Article  PubMed  CAS  Google Scholar 

  24. S. Villet, A. Ollivet, C. Pichoud, L. Barraud, J.P. Villeneuve, C. Trepo et al., Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J. Hepatol. 46, 531–538 (2007)

    Article  PubMed  CAS  Google Scholar 

  25. F. Zoulim, Hepatitis B virus resistance to entecavir in nucleoside naive patients: does it exist? Hepatology 44, 1404–1407 (2006)

    Article  PubMed  CAS  Google Scholar 

  26. H.J. Yim, M. Hussain, Y. Liu, S.N. Wong, S.K. Fung, A.S. Lok, Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology 44, 703–712 (2006)

    Article  PubMed  CAS  Google Scholar 

  27. J.P. Villeneuve, D. Durantel, S. Durantel, C. Westland, S. Xiong, C.L. Brosgart et al., Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J. Hepatol. 39, 1085–1089 (2003)

    Article  PubMed  CAS  Google Scholar 

  28. F. Liu, L. Chen, D.M. Yu, L. Deng, R. Chen, Y. Jiang et al., Evolutionary patterns of hepatitis B virus quasispecies under different selective pressures: correlation with antiviral efficacy. Gut 60, 1269–1277 (2011)

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by Grants from the National Natural Science Foundation of China (Grant No. 30972583 and 81071338).

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjianglu Road, Yuzhong District, Chongqing, 400010, China

    Xiao-Lin Deng, Qing-Ling Li & Jin-Jun Guo

  2. Institute of Life Sciences, Chongqing Medical University, Chongqing, China

    Qing-Ling Li

Authors
  1. Xiao-Lin Deng
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  2. Qing-Ling Li
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  3. Jin-Jun Guo
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Correspondence to Jin-Jun Guo.

Additional information

Xiao-Lin Deng and Qing-Ling Li contributed equally to this study.

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Deng, XL., Li, QL. & Guo, JJ. Dynamics of lamivudine-resistant hepatitis B virus strains in patients with entecavir rescue therapy. Virus Genes 47, 1–9 (2013). https://doi.org/10.1007/s11262-013-0915-1

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  • DOI: https://doi.org/10.1007/s11262-013-0915-1

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