Skip to main content
SpringerLink
Log in

Extended treatment with lamivudine and adefovir dipivoxil in chronic hepatitis B patients with lamivudine resistance

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Purpose

We and others have reported that adding adefovir dipivoxil (adefovir) to lamivudine results in virological and biochemical improvement in cases of lamivudine resistance. The current study assessed the efficacy and safety of combined therapy after 104 weeks of combined treatment and analyzed the frequency of persistent lamivudine resistant HBV.

Methods

A total of 78 patients with compensated CHB (Group A) were maintained on either adefovir 10 mg daily (n = 38) or placebo (n = 40) while continuing lamivudine. An additional 38 patients with decompensated cirrhosis or post liver transplantation (Group B) received lamivudine plus adefovir. The primary endpoint was HBV DNA response at year 2.

Results

At week 104 of therapy, a significantly greater proportion of patients in Group A on combination therapy (76%) had a decline in serum HBV DNA to ≤105 copies or >2 log10 reduction from baseline compared to those receiving lamivudine alone (13%; p < 0.001). Fifty-two percent of Group A patients on combination treatment continued to have the M204V/I HBV mutation compared to 92% receiving lamivudine alone (p = 0.0013). Virologic response occurred less frequently in patients expressing persistent lamivudine resistant HBV. In Group B, 87% of patients had HBV DNA response at week 104 (median change from baseline of −5.84 log10 copies/mL).

Conclusions

The combination of lamivudine and adefovir for 2 years generally proved effective in lamivudine-resistant cases, but there was a persistently high rate of detection of lamivudine resistant mutants and impaired virologic response in compensated patients.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepatol 2004;11:97–107

    Article  CAS  Google Scholar 

  2. Dienstag J, Schiff ER, Wright TL, Perrillo RP, Hann HWL, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256–1263

    Article  PubMed  CAS  Google Scholar 

  3. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray F. A one-year trial of lamivudine for chronic hepatitis B. New Engl J Med 1998;339:61–68

    Article  PubMed  CAS  Google Scholar 

  4. Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, Dhillon A, Moorat A, Barber J, Gray DF. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomized trial. Gut 2000;46:562–568

    Article  PubMed  CAS  Google Scholar 

  5. Jonas M, Kelley D, Mizerski J, Badia IB, Areias JA, Schwarz KB, Little NR, Greensmith MJ, Gardner SD, Bell MS, Sokal EM. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002;346:1706–1713

    Article  PubMed  CAS  Google Scholar 

  6. Liaw Y-F, Sung JJY, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, D Gray F, Sabbat, J. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521–1531, 1587

    Google Scholar 

  7. Perrillo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T, Gutfreund K, Lamy P, Murray A. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000;32:129–134

    Article  PubMed  CAS  Google Scholar 

  8. Peters MG, Hann HW, Martin P, Heathcote J, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray DF, Sullivan M, Kleber K, Ebrahimi R, Xiong S, Brosgart CL. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004;126:91–101

    Article  PubMed  CAS  Google Scholar 

  9. Perrillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, Moorat A, Gardner S, Woessner M, Bourne E, Brosgart CL, Schiff E. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004;126:81–90

    Article  PubMed  CAS  Google Scholar 

  10. Lampertico P, Viganò M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology 2005;42:1414–1419

    Article  PubMed  CAS  Google Scholar 

  11. Ono-Nita SK, Kato N, Shiratori Y, Masaki T, Lan KH, Carrilho FJ, Omata M. YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: a study by in vitro full-length viral DNA transfection. Hepatology 1999;29:939–945

    Article  PubMed  CAS  Google Scholar 

  12. Pallier C, Castera L, Soulier A, Hézode C, Nordmann P, Dhumeaux D, Pawlotsky JM. Dynamics of hepatitis B virus resistance to lamivudine. J Virol 2006;80:643–653

    Article  PubMed  CAS  Google Scholar 

  13. Mutimer D, Pillay D, Shields P, Cane P, Ratcliffe D, Martin B, Buchan S, Boxall L, O’Donnell K, Shaw J, Hubscher S, Elias E. Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient. Gut 2000;46:107–113

    Article  PubMed  CAS  Google Scholar 

  14. Benhamou Y, Bochet M, Thibault V, Calvez M, Fievet H, Vig P, Gibbs CS, Brosgart C, Fry J, Namini H, Katlama C, Poynard T. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open label pilot study. Lancet 2001;358:718–723

    Article  PubMed  CAS  Google Scholar 

  15. Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann HL, Samuel D, Zeuzem S, Lilly L, Rendina M, Villeneuve JP, Lama N, James C, Wulfsohn MS, Namini H, Westland C, Xiong S, Choy GS, Van Doren S, Fry J, Brosgart CL. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 2003;38:1419–1427

    PubMed  CAS  Google Scholar 

  16. Allen MI, Gauthier J, DesLauriers M, Bourne EJ, Carrick KM, Baldanti F, Ross LL, Lutz MW, Condreay LD. Two sensitive PCR-based methods for detection of hepatitis B virus variants associated with reduced susceptibility to lamivudine. J Clin Microbiol 1999;37:3338–3347

    PubMed  CAS  Google Scholar 

  17. Shaw T, Bartholomeusz A, Locarnini S. HBV drug resistance: mechanism, detection and interpretation. J Hepatol 2006;44:593–606

    Article  PubMed  CAS  Google Scholar 

  18. Lok ASF, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL, Heathcote EJ, Little NR, Griffiths DA, Gardner SD, Castiglia M. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003;125:1714–1722

    Article  PubMed  CAS  Google Scholar 

  19. Fabien Z, Perrillo R. Hepatitis B: reflections on the current approach to antiviral therapy. J Hepatol 2008;48:S2–S19

    Article  Google Scholar 

  20. Snow A, Thibault V, Qi X, Zhu Y, Westland CE, Arterbrun S. Combination of adefovir dipivoxil (ADV) and lamivudine (LAM) prevented emergence of ADV resistance mutations in chronic hepatitis B (CHB) patients with LAM-Resistant HBV. Gastroenterology 2005;128:M945

    Google Scholar 

  21. Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, Hussain M, Lok AS. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006;44:283–290

    Article  PubMed  CAS  Google Scholar 

  22. Lok ASF, McMahon BJ. AASLD practice guidelines, chronic hepatitis B. Hepatology 2007;47:507–539

    Article  Google Scholar 

  23. Sung JJY, Lai JY, Zeuzem S, Chow WC, Heathcote EJ, Perrillo RP, Brosgart CL, Woessner MA, Scott SA, Gray DF, Gardner SD. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatology 2008;48:728–735

    Article  CAS  Google Scholar 

  24. Xiong S, Flores C, Yang H, Toole JJ, Gibbs CS. Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro. Hepatology 1998;28:1669–1673

    Article  PubMed  CAS  Google Scholar 

  25. Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, Plym M, Pokornowski K, Yu CF, Angus P, Ayres A, Bartholomeusz A, Sievert W, Thompson G, Warner N, Locarnini S, Colonno RJ. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob Agents Chemother 2004;48:3498–3507

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge and thank both the NUC20917 investigators and patients who participated in this study. Study (Protocol NUC20917) supported by GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA. Adefovir dipivoxil was provided for the study by Gilead Sciences, Foster City, CA, USA.

Author information

Authors and Affiliations

  1. Baylor University Medical Center, Dallas, TX, USA

    Robert P. Perrillo

  2. Jefferson Medical College, Philadelphia, PA, USA

    Hie-Won Hann

  3. University of Miami, Miami, FL, USA

    Eugene Schiff

  4. Queen Elizabeth Hospital, Birmingham, UK

    David Mutimer

  5. Hospital Saint Luc, Montreal, Canada

    Bernard Willems

  6. Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China

    Nancy Leung

  7. University of Texas Southwestern Medical Center, Dallas, TX, USA

    William M. Lee

  8. GlaxoSmithKline Research and Development, Greenford, UK

    Susan Dixon

  9. GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA

    Mary Woessner, Lynn D. Condreay & Stephen D. Gardner

  10. Gilead Sciences, Foster City, CA, USA

    Carol L. Brosgart

Authors
  1. Robert P. Perrillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hie-Won Hann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eugene Schiff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Mutimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernard Willems
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nancy Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. William M. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Susan Dixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mary Woessner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carol L. Brosgart
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lynn D. Condreay
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Stephen D. Gardner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert P. Perrillo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perrillo, R.P., Hann, HW., Schiff, E. et al. Extended treatment with lamivudine and adefovir dipivoxil in chronic hepatitis B patients with lamivudine resistance. Hepatol Int 5, 654–663 (2011). https://doi.org/10.1007/s12072-010-9228-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-010-9228-9

Keywords

Search

Navigation