Digestive Diseases and Sciences

, Volume 57, Issue 1, pp 221–231 | Cite as

Antiviral Drug Resistance Testing in Patients with Chronic Hepatitis B

  • Vincent Wai-Sun Wong
  • Grace Lai-Hung Wong
  • Chi-Hang Tse
  • Lilly K. W. Yuen
  • Hoi-Yun Chan
  • Stephen A. Locarnini
  • Henry Lik-Yuen Chan
Original Article



Antiviral drugs against hepatitis B virus are limited by the emergence of drug resistance.


We aimed to study the impact of drug resistance testing on treatment decisions.


In part 1 of this study, consecutive patients with chronic hepatitis B who had antiviral drug resistance testing were studied. Part 2 was a two-step questionnaire survey including ten characteristic case scenarios. Hepatologists were asked about their treatment decisions before and after the knowledge of drug resistance results.


Fifty-one patients underwent drug resistance testing, most of whom were on lamivudine, adefovir dipivoxil or entecavir monotherapy. Thirty-four (67%) patients had drug-resistant mutants detected, 4 (8%) had low viral load, and 13 (25%) harboured wild-type virus. Twenty-nine of 34 (85%) patients harbouring drug-resistant mutants and 9 of 17 (53%) patients with no mutants detected changed their drug regimens (P = 0.038). In part 2, 18 hepatologists completed all two questionnaires. Overall, treatment decision was modified in 52% of cases upon receiving the drug resistance testing results. The detection of rtA181V/I resulted in decision changes in most hepatologists, with the preferred treatment switching from tenofovir to entecavir. When no mutants were detected in partial responders to entecavir monotherapy, most hepatologists chose to increase the dose of entecavir.


Drug-resistant mutations are detected in around two-thirds of chronic hepatitis B patients undergoing drug resistance testing. Drug resistance testing alters management in over half of the cases, and should be considered in all patients with virological breakthrough and suboptimal virological suppression.


Viral load Lamivudine Adefovir dipivoxil Telbivudine Entecavir Tenofovir 



Adefovir dipivoxil


Alanine aminotransferase


Antibody against hepatitis B e antigen




Hepatitis B e antigen


Hepatitis B surface antigen


Hepatitis B virus








  1. 1.
    Chan HL, Sung JJ. Hepatocellular carcinoma and hepatitis B virus. Semin Liver Dis. 2006;26:153–161.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    Wong VW, Chan SL, Mo F, et al. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J Clin Oncol. 2010;28:1660–1665.PubMedCrossRefGoogle Scholar
  4. 4.
    Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008;28:1067–1077.PubMedCrossRefGoogle Scholar
  5. 5.
    Wong VW, Wong GL, Chim AM, et al. Surrogate end points and long-term outcome in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2009;7:1113–1120.PubMedCrossRefGoogle Scholar
  6. 6.
    Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2:263–283.PubMedCrossRefGoogle Scholar
  7. 7.
    European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50(2):227–242.Google Scholar
  8. 8.
    Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–662.PubMedCrossRefGoogle Scholar
  9. 9.
    Leung NW, Lai CL, Chang TT, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology. 2001;33:1527–1532.PubMedCrossRefGoogle Scholar
  10. 10.
    Wong VW, Wong GL, Tsang SW, et al. Long-term follow-up of lamivudine treatment in patients with severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. Antivir Ther. 2008;13:571–579.PubMedGoogle Scholar
  11. 11.
    Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743–1751.PubMedCrossRefGoogle Scholar
  12. 12.
    Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125:1714–1722.PubMedCrossRefGoogle Scholar
  13. 13.
    Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009;136:486–495.PubMedCrossRefGoogle Scholar
  14. 14.
    Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43:1385–1391.PubMedCrossRefGoogle Scholar
  15. 15.
    Chan HL, Chui AK, Lau WY, et al. Factors associated with viral breakthrough in lamivudine monoprophylaxis of hepatitis B virus recurrence after liver transplantation. J Med Virol. 2002;68:182–187.PubMedCrossRefGoogle Scholar
  16. 16.
    Chan HL, Tsang SW, Liew CT, et al. Viral genotype and hepatitis B virus DNA levels are correlated with histological liver damage in HBeAg-negative chronic hepatitis B virus infection. Am J Gastroenterol. 2002;97:406–412.PubMedCrossRefGoogle Scholar
  17. 17.
    Ayres A, Locarnini S, Bartholomeusz A. HBV genotyping and analysis for unique mutations. Methods Mol Med. 2004;95:125–149.PubMedGoogle Scholar
  18. 18.
    Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445–1451.PubMedCrossRefGoogle Scholar
  19. 19.
    Villet S, Pichoud C, Billioud G, et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol. 2008;48:747–755.PubMedCrossRefGoogle Scholar
  20. 20.
    Warner N, Locarnini S. The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology. 2008;48:88–98.PubMedCrossRefGoogle Scholar
  21. 21.
    Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010.PubMedCrossRefGoogle Scholar
  22. 22.
    Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–1514.PubMedCrossRefGoogle Scholar
  23. 23.
    Karino Y, Toyota J, Kumada H, et al. Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B. Hepatol Int. 2010;4:414–422.PubMedCrossRefGoogle Scholar
  24. 24.
    Ide T, Sata M, Chayama K, et al. Evaluation of long-term entecavir treatment in stable chronic hepatitis B patients switched from lamivudine therapy. Hepatol Int. 2010;4:594–600.PubMedCrossRefGoogle Scholar
  25. 25.
    Degertekin B, Hussain M, Tan J, Oberhelman K, Lok AS. Sensitivity and accuracy of an updated line probe assay (HBV DR v.3) in detecting mutations associated with hepatitis B antiviral resistance. J Hepatol. 2009;50:42–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Ding C, Wong VW, Chow KC, et al. Quantitative subtyping of hepatitis B virus reveals complex dynamics of YMDD motif mutants development during long-term lamivudine therapy. Antivir Ther. 2006;11:1041–1049.PubMedGoogle Scholar
  27. 27.
    Lui YY, Tsoi KK, Wong VW, et al. Cost-effectiveness analysis of roadmap models in chronic hepatitis B using tenofovir as the rescue therapy. Antivir Ther. 2010;15:145–155.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Vincent Wai-Sun Wong
    • 1
    • 2
  • Grace Lai-Hung Wong
    • 1
    • 2
  • Chi-Hang Tse
    • 1
    • 2
  • Lilly K. W. Yuen
    • 3
  • Hoi-Yun Chan
    • 1
    • 2
  • Stephen A. Locarnini
    • 3
  • Henry Lik-Yuen Chan
    • 1
    • 2
  1. 1.Department of Medicine and TherapeuticsPrince of Wales Hospital, The Chinese University of Hong KongShatinHong Kong
  2. 2.Institute of Digestive DiseaseThe Chinese University of Hong KongShatinHong Kong
  3. 3.Victorian Infectious Disease Research LaboratoryMelbourneAustralia

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