Hepatology International

, Volume 2, Issue 2, pp 147–151 | Cite as

Primary resistance, multidrug resistance, and cross-resistance pathways in HBV as a consequence of treatment failure

Review Article

Abstract

Antiviral resistance is now the single most important factor in treatment failure using nucleos(t)ide analogues (NA). Primary drug resistance mutations refer to amino acid change(s) that result in reduced susceptibility to an antiviral agent. Secondary compensatory mutations restore replication defects associated with primary drug resistance and may be associated with low level reduced susceptibility. Several evolutionary pathways of drug resistant HBV have been observed in patients treated with NAs. It is possible that the drug resistance mutations selected with one agent may affect the efficacy of other NAs. Several major HBV-evolutionary NA-resistance pathways (rtM204I/V, rtN236T and rtA181T/V) have now been characterised. The rtM204V/I pathway is responsible for resistance to the l-nucleosides, such as lamivudine (LMV), telbivudine (LdT) and clevudine (CLD), and also entecavir (ETV), whilst the rtN236T pathway is responsible for adefovir (ADV) and tenofovir (TFV) resistance. Both pathways are associated with clusters of secondary mutations that can affect subsequent treatment with NAs (rtT184G, rtS202I) such as ETV. The third pathway, rtA181T/V, is associated with resistance to LMV and ADV and is a potential multi-drug resistance pathway and will probably have an impact on TFV sensitivity, either alone or with the rtN236T. In naïve patients treated with ETV, atleast three mutations arising at the same time are required: rtL180M + rtM204V plus either one of rtT184, rtS202 or rtM250 codon changes. Finally, in highly drug-experienced patients, clusters of mutations such as rtA181T/I233V/N236T/M250L, all on the one dominant HBV genome, are being detected which are associated with multi-drug resistance. Sequential treatment with nucleos(t)ide analogue reverse transcriptase inhibitors (NRTI) promotes multidrug resistance. It is likely, therefore, that development of multi-drug resistance could be reduced by combination therapy optimised to individual viral phenotypes.

References

  1. 1.
    Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 2007;46:254–65.PubMedCrossRefGoogle Scholar
  2. 2.
    Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003;36:687–96.PubMedCrossRefGoogle Scholar
  3. 3.
    Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001;33:1527–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Locarnini S, Mason WS. Cellular and virological mechanisms of HBV drug resistance. J Hepatol 2006;44:422–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005;352:2673–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Lee YS, Suh DJ, Lim YS, Jung SW, Kim KM, Lee HC, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology 2006;43:1385–91.PubMedCrossRefGoogle Scholar
  7. 7.
    Perrillo RP. Current treatment of chronic hepatitis B: benefits and limitations. Semin Liver Dis 2005;25 Suppl 1:20–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF, et al. Entecavir resistance is rare in nucleoside naive patients with hepatitis B. Hepatology 2006;44:1656–65.PubMedCrossRefGoogle Scholar
  9. 9.
    Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507–39.PubMedCrossRefGoogle Scholar
  10. 10.
    Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 2003;125:292–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Van Bommel F, Zollner B, Moller B, Huppe D, Feucht H-H, Wiedenmann B, et al. Is tenofovir effective in treatment of adefovir resistant hepatitis B virus (HBV) infections [Abstract 1016]? Hepatology 2006;44 4 Suppl 1:567A.Google Scholar
  12. 12.
    Suzuki F, Akuta N, Suzuki Y, Yatsuji H, Sezaki H, Arase Y, et al. Selection of a virus strain resistant to entecavir in a nucleoside-naive patient with hepatitis B of genotype H. J Clin Virol 2007;39:149–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Torresi J, Earnest-Silveira L, Deliyannis G, Edgtton K, Zhuang H, Locarnini S, et al. Reduced antigenicity of the hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by lamivudine therapy. Virology 2002;293:305–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Warner N, Locarnini S. The multi-drug resistant hepatitis B virus rtA181T has a secretion defect and significantly reduces the kinetics of viral rebound. Hepatology 2007; in press.Google Scholar

Review—suggested reading

  1. 15.
    Locarnini S, McMillan J, Bartholomeusz A. The hepatitis B virus and common mutants. Semin Liver Dis 2003;23:5–20.PubMedCrossRefGoogle Scholar
  2. 16.
    Locarnini S, Hatzakis A, Heathcote J, Keeffe E, Liang TJ, Mutimer D, et al. Management of antiviral resistance in patients with chronic hepatitis B. Antiviral Ther 2004;9:679–93.Google Scholar
  3. 17.
    Yuen LKW, Ayres A, Littlejohn M, Colledge D, Edgely A, Maskill WJ, et al. SEQHEPB: a sequence analysis program and relational database system for chronic hepatitis B. Antiviral Res 2007;75:64–74.PubMedCrossRefGoogle Scholar
  4. 18.
    Locarnini S, Warner N. Major causes of antiviral drug resistance and implications for treatment of HBV mono-infection and co-infection with HIV. Antiviral Ther 2007; in press.Google Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2008

Authors and Affiliations

  1. 1.VIDRLNorth MelbourneAustralia

Personalised recommendations