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. 2008 Jun;2(2):147-51.
doi: 10.1007/s12072-008-9048-3. Epub 2008 Mar 28.

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

Stephen Locarnini  1
Affiliations

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

Stephen Locarnini. Hepatol Int. 2008 Jun.

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.

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Figures

Fig. 1
Fig. 1
Primary resistance mutations for lamivudine (LMV), telbivudine (LdT), adefovir (ADV), tenofovir (TDF), and entecavir (ETV) mapped onto the HBV polymerase gene
Fig. 2
Fig. 2
The proposed pathways for the l-nucleosides (LMV, LdT), acyclic phosphonates, and shared and multidrug resistance (MDR) linked to the eight codons associated with nucleos(t)ide analogues (NA) drug failure
Fig. 3
Fig. 3
Pathways of HBV quasispecies evolution observed in patients failing (a) l-nucleosides such as lamivudine (LMV) or (b) telbivudine (LdT), (c) the acyclic phosphonates such as adefovir (ADV), and (d) the cyclopentane ring group such as entecavir (ETV). X, cross-resistance; P, partial response; S, sensitive
Fig. 4
Fig. 4
Two recently characterized pathways of multidrug resistance in HBV. These pathways emerge when patients are placed on sequential monotherapies. X, cross-resistance; ?, unknown sensitivity
Fig. 5
Fig. 5
Polymerase-envelope overlap in the HBV genome highlighting that drug-resistant changes in polymerase can cause potentially important changes in HBsAg with all the NA currently available
See this image and copyright information in PMC

References

    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/hep.21698', 'is_inner': False, 'url': 'https://doi.org/10.1002/hep.21698'}, {'type': 'PubMed', 'value': '17596850', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/17596850/'}]}
    2. 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. - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1086/368083', 'is_inner': False, 'url': 'https://doi.org/10.1086/368083'}, {'type': 'PubMed', 'value': '12627352', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/12627352/'}]}
    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. - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1053/jhep.2001.25084', 'is_inner': False, 'url': 'https://doi.org/10.1053/jhep.2001.25084'}, {'type': 'PubMed', 'value': '11391543', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/11391543/'}]}
    2. 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. - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/j.jhep.2005.11.036', 'is_inner': False, 'url': 'https://doi.org/10.1016/j.jhep.2005.11.036'}, {'type': 'PubMed', 'value': '16364492', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/16364492/'}]}
    2. Locarnini S, Mason WS. Cellular and virological mechanisms of HBV drug resistance. J Hepatol 2006;44:422–31. - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1056/NEJMoa042957', 'is_inner': False, 'url': 'https://doi.org/10.1056/nejmoa042957'}, {'type': 'PubMed', 'value': '15987916', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/15987916/'}]}
    2. 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. - PubMed
Review—suggested reading
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1055/s-2003-37587', 'is_inner': False, 'url': 'https://doi.org/10.1055/s-2003-37587'}, {'type': 'PubMed', 'value': '12616447', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/12616447/'}]}
    2. Locarnini S, McMillan J, Bartholomeusz A. The hepatitis B virus and common mutants. Semin Liver Dis 2003;23:5–20. - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15535405', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/15535405/'}]}
    2. 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. - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/j.antiviral.2006.11.014', 'is_inner': False, 'url': 'https://doi.org/10.1016/j.antiviral.2006.11.014'}, {'type': 'PubMed', 'value': '17215050', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/17215050/'}]}
    2. 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. - PubMed
    1. 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. - PubMed

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