Complex dynamics of hepatitis B virus resistance to adefovir. - Archive ouverte HAL Access content directly
Journal Articles Hepatology Year : 2009

Complex dynamics of hepatitis B virus resistance to adefovir.

(1, 2) , (1, 2) , (1, 2) , (3) , (1, 2) , (1, 2)
1
2
3

Abstract

In patients with hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil administration selects variants bearing reverse transcriptase rtN236T and/or rtA181V/T substitutions in 29% of cases after 5 years. The aim of this study was to characterize the dynamics of adefovir-resistant variant populations during adefovir monotherapy in order to better understand the molecular mechanisms underlying hepatitis B virus resistance to this class of nucleotide analogues. Patients included in a 240-week clinical trial of adefovir monotherapy who developed adefovir resistance-associated substitutions were studied. The dynamics of hepatitis B virus populations were analyzed over time, after generating nearly 4,000 full-length reverse transcriptase sequences, and compared with the replication kinetics of the virus during therapy. Whatever the viral kinetics pattern, adefovir resistance was characterized by exclusive detection of a dominant wild-type, adefovir-sensitive variant population at baseline and late and gradual selection by adefovir of several coexisting resistant viral populations, defined by the presence of amino acid substitutions at position rt236, position rt181, or both. The gain in fitness of one or the other of these resistant populations during adefovir administration was never associated with the selection of additional amino acid substitutions in the reverse transcriptase. Conclusion: Our results suggest that adefovir administration selects poorly fit preexisting or emerging viral populations with low-level adefovir resistance, which subsequently compete to fill the replication space. Viral kinetics depends on the initial virological response to adefovir. Lamivudine add-on restores some antiviral efficacy, but adefovir-resistant variants remain predominant. Whether these adefovir resistance-associated substitutions may confer cross-resistance to tenofovir in vivo will need to be determined.
Fichier principal
Vignette du fichier
Pallier_et_al-REVISED3.pdf (131.66 Ko) Télécharger le fichier
Vignette du fichier
Figure_1.ppt (762.5 Ko) Télécharger le fichier
Vignette du fichier
Figure_2.ppt (1016.5 Ko) Télécharger le fichier
Vignette du fichier
inserm-00357243_edited.pdf (863.27 Ko) Télécharger le fichier
Origin : Files produced by the author(s)
Format : Other
Format : Other
Origin : Files produced by the author(s)

Dates and versions

inserm-00357243 , version 1 (22-09-2010)

Identifiers

Cite

Coralie Pallier, Christophe Rodriguez, Rozenn Brillet, Patrice Nordmann, Christophe Hézode, et al.. Complex dynamics of hepatitis B virus resistance to adefovir.. Hepatology, 2009, 49 (1), pp.50-9. ⟨10.1002/hep.22634⟩. ⟨inserm-00357243⟩

Collections

INSERM IMRB UPEC
98 View
692 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More