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Complex dynamics of hepatitis B virus resistance to adefovir.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Pallier, Coralie Rodriguez, Christophe Brillet, Rozenn Nordmann, Patrice Hézode, Christophe Pawlotsky, Jean-Michel
Description	Country affiliation: France Author Affiliation: Pallier C ( French National Reference Center for Viral Hepatitis B, C, and delta, Department of Virology, Hôpital Henri Mondor, Université Paris 12, Créteil, France.)
Abstract	UNLABELLED: 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.
File Format	HTM / HTML
ISSN	02709139
e-ISSN	15273350
DOI	10.1002/hep.22634
Journal	Hepatology
Issue Number	1
Volume Number	49
Language	English
Publisher	Wiley
Publisher Date	2009-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Hepatology Adenine Analogs & Derivatives Antiviral Agents Therapeutic Use Drug Resistance, Viral Hepatitis B Virus Drug Effects Hepatitis B, Chronic Drug Therapy Organophosphonates Pharmacology Dna, Viral Chemistry Molecular Sequence Data Reverse Transcriptase Polymerase Chain Reaction Virus Replication Randomized Controlled Trial Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Hepatology

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Complex dynamics of hepatitis B virus resistance to adefovir.

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