Complex dynamics of hepatitis B virus resistance to adefovir

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http://www3.interscience.wiley.com/journal/121411765/abstract

Hepatology

Published Online: 18 Sep 2008

Viral Hepatitis

Complex dynamics of hepatitis B virus resistance to adefovir

Coralie Pallier 1 2 3, Christophe 1 2, Rozenn Brillet 1 2, Patrice

Nordmann 3, Christophe Hézode 1 2 4, Jean-Michel Pawlotsky 1 2 *§

1French National Reference Center for Viral Hepatitis B, C, and delta,

Department of Virology, Hôpital Henri Mondor, Université Paris 12, Créteil,

France

2INSERM U841, Créteil, France

3Department of Bacteriology and Virology, Hôpital de Bicêtre, Université Paris

XI, Le Kremlin-Bicêtre, France

4Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université

Paris 12, Créteil, France

email: Jean-Michel Pawlotsky (jean-michel.pawlotsky@...)

*Correspondence to Jean-Michel Pawlotsky, Department of Virology, Hôpital Henri

Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France

Potential conflict of interest: Nothing to report.

These authors contributed equally to the study.

§fax: (33)-1-4981-4831.

Funded by:

VIRGIL European Network of Excellence on Antiviral Drug Resistance

Priority 1 Life Sciences, Genomics, and Biotechnology for Health program in the

6th Framework Programme of the European Union; Grant Number: LSHM-CT-2004-503359

Gilead Sciences

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. (HEPATOLOGY 2008.)

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Received: 6 April 2008; Accepted: 9 September 2008

Digital Object Identifier (DOI)

10.1002/hep.22634