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Multidrug-resistant hepatitis B virus resulting from sequential monotherapy with lamivudine, adefovir, and entecavir: clonal evolution during lamivudine plus adefovir therapy.

Authors
Kim, SS; Cho, SW; Kim, SO; Hong, SP; Cheong, JY
Citation
Journal of medical virology, 85(1):55-64, 2013
Journal Title
Journal of medical virology
ISSN
0146-66151096-9071
Abstract
Whether multidrug-resistant (MDR) hepatitis B virus (HBV) harbors mutations co-located in the same HBV clones that confer reduced sensitivity to antiviral therapy remains uncertain. This study investigated the evolution of MDR HBV strains developed from sequential monotherapy with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) during LAM plus ADV salvage therapy. Sera were obtained from six patients who had developed sequential resistance to LAM, ADV, and ETV before and during LAM plus ADV therapy. The HBV genomes from each patient were amplified, cloned, and sequenced. Among 6 sets of 20 clones obtained before salvage therapy, all clones harbored the rtM204V mutation, and ETV-resistant mutations were detected with the rtM204V in 108 clones. The rtA181 mutation was not detected at baseline, but emerged in five patients during therapy. Among 9 sets of 20 clones obtained during salvage therapy, 39 clones harbored rtA181T/V ± rtN236T mutations, which were detected in the absence of rtM204 and ETV-resistant mutations in 37 clones (94.9%). Only two clones (5.1%) harbored both rtA181T/V and ETV-resistant mutations. The rtA181T/V mutation emerged after reversion from ETV-resistant mutants to wild-type HBV. Five patients achieved a partial virologic response to LAM plus ADV therapy. In conclusion, the majority of MDR mutations existed in different genomes. Suboptimal response to LAM plus ADV therapy may not result from the co-localization of MDR HBV mutations in the same genome, but instead the low antiviral potency of these drugs. Thus, more potent antiviral drug combinations may be an effective salvage therapy for patients infected with MDR HBV.
MeSH terms
Adenine/administration & dosage/*analogs & derivativesAdultAntiviral Agents/*administration & dosageClonal EvolutionDNA, Viral/chemistry/genetics*Drug Resistance, Multiple, ViralGuanine/administration & dosage/*analogs & derivativesHepatitis B virus/*drug effects/isolation & purificationHepatitis B, Chronic/*drug therapy/virologyHumansLamivudine/*administration & dosageMaleMiddle AgedMutation, MissenseOrganophosphonates/*administration & dosageRNA-Directed DNA Polymerase/genetics
DOI
10.1002/jmv.23440
PMID
23096938
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Gastroenterology
AJOU Authors
김, 순선조, 성원정, 재연
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