首页|Clonal evolution of hepatitis B virus polymerase gene mutations during lamivudine-adefovir combination treatment
Clonal evolution of hepatitis B virus polymerase gene mutations during lamivudine-adefovir combination treatment
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AIM:To identify hepatitis B virus polymerase gene mutations during antiviral therapy using lamivudineadefovir sequential monotherapy followed by lamivudine-adefovir combination therapy.METHODS:The patient cohort included four adult chronic hepatitis B patients who had undergone sequential monotherapy,first with lamivudine (LMV)and then,after developing viral breakthrough,with adefovir (ADV) therapy.All of the patients had non-response or viral breakthrough after LMV-ADV sequential monotherapy,which resulted in the switching of their antiviral regimen to LMV-ADV combination therapy.Eleven serum samples from the four patients who showed non-response to rescue LMV-ADV combination therapy were collected sequentially at a time before the antiviral treatment and then during the LMV monotherapy,ADV monotherapy,and LMV-ADV combination therapy.For the genotypic analysis,the whole 1310-bp polymerase gene region was amplified,cloned and sequenced.RESULTS:All patients had been previously treated with 100 mg of LMV once daily for a 15-to 26-mo period.The emergence of resistance mutations to LMV,such as rtM204V/I and/or rtL180M,were found in all patients.Their antiviral regimens were switched to ADV monotherapy as the second line treatment.All patients had viral breakthrough or non-response after the LMV-ADV sequential monotherapy.ADV-resistant mutations were detected after 13 to 19 mo of LMV-ADV sequential monotherapy.The rtA181V/T mutations were predominantly identified during the ADV treatment in the LMV-resistant patients.Twenty-seven of 38 clones were combined with an amino acid change at rt181;three clones had mutations in rt236 and one clone had a combined mutation.The rtA181V/T mutations were not suppressed by the LMV-ADV combination therapy.Thirty-nine of 64 clones showed an rtA181V/T mutation and six clones showed combined mutations in rt181 and rt236.Mutations in rt204 re-emerged during the combination treatment.The rt181 and rt204 mutations did not co-exist in one clone.CONCLUSION:Add-on lamivudine therapy with adefovir for adefovir resistance may not suppress the pre-existing adefovir-resistant mutation that develops during lamivudine-adefovir sequential monotherapy.
Hepatitis B virusLamivudineAdefovirMutationDrug resistance
Soon Young Ko、Byung Kook Kim、So Young Kwon、Kyun-Hwan Kim、Jeong Han Kim、Won Hyeok Choe、Chang HongLee
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Department of Internal Medicine, Konkuk University School of Medicine Seoul 143-729, South Korea
Department of Pharmacology, Konkuk University School of Medicine, Seoul 143-729, South Korea
A grant from the South Korea Heathcare Technology R and D Project,Ministry for Health,Welfare and Family Affairs,South Korea
NETL
NSTL
万方数据
维普
