Abstract
BackgroundEntecavir-resistance mutations are commonly induced by entecavir treatment in chronic hepatitis B patients. However, entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations induced by sequential or combination treatment with lamivudine and adefovir dipivoxil have never been reported.ResultsWe retrospectively reviewed 1200 patients who had been tested for anti-HBV drug resistance at Beijing Ditan Hospital of Capital Medical University, and five patients showing multidrug resistance to lamivudine and adefovir dipivoxil were enrolled. Stored serum samples were used for genetic analysis, which yielded a total of 135 clones. Entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations were identified in 60 % (3/5) entecavir-naïve patients who received sequential therapy with adefovir dipivoxil and lamivudine. Specifically, we found one rtM204I+rtL180 M+rtM250 V+rtA181 V clone among 23 clones from patient 1 (4.35 %), one rtM204 V+vrtL180 M +rtM250 V+rtA181 V clone among 24 clones from patient 2 (4.17 %), and 2 clones harboring rtM204 V+rtL180 M+rtM250 V+rtA181 V and rtM204 V+rtL180 M+rtI169 V+rtA181 V among 20 clones from patient 3 (10.0 %). The other 2 patients showed multidrug resistance after lamivudine/telbivudine and adefovir dipivoxil combination therapy, but no entecavir-resistance mutations were found in these two patients.ConclusionDe novo entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations can be induced by sequential therapy with adefovir dipivoxil and lamivudine in patients who never take entecavir. These results provide important information for sequential therapy with adefovir dipivoxil and lamivudine and the use of entecavir as a rescue therapy for these patients with multidrug resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12941-016-0138-0) contains supplementary material, which is available to authorized users.
Highlights
Entecavir-resistance mutations are commonly induced by entecavir treatment in chronic hepatitis B patients
Patient 1 received adefovir dipivoxil (ADV) and LAM sequential therapy, and direct sequencing of the nested polymerase chain reaction (PCR) product showed rtM204 V+rtL180 M+rtA181 V mutations upon secondary virological breakthrough, whereas rtM204 V+rtL180 M+rtA181 V strains accounted for 78.26 % (18/23) of the clones in the clonal analysis
One clone (4.35 %) harbored rtM204 I+rtL180 M+rtM250 V+rtA181 V mutations, which resulted in resistance to LAM+ADV+ETV (Additional file 2: Figure S1); this patient had never received ETV therapy
Summary
Entecavir-resistance mutations are commonly induced by entecavir treatment in chronic hepatitis B patients. Inoue et al described a patient who received LAM+ADV and developed de novo ETV resistance with rtM204 V+rtL180 M+rtT184 S mutations [8]. Patient 1 received ADV and LAM sequential therapy, and direct sequencing of the nested PCR product showed rtM204 V+rtL180 M+rtA181 V mutations upon secondary virological breakthrough, whereas rtM204 V+rtL180 M+rtA181 V strains accounted for 78.26 % (18/23) of the clones in the clonal analysis.
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