Pre-existing or rapid emergence of A181T polymerase mutation in lamivudine resistant chronic hepatitis B patients treated with adefovir

Abstract

Background/Aim: The known HBV polymerase mutations which confer to resistance to adefovir (ADV) were rtN236T and rtA181V. The rtA181T mutation, which was detected during lamivudine(LMV) treatment, is also reported to increase resistance to ADV by 4 fold in vitro. The aim of our study was to define the clinical significance of rtA181T mutation in ADV treated LMV-resistant chronic hepatitis B patients (LMV-R CHB).

Method: 204 LMV-RCHB treated with ADV were included; the mean treatment duration was 18 months (range 6 months-39 months). All patients enrolled in our study were treated with ADV monotherapy with (n=83) or without (n=121) an initial short course of LMV combination. Serum HBV DNA was quantified by real time PCR. Biochemical and virologic parameters were measured every 2-3 months. Genotypic mutation to ADV was detected using mass spectrometry-based genotyping assay (RFMP). Antiviral efficacy to ADV, virologic breakthrough (VBT) and ALT flare were compared between patients carrying A181T and N236T/A181V.

Result: During the course of ADV therapy, rtA181T, rtA181V, and rtN236T mutations were detected in 40 (20%), 24 (12%), and 20 (10%) patients, respectively. At 12 months of treatment, rtA181V was detected in 4 of 24 patients (17%), and rtN236T was detected in 3 of 20 patients (15%). On the contrary, 31 of 40 patients (77%) with rtA181T mutation were detected within 12 months of treatment. At the initiation of ADV treatment, 6 patients had A181T mutation. There were no significant differences in the detection rates of genotypic mutation in patients treated with or without an initial short course of LMV treatment. No significant differences were found in the rate of VBT (14% vs 15%) and ALT flare (0% vs 9%) in patients with A181T and with N236T/A181V.

Conclusion: A high prevalence of rtA181T mutation was detected in LMV-R CHB treated with ADV. The rtA181T mutation was detected at the initiation of ADV treatment or during the early course of ADV treatment. The clinical consequences of patients with rtA181T mutation were not significantly different from those with rtN236T mutation or rtA181V mutation. Further studies are needed to define the role of rtA181T mutation in prolonged ADV therapy.