Title: M1902 Detection of Entecavir-Resistant (ETV-R) Mutations in Nucleoside-NaïVe and in Lamivudine-Refractory (Lvd-R) HBV Patients and Implications On Response to ETV Treatment
Abstract: Background: ETV-r mutations had been reported in up to 6% of LVD-r HBV patients in a phase III trial and in isolated cases of nucleoside naive HBV patients. The impact of preexisting ETV-r mutations on response to ETV treatment is unclear. Aim: To determine (i) the prevalence of ETV-r mutations in nucleoside naive and in LVD-r HBV patients, and (ii) the impact of ETV-r mutations on response to subsequent ETV treatment. Methods: Baseline samples from 25 nucleoside naive HBV patients and samples at the time of virological breakthrough in 69 LVD-r HBV patients were tested for antiviral-drug resistant mutations using direct sequencing and a sensitive line probe assay (InnoLipa DRv.3). Samples with ETV-r mutations were further tested by sequencing of 20-25 clones. Results: ETV-r mutations were detected in 1/25 (4%) nucleoside naive and in 10/69 (14%) LVD-r patients who had not been exposed to ETV by DRv.3 assay but no ETV-r mutation was detected by direct sequencing. The nucleoside naive patient had S202G on DRv.3 and in 2/22 clones analyzed. HBV DNA became undetectable within 6 months of ETV treatment in this patient and in 17/24 (71%) nucleoside naive patients without ETV-r mutation at baseline. Of the 10 LVDr patients who had ETV-r mutation before any exposure to ETV, 7 had S202G and 1 had M250I in association with M204V. The other 2 patients had dual ETV-r mutations: T184A+M250L and S202G+M250I in association with A181V but not M204 mutations. Both patients had M204V/I mutation only at the time of LVD breakthrough, ETV-r and A181V mutations were detected 6 and 8 months after switching to adefovir (ADV) monotherapy. ETV-r mutations were present in 1-3 clones analyzed while LVD-r or ADV-r mutations were present in most clones. In 2 LVD-r patients with ETV-r mutation (M204V + S202G) at baseline, HBV DNA decreased by 3.4 and 2.6 log after 6 months of ETV treatment, and both remained HBV DNA positive after 7 and 14 months of ETV. In comparison, in 8 LVDr patients without ETV-r mutation at baseline, HBV DNA decreased by a mean of 4.6 and 5.6 log after 6 and 12 months ETV treatment, respectively and 4 (50%) had undetectable HBV DNA at month 6. Conclusions: ETV-r mutations were detected in 4% nucleoside naive and in 14% LVD-r HBV patients who had not been exposed to ETV. Virologic response to ETV was impaired in patients with both LVD-r and ETV-r mutations but appeared to be unaffected in one patient with ETV-r mutation alone. Switching from LVD to ADV monotherapy in LVD-r patients did not eliminate the risk of selection for ETV-r mutations.
Publication Year: 2008
Publication Date: 2008-04-01
Language: en
Type: article
Indexed In: ['crossref']
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Cited By Count: 1
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