High frequency of complex mutational patterns in lamivudine resistant hepatitis B virus isolates

Abstract

The evolution of hepatitis-B virus (HBV) drug resistance is characterized by the emergence of resistance conferring mutations and compensatory mutations. Therefore HBV drug-resistant isolates often harbor multiple mutations in the reverse transcriptase (RT) and corresponding mutations in the hepatitis B surface antigen (HBsAg). In this study mutational patterns of 60 HBV isolates harboring drug resistance mutations rtM204V or rtM204I were retrospectively analyzed. Both mutations, especially mutation rtM204V, were most often accompanied by compensatory mutations rtV173L and rtL180M but also by mutations conferring entecavir (n = 5) or adefovir resistance (n = 4). In addition, 22 (36.7%) drug resistant HBV isolates carried mutations related to immune escape in the HBsAg. In seven cases premature stop codons in HBsAg were detected resulting in the expression of truncated HBsAg. Clonal analysis of these seven quasispecies even disclosed the presence of HBV isolates carrying further stop codons and in one case the occurrence of resistance mutation rtA181T without the stop codon mutation sW172*. Interestingly, only one HBV clone carried the resistance mutations rtM204V and rtA181T. HBV drug resistant isolates frequently harbored HBsAg mutations associated with immune escape or disease progression pointing to a complex interaction of both proteins. HBV genotypic resistance tests based on population sequencing methods seemed to be inappropriate for determining the clinical relevance of stop codons in the HBsAg.

Comparison of Detection Rate and Mutational Pattern of Drug-Resistant Mutations Between a Large Cohort of Genotype B and Genotype C Hepatitis B Virus-Infected Patients in North China

“…This and other European studies showed that there was a mutational pattern bias of rtM204 V for HBV/A and rtM204I for HBV/D. 24,25 By contrast, no such bias was observed between HBV/B-and HBV/C-infected patients in our current study. In NA-untreated patients, drug-resistant mutations were detected in 2/140 (1.4%) of European patients with HBV/D.…”

Efficacy and resistance in de novo combination lamivudine and adefovir dipivoxil therapy versus entecavir monotherapy for the treatment-naive patients with chronic hepatitis B: a meta-analysis

“…It has been demonstrated that the main mutations associated with LAM-resistance are rtM204I and/or rtL180M, and these do not confer resistance to ADV [29,30]. The mutations associated with resistance ADV are mainly rtA181V and/or rtN236T [31].…”

How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach?

“…M204 of reverse transcriptase YMDD motif), mutations related to immune escape in the HBsAg, and insertion/deletion mutants are selected for by NA therapies. [128][129][130][131][132][133][134][135][136][137] A recent study has quantitatively assessed selection of drug-resistant mutants in non-responders, by means of matrixassisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS). 138 It has been shown that drug resistance mutations can exist as minor or major variants prior to treatment, [139][140][141][142] and that existing mutations can influence the outcome of switching therapies.…”