Selection and counterselection of the rtI233V adefovir resistance mutation during antiviral therapy

Abstract

Recently, we reported on three patients with chronic hepatitis B virus (HBV) infection for whom adefovir (ADF) therapy virologically failed, most likely due to a preexisting rtI233V HBV polymerase mutation. Here, we describe two further patients with chronic HBV infection who were found to develop the rtI233V mutation after initiation of ADF therapy. These patients represent the first cases known so far in which the rtI233V ADF resistance mutation evolved under persistent HBV replication during HBV therapy with ADF. Interestingly, one of the previously described patients, who was initially successfully switched from ADF to tenofovir (TDF) and became virologically suppressed subsequently, experienced a moderate but remarkable rebound of HBV viremia after switching from TDF to entecavir, due to the emergence of renal toxicity. Thus, we provide evidence for the selection and counterselection of the rtI233V ADF resistance mutation during antiviral therapy.

FIG. 1.

Quasispecies analyses and alignments of four representative clones, each obtained from RT polymerase gene PCR amplificates before and after therapy for patients 1 and 2. In total, up to 10 clones per patient were sequenced, and of those, 4 representative clones are shown in the figure. Panel “a” indicates the sequences obtained before ADF therapy, whereas panel “b” indicates the sequences obtained after the increase of viral load, i.e., during or immediately after ADF therapy.

FIG. 2.

Time course of viremia and HBsAg levels in two novel patients (patients 1 [a] and 2 [b]) for whom ADF therapy failed in association with the rtI233V polymerase mutation.