Novel Lamivudine Resistance

Abstract

With great interest I have read and appreciate the recent publication by Warner and coworkers (6). Those authors described the effects of a novel mutation in the hepatitis B virus (HBV) polymerase reverse transcriptase domain, namely, the rtL80I substitution that confers resistance to lamivudine. This mutation was initially described to occur in Japanese patients with lamivudine treatment failure, but its impact remained to be investigated (3). Not surprisingly, based on molecular modeling of the reverse transcriptase domain of the HBV polymerase, Warner et al. (6) concluded that this novel mutation is not located in the supposed drug binding domain. Nevertheless, the fact that rtL80I is able to mediate lamivudine resistance also in vitro, as shown by phenotyping, is of high general interest and deserves foremost attention for two reasons. First, the fact that mutations in the periphery of the nucleos(t)ide binding site may lead to resistance has to be taken into account in all future resistance testing approaches. Second, the observation by Warner and colleagues (6) may be true not only for lamivudine but also for other drugs and may thus have an impact also on further therapy and monitoring regimens, mainly as the therapy for chronic HBV infection is becoming more and more complex (1). Especially for adefovir, it is believed that besides mutations, host factors such as failures in liver uptake, defective or nonappropriate esterases, and phosphorylation failures may also confer resistance to the drug (5). Yet, although extensively discussed, novel mutations (e.g., see references 2 and 4) or mutations in the periphery of the nucleos(t)ide binding site have been taken into account only marginally or even disbelieved (5). Based on the observations of Warner et al., investigators should systematically check as to whether new or unexpected mutation patterns in the nucleos(t)ide binding site in concert with or even without mutations in the periphery lead to resistance or predispose to resistance to antivirals.