<i>In Vitro</i> Susceptibility of Adefovir-Associated Hepatitis B Virus Polymerase Mutations to other Antiviral Agents

Abstract

The rtN236T mutant had 7-fold resistance to adefovir but remained sensitive to entecavir, telbivudine and torcitabine (53.2-fold reduced susceptibility). The A181V mutant had 4.3-fold resistance to adefovir and had reduced susceptibility to multiple other agents ranging from 3.2-fold (tenofovir) to >191-fold (clevudine). The A181V + rtN236T double mutant was the most highly resistant showing 18-fold resistance to adefovir and higher levels of resistance to other tested drugs with the exception of tenofovir (10-fold reduced susceptibility). Our results and preliminary clinical data suggest that patients with rtN236T or rtA181V remain susceptible to tenofovir, entecavir and lamivudine. Further clinical data are necessary to precisely define in vitro cutoffs indicative of clinically-relevant resistance, particularly for drugs in development such as emtricitabine, telbivudine, torcitabine and clevudine.