Treatment with lamivudine of patients infected with hepatitis B virus (HBV) results in a highrate of drug resistance, which is primarily associated with the rtm204I/V substitution in theHBV reverse transcriptase domain. Here we show that the rtm204I/V substitution, althoughessential, is insufficient for establishing resistance against lamivudine. The analysis of 639 HBVwhole-genome sequences obtained from 11 patients shows that rtm204I/V is independentlyacquired by more than one intra-host HBV variant, indicating the convergent nature oflamivudine resistance. The differential capacity of HBV variants to develop drug resistancesuggests that fitness effects of drug-resistance mutations depend on the genetic structure ofthe HBV genome. An analysis of Bayesian networks that connect rtm204I/V to many sites ofHBV proteins confirms that lamivudine resistance is a complex trait encoded by the entire HBVgenome rather than by a single mutation. These findings have implications for public health andoffer a more general framework for understanding drug resistance.
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