Convergence and coevolution of Hepatitis B virus drug resistance

Hong Thai (), David S. Campo, James Lara, Zoya Dimitrova, Sumathi Ramachandran, Guoliang Xia, Lilia Ganova-Raeva, Chong-Gee Teo, Anna Lok and Yury Khudyakov
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Hong Thai: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention
David S. Campo: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention
James Lara: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention
Zoya Dimitrova: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention
Sumathi Ramachandran: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention
Guoliang Xia: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention
Lilia Ganova-Raeva: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention
Chong-Gee Teo: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention
Anna Lok: University of Michigan Health System
Yury Khudyakov: Molecular Epidemiology and Bioinformatics Laboratory, Center for Disease Control and Prevention

Nature Communications, 2012, vol. 3, issue 1, 1-8

Abstract: Abstract Treatment with lamivudine of patients infected with hepatitis B virus (HBV) results in a high rate of drug resistance, which is primarily associated with the rtM204I/V substitution in the HBV reverse transcriptase domain. Here we show that the rtM204I/V substitution, although essential, is insufficient for establishing resistance against lamivudine. The analysis of 639 HBV whole-genome sequences obtained from 11 patients shows that rtM204I/V is independently acquired by more than one intra-host HBV variant, indicating the convergent nature of lamivudine resistance. The differential capacity of HBV variants to develop drug resistance suggests that fitness effects of drug-resistance mutations depend on the genetic structure of the HBV genome. An analysis of Bayesian networks that connect rtM204I/V to many sites of HBV proteins confirms that lamivudine resistance is a complex trait encoded by the entire HBV genome rather than by a single mutation. These findings have implications for public health and offer a more general framework for understanding drug resistance.

Date: 2012
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DOI: 10.1038/ncomms1794

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