Resistance of Hbv to Adefovir Dipivoxil: A Case for Combination Antiviral Therapy?

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Abstract
: Background & Aims: Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo–controlled 48–week studies with this drug. The aim of this study was to characterize adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96–week course of treatment. Methods: HBV DNA was PCR amplified and sequenced. Phenotypic studies used patient–derived HBV as well as specific mutations created by site–directed mutagenesis of a HBV/baculovirus recombinant. Results: Following the commencement of treatment with adefovir dipivoxil, the patient initially responded with a 2.4 log10 decrease in serum HBV DNA and normalization of alanine aminotransaminase levels by week 16. During the second year of treatment, however, serum HBV DNA rose progressively, eventually returning to near–pretreatment levels. This increase in viral replication was associated with a marked increase in alanine aminotransferase and mild changes in bilirubin, albumin, and prothrombin time. Comparison of pretreatment and posttreatment HBV DNA by polymerase chain reaction sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase. In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient–derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to adefovir. Conclusions: The development of this novel mutation in the HBV polymerase confers resistance to adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, achieving normalization of alanine aminotransferase and a significant decrease in serum HBV DNA.