Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase

Gastroenterology. 2003 Aug;125(2):292-7. doi: 10.1016/s0016-5085(03)00939-9.


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 log(10) 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.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / therapeutic use*
  • Alanine Transaminase / blood
  • Antiviral Agents / therapeutic use*
  • DNA, Viral / blood
  • DNA-Directed DNA Polymerase / chemistry
  • DNA-Directed DNA Polymerase / genetics*
  • Drug Resistance, Viral
  • Hepatitis B virus / drug effects
  • Hepatitis B virus / enzymology
  • Hepatitis B virus / genetics*
  • Hepatitis B, Chronic / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Organophosphonates*
  • Viral Proteins / genetics*


  • Antiviral Agents
  • DNA, Viral
  • Organophosphonates
  • Viral Proteins
  • Alanine Transaminase
  • DNA-Directed DNA Polymerase
  • Adenine
  • adefovir dipivoxil