Adefovir dipivoxil (Hepsera) was approved for the treatment of chronic hepatitis B in 2002. While the drug has proven effective, long-term use of single agents for the treatment of HBV can promote the development of resistance mutations.

Researchers presented data from Study GS-98-438 on efficacy and resistance after five years of adefovir monotherapy. Since varying definitions of resistance have made it difficult to compare incidence rates across studies, they used specified definitions of resistance based on the presence of mutations, virological breakthrough, and clinical signs. Patients’ HBV DNA and ALT were evaluated every four weeks for the first two years, then every 12 weeks thereafter. Genetic sequencing for mutations was performed annually on all samples with detectable HBV DNA.

Results

• 29 patients (29%) developed mutations in the HBV polymerase associated with adefovir resistance (N236T and/or A181V) after a median follow-up of 30 weeks.
• 18 patients (16%) with mutations experienced virological evidence of resistance: an HBV viral load increase of at least 1 log10 copies/mL over the nadir (lowest ever level), or else HBV DNA never suppressed below 3 log10 copies/mL.
• 13 patients (11%) had mutations, virological resistance, and clinical evidence of resistance: ALT elevations greater than 1 x the upper limit of normal (ULN) after previous normalization.

Conclusion

The researchers concluded that the development of adefovir-associated mutations is “delayed and infrequent during long-term therapy” among HBeAg-negative patients with chronic hepatitis B. Furthermore, emergence of genotypic resistance is not always associated with virological breakthrough and/or increased ALT levels. Viral load was reduced when patients who developed adefovir-associated mutations added or switched to lamivudine.

View slide presentation http://www.hivandhepatitis.com/2006icr/ddw/pdf/Borroto-Esoda.pdf

6/2/06

Reference