icon-folder.gif   Conference Reports for NATAP  
  57th Annual Meeting of the American Association
for the Study of Liver Diseases
October 27-31, 2006
Boston, MA
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In Vitro Susceptibility of HBV Polymerase Encoding Mutations Acquired During Adefovir Dipivoxil Therapy to Other Anti-HBV Agents
  Reported by Jules Levin
AASLD, Oct 27-31, 2006, Boston, MA
X Qi, S Xiong, H Yang, M Miller, and W Delaney IV* Gilead Sciences, Inc., Foster City, CA
Long-term nucleos/tide therapy is limited by the emergence of resistance.
Defining resistance profiles of drugs is essential for optimal patient management
Long-term Genotypic Resistance Rates:
Treatment Naive Patients

In this table adefovir resistance development rates are about 0 in year 1, 3% after 2 yrs, 10% after 3 yrs, 20% after 4 yrs, and 30% after 5 yrs. Lamivudine rates are about 22% after 1 year, 42% after 2 yrs, 55% after 3 yrs, and 70% after 4 yrs.



To quantify in vitro levels of resistance for adefovir-associated mutations
To quantify in vitro cross-resistance of adefovir-associated mutations to other anti-HBV agents
Generated stable cell lines expressing five patterns of adefovir-associated mutations
- rtN236T
- rtA181V
- rtA181V + rtN236T
- rtA181T + rtN236T
- rtA181T
Used previously validated qPCR assay to test drug susceptibility - Yang et al. Antiviral Therapy 2005 10:625


In Vitro Susceptibility Changes
These are in vitro data and are informative but in patients entecavir has demonstrated significant antiviral efficacy against adefovir resistance in Phase III study. As well, tenofovir has efficacy against adefovir resistance.


In Vitro ADV Cross-resistance Summary (I)
- A181T is not resistant to adefovir or tenofovir
- Tenofovir is more active than adefovir against ADV-associated mutants Entecavir and tenofovir are likely active clinically against ADV-associated mutations
- Villeneuve et al. Hepatology 2005 42:588A.
- Fung et al. J Hepatol 2005 43:937-43.
- Ratziu et al. Comp Hepatol 2006 5:1
A181V/T shows reduced susceptibility to all L-nucleosides
- lamivudine, emtricitabine may retain sufficient activity for clinical efficacy
- clevudine, telbivudine, torcitabine lose substantial activity
- Further clinical studies necessary for establishing in vitro cutoffs