HBV Mutants Associated with Clinical Resistance to Adefovir Cause Only Small Decreases in Drug Sensitivity?/font>
Emergence of drug resistant hepatitis B virus (HBV) is the main factor limiting the efficacy of antiviral therapy for chronic HBV (CH-B). Viral resistance to lamivudine/ LMV (Epivir-HBV) develops rapidly in CH-B patients; by contrast, development of resistance to adefovir dipivoxil/ ADV (Hepsera) is slow, becoming detectable in only a small proportion (2-3%) of treated patients after 96 weeks treatment.
Sequencing of clinical isolates of HBV from patients who showed sub-optimal viral load suppression during long-term treatment with ADV revealed mutations in the viral polymerase (pol) gene which resulted in rtN236T or rtA181V substitutions in the viral polymerase (Angus et al. Gastroenterology 2003;125:292-7).
The aim of this study was to further characterise the effects of rt236T and rtA181V on antiviral sensitivity by means of in vitro assays.
Each assay was performed in duplicate on three separate occasions. Viral replication in drug-treated cultures was expressed as a fraction of the amount measured in replicate drug-free controls.
Statistical and graphical analyses of the resulting data revealed that both rtN236T and rtA181V confer small decreases in sensitivity to LMV, ADV and TFV. The rtN236T had more effect than rtA181V (increases in EC50 of up to about 4- and 7- fold respectively). HBeAg negativity either had no effect or was associated with a further small decrease in drug sensitivity.
PolymeraseHBeAgResistance Factor (Fold)* LMVADVTFV
None (WT) WT (+)
1.0
1.0
1.0 PC (-)
1.2
1.0
1.4
rtA181V WT (+)
1.3
1.6
1.0 PC (-)
2.2
3.6
1.6
rtN236T WT (+)
2.1
6.7
3.1 PC (-)
4.9
6.7
3.7
Conclusions
In contrast to the effects of mutations that confer LMV resistance, those associated with clinical ADV resistance cause only small decreases in drug sensitivity (1.3 - 3.6 fold and 2.1-6.7 fold for rtA181V and rtN236T respectively, based on EC50 estimates).
揊urthermore, rtN236T, which confers the greatest resistance to ADV confers less resistance to LMV and TFV. In general, mutants associated with ADV resistance remain relatively sensitive to LMV and TFV.?/span>
12/06/04
Reference
S Locarnini and others. HBV MUTANTS ASSOCIATED WITH CLINICAL RESISTANCE TO ADEFOVIR DIPIVOXIL DISPLAY ONLY SMALL DECREASES IN ANTIVIRAL SENSITIVITY IN VITRO. Abstract 182 (poster). 55th AASLD. October 29-November 2, 2004. Boston, MA. |