Researchers identified a common polymorphism and a rare variant combination in hepatitis C genotype 3 that are responsible for a reduced response to Sovaldi, according to a study published in Gastroenterology.
“Studies on [Sovaldi] ‘resistance’ have been hampered by the extraordinary efficacy of the drug, which has led to very few treatment failures,” Peter A.C. Wing, PhD, from the Queen Mary University of London in the United Kingdom, and colleagues wrote. “Our analysis shows that reduced response to [Sovaldi] may occur if multiple viral polymorphisms are combined.”
To evaluate resistance to Sovaldi (sofosbuvir, Gilead Sciences) as well as ribavirin, Wing and colleagues used capture-fusion assays to assess 14 samples of HCV genotype 3. Ten of the samples were from treatment-naive patients with advanced liver disease, while the other four were from patients who had shown response in early access programs or in vitro testing.
They found that alanine at position 150 was particularly common (40.55%) along with the valine variant (36.66%). At position 206, lysine demonstrated a frequency of 76.31% and glutamic acid presented at a frequency of 12.74%. However, an analysis of the combination of polymorphisms (A150V and K206E) showed both were present in less than 4% of the population.
Using transient replicon assay, the researchers found that each common polymorphism correlated with an eightfold reduction in sensitivity to sofosbuvir and the combination correlated with a reduced sensitivity of more than 35-fold.
The effect of these polymorphisms on ribavirin sensitivity ranged from 10-fold for K206E to more than 40-fold for A150V, but in combination, the effect was enhanced to approximately 70-fold.
“For treatment naive patients, responses to [sofosbuvir] based treatments are so effective that any impact of these viral variants is likely to be minimal and we would not recommend that such patients undergo pre-treatment ‘resistance’ testing,” Wing and colleagues concluded. “For patients who have been exposed to multiple drug regimens (including interferon and NS5a inhibitors that can lead to resistance associated polymorphisms) we speculate that the polymorphisms identified here might be of significance and we suggest that pre-treatment viral sequencing may be useful in selecting the optimal regimen for such patients.”
By Talitha Bennett