Unusual viral polymorphisms may impair the response to sofosbuvir in patients with chronic hepatitis C virus (HCV) infections, according to a study published in Gastroenterology.

Sofosbuvir is a pan-genotype inhibitor of HCV polymerase that eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, studies have shown that HCV genotype 3 is less sensitive to sofosbuvir than other HCV genotypes and prior therapy with interferon has an impact on response. Therefore, researchers collected data from England’s National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure in 14 HCV genotype 3 samples. They identified polymorphisms associated with reduced response and examined their effects by performing a logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon. A common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, was found to reduce the virus response to sofosbuvir. Therefore, clinically, infection with HCV G3 containing this variant reduces the odds of sustained virologic response. 

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The study authors concluded that, “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.” However, further studies are needed in large cohorts of patients who are exposed to various treatment regimens to identify the cohorts of patients who require virologic analysis prior to therapy. 


Reference
Wing PAC, Jones M, Cheung M, et al. Amino acid substitutions in genotype 3a hepatitis C virus polymerase protein affect responses to sofosbuvir. Gastroenterology. doi:10.1053/j.gastro.2019.05.007