Amino Acid Variants Responsible for Reduced Response to Hepatitis C Treatment

Peter A.C. Wing, PhD

New insights show why a certain hepatitis C virus (HCV) genotype is resistant to a common drug used to treat the viral infection.

An investigative team, including Peter A.C. Wing, PhD, Barts Liver Centre, Blizard Institute Queen Mary University of London, collected patient serum samples from the HCV Research UK Biobank and used capture-fusion assay techniques to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples.

The investigators performed logistic regression multivariate analysis on the associations of the polymorphisms 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.

Sofosbuvir, a highly effective HCV polymerase pan-genotype inhibitor that has replaced interferon as the backbone of many therapies of chronic HCV patients, eliminates most chronic HCV infections, while resistance-associated substitution in the polymerase remain rare.

However, HCV genotype 3 does not respond as well to sofosbuvir-based therapies than other genotypes for unknown reasons. A better understanding of sofosbuvir is particularly importance due to the availability of alternative regimens for HCV genotype 3 that are based on the protease inhibitor gearlever.

Studies on the drug’s resistance have been hampered by the extraordinary efficacy of the drug, which has led to very few treatment failures, while some very rare polymorphisms that can modify response, particularly in genotype 1 infection, have been identified.

In the study, the investigators identified a substation in the HCV genotype 3a NS5b polymerase at amino acid 150 alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays.

“A common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir,” the authors wrote. “Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.”

The A150V variant was linked to a reduced response to treatment with sofosbuvir and ribavirin with or without pegylated interferon in patients treated with the sofosbuvir-containing regimens.

“In 326 patients with V at position 150, 71% achieved a sustained virologic response compared to 88% with A at position 150,” the authors wrote. “In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold.”

The investigators also identified 5 rare polymorphisms that reduced sensitivity to the drug in a single patient’s cell system.

HCV genotype 3a is common in the Indian sub-continent and comprises 30% of all HCV infections in Eastern and Western Europe. Infected patients respond well to IFN-based regimens, with response rates approaching 80% in patients without cirrhosis, but the response is greatly reduced in those with advanced fibrosis.

The study, “Amino Acid Substitutions in Genotype 3a Hepatitis C Virus Polymerase Protein Affect Responses to Sofosbuvir,” was published online in Gastroenterology.