Resistance to direct-acting antiviral agents: clinical utility and significance

This article examines the dynamics and factors underlying hepatitis C virus (HCV) resistance, along with their impact on daily clinical management of HCV-infected patients.

Across available treatment-regimens, GT-3 is the most difficult-to-cure genotype, but also genotype-1a may show lower success-rates compared with genotype-1b. Natural resistance to NS3, NS5A and NS5B inhibitors may contribute to treatment failures. The Q80K NS3-protease mutation affects sensibility to simeprevir + peg-interferon/ribavirin combinations. It reaches up to 48% prevalence in genotype-1a in some studies (but it is lower in other). Resistant variants (particularly in NS5A) developed at failure can persist, in a substantial proportion of patients, even 3 years after treatment-discontinuation, potentially affecting readministration of the same direct-acting antiviral agent (DAA)-class. This will become an issue for those patients failing all-oral regimens with multiple-resistant viruses.

Recent data support the importance of an accurate genotype and genotype-1 subtype (1a/1b) assignment prior therapy. Resistance testing at baseline has no clear indication so far in clinical practice for all-DAA regimens selection, while it remains a valuable option at the retreatment of patients who failed DAA-containing regimens, provided that data are generated to inform treatment decisions based on the results of resistance testing. In this context, long-term RAVs persistence after failure should be taken into account.