The global origins of resistance-associated variants in the non-structural proteins 5A and 5B of the hepatitis C virus

New, costly, fast acting, therapies targeting the non-structural proteins 5A and 5B (NS5A and NS5B) regions of the hepatitis C virus (HCV) genome are curative in themajority of cases. Variants with certainmutations in the NS5A and NS5B regions of HCV have been shown to reduce susceptibility to direct-acting NS5A and NS5B therapy and are found in treatment naive patients. Despite this, the ease with which these variants evolve is poorly known, as are their evolutionary and geographic origins. To address this crucial gap we inferred the evolutionary and geographic origins of resistance-associated variants (RAVs) in the HCV NS5A and NS5B regions of subtypes 1a, 1b, and 3a sequences available from global databases. We found that RAVs in the NS5A region of HCV, when prevalent, were widely dispersed throughout the phylogenetic tree of HCV withmultiple independent origins and that these variants are globally distributed. In contrast, most of the NS5B C316N variants came from one of two clades in the phylogenetic tree of HCV subtype 1b. The presence of serine (S) at codon 218 of HCV NS5B appears to facilitate the evolution of the C316N RAV. Other NS5B RAVs did not arise very frequently in our data set, except for S556G in subtype 1b and with respect to geography NS5B RAVs were also globally distributed. The inferred distribution of RAVs in the NS5A region and frequency of their origin suggest a low fitness barrier without the need for co-evolution of compensatory mutations. A low fitness barriermay allow rapid selection of de novo resistance to NS5A inhibitors during therapy.