LAUSR

BACKGROUND AIMS Suboptimal rates of sustained virological response (SVR) have been reported in patients infected with an "unusual", non-1a/1b hepatitis C virus (HCV) genotype 1 subtype. The objectives of this study were to assess the proportion of non-1a/1b genotype 1 subtypes in a population of HCV-infected patients who failed to achieve SVR after first-line direct-acting antiviral treatment, to virologically characterize their failures, and to assess their outcomes on retreatment. APPROACH AND RESULTS Samples addressed between January 2015 and December 2021 to the French National Reference Center for Viral Hepatitis B, C and D were prospectively analyzed by means of Sanger and deep sequencing. Among 640 failures, 47 (7.3%) occurred in patients infected with an "unusual" genotype 1 subtype. Samples were available in 43 of them; 92.5% of these patients were born in Africa. Our results show the presence at baseline and at treatment failure of NS3 protease and/or NS5A polymorphisms conferring inherent reduced susceptibility to DAAs in these patients, together with the presence at failure of additional RASs not naturally present as dominant species, but jointly selected by first-line therapy. CONCLUSIONS Patients infected with "unusual" HCV genotype 1 subtypes are overrepresented among DAA treatment failures. Most of them were born and likely infected in sub-Saharan Africa. "Unusual" HCV GT-1 subtypes naturally carry polymorphisms that confer reduced susceptibility to the drugs currently used to cure hepatitis C, in particular the NS5A inhibitors. Retreatment with sofosbuvir plus an NS3 protease and an NS5A inhibitor is generally efficacious.