Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients

Background Data on the prevalence and characteristics of so called rare HCV genotypes (GT) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results Overall 1.5% (69/4656) of DAA-naïve and 4.4% (60/1376) of DAA-failure patients were infected with rare GT. While rare GT were almost equally distributed throughout GT1-6 in DAA-naïve patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n=17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n=8, subtype 3b) among DAA-failures. 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). While NS5A RASs were uncommon in rare GT2, GT5a and GT6, we observed combined RASs in rare GT1, GT3 and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 mITT; 92%, 45/49 ITT). Three patients with GT4f, 4r or 3b, respectively, had virological treatment failure. Conclusions In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV genotypes (GT) among European HCV-infected patients. In DAA failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after 1st generation DAA failure and viral resistance was detected at NS5A positions 28, 30 and 31. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.