Frequent NS5A and multiclass resistance in almost all HCV genotypes at DAA failures: What are the chances for second-line regimens?

Treatment with direct-acting antivirals (DAA) has shown high efficacy, but a substantial proportion of patients (5–15%) remain NS3-4A mutation at baseline. The presence of NS5A RASs/poly- morphisms was found in 20 (80%) patients at baseline of retreatment (Table 1). Among these 20 patients, 16 were re- treated with at least one anti-NS5A DAA; the remaining four patients were re-treated with a combination of anti-NS5B and anti-NS3/4A DAAs. Among the four patients with no RAS at baseline of retreatment, all were retreated with NS5A inhibi- tors; three patients were retreated with a combination of NS5A + NS5B inhibitors, and one patient was retreated with a combination of NS5A + NS5B+NS3/4A inhibitors. Overall, 24 weeks of DAA therapy was administered more as a second-line treatment than it was as a first-line treatment: 15/24 (63%) vs. 5/24 (21%), respectively (Fisher p = 0.0043). Among the 17 GT1 patients, 14 (82%) had a least one NS5A RAS at the time of failure. The SVR rate was 100% for all regi- mens except for ombitasvir + paritaprevir + ritonavir + dasabu- vir + ribavirin; one patient out of four failed to achieve SVR (failure occurred in a patient with a 93N RAS). Discussion Given the emergence and persistence of RASs, retreatment of patients after first-line DAA therapy failure remains a challenge. The present study showed that retreatment of patients after a resistant to DAAs. As previously reported, treatment failure is generally associated with the emergence of HCV resistance- associated substitutions (RASs), which reduce susceptibility to ment according to baseline nonstructural protein 5A (NS5A) RASs after the failure of first-line DAA treatment.