Virological patterns of HCV patients with failure to interferon‐free regimens

Abstract

The study characterized the virological patterns and the resistance-associated substitutions (RASs) in patients with failure to IFN-free regimens enrolled in the real-life setting. All 87 consecutive HCV patients with failed IFN-free regimens, observed at the laboratory of the University of Campania, were enrolled. All patients had been treated with DAA regimens according to the HCV genotype, international guidelines, and local availability. Sanger sequencing of NS3, NS5A, and NS5B regions was performed at failure by home-made protocols. Of the 87 patients enrolled, 13 (14.9%) showed a misclassified HCV genotype, probably causing DAA failure, 16 had been treated with a sub-optimal DAA regimen, 19 with a simeprevir-based regimen and 39 with an optimal DAA regimen. A major RAS was identified more frequently in the simeprevir regimen group (68.4%) and in the optimal regimen group (74.4%) than in the sub-optimal regimen group (56.3%). The prevalence of RASs in NS3 was similar in the three groups (30.8-57.9%), that in NS5A higher in the optimal regimen group (71.8%) than in the sub-optimal regimen group (12.5%, P < 0.0001) and in the simeprevir regimen group (31.6%, P < 0.0005), and that in NS5B low in all groups (0-25%). RASs in two or more HCV regions were more frequently identified in the optimal regimen group (46.6%) than in the simeprevir-based regimen group (31.6%) and sub-optimal regimen group (18.7%). In our real-life population the prevalence of RASs was high, especially in NS3 and NS5A and in those treated with suitable DAA regimens.

Hepatitis C late relapse in patients with directly acting antiviral‐related sustained virological response at week 12

“…Moreover, our population was at low probability of re‐infection, since the presumed duration of HCV infection was very long (at least 12 years). Instead, patient #6 harboured different HCV 1 subgenotypes (1b and 1a respectively) before the start of the DAA regimen and at relapse; therefore, in this case, we can hypothesize a re‐infection with another subgenotype of HCV, although an erroneous identification of the HCV subgenotype before the start of DAA may also be possible …”

“…Instead, patient #6 harboured different HCV 1 subgenotypes (1b and 1a respectively) before the start of the DAA regimen and at relapse; therefore, in this case, we can hypothesize a re-infection with another subgenotype of HCV, although an erroneous identification of the HCV subgenotype before the start of DAA may also be possible. 17 The clinical significance of a late relapse remains unclear; it suggested that some patients thought to have achieved an SVR may still harbour HCV. In some studies, despite serum HCV-RNA negativity after interferon treatment, patients may occasionally present low levels of detectable virus in the liver tissue during a follow-up period of 1-2 years after the end of treatment, 30,31 a condition that has been demonstrated to be a predictor of a later recurrence of HCV infection.…”

“…Sanger sequencing of NS3, NS5A and NS5B was performed applying home‐made protocols for all patients enrolled, as previously reported . Briefly, the NS3 (181aa), NS5A (140aa) and NS5B (565aa) regions were amplified and sequenced from stored serum/plasma samples using ABI 3500 Genetic Analyzer (Applied Biosystems Inc, Foster City, CA, USA).…”

“…Sanger sequencing of NS3, NS5A and NS5B was performed applying home-made protocols for all patients enrolled, as previously reported. 17 Briefly, the NS3 (181aa), NS5A (140aa) and NS5B (565aa) regions were amplified and sequenced from stored serum/plasma samples using ABI 3500 Genetic Analyzer (Applied Biosystems Inc, In the patients with a late relapse for whom also a serum sample collected before the DAA-failed regimen was available, NS3, NS5A and NS5B phylogenetic trees, which also included HCV-1b reference sequences, were performed. Bootstrap analysis with 1000 replicates was performed to assess the significance of the nodes; values greater than 70% were considered significant.…”

Hepatitis C resistance to NS5A inhibitors: Is it going to be a problem?

“…These NS5A RASs could be found at different levels of a mixed population of the mutated and wild-type viruses[ 21 , 22 ]. In NS5A inhibitor-experienced patients, especially those who have undergone a complete course of 12-wk or > 12-wk treatment, DAA-selected NS5A RASs are observed in > 75% of patients following treatment failure[ 10 , 23 - 25 ]. Most of these patients with failure to NS5A inhibitor-containing regimens harbor isolates with NS5A RASs > 100X[ 24 , 26 ].…”