Kinetics of hepatitis C virus RNA decay, quasispecies evolution and risk of virological failure during telaprevir-based triple therapy in clinical practice

Abstract

The used first generation protease inhibitors may be hampered by virological failure in partially interferon-sensitive patients. Aim: To investigate early hepatitis C virus (HCV)-RNA decay and quasispecies modifications, and disclose viral dynamics underlying failure. Methods: Viraemia decay at early time-points during telaprevir treatment was modelled according to Neumann et al. (1998). NS3-sequences were obtained by population-sequencing and ultradeep-454-pyrosequencing. Results: 13 treatment-experienced (8 non-responders, 5 relapsers), and two cirrhotic naïve patients, received telaprevir + pegylated-interferon-␣ + ribavirin.Viraemia decay was biphasic. In all patients, first-phase was rapid and consistent, with a median [interquartile-range] viraemia decay of 2.8 [2.6-3.2] log IU/ml within 48 h. Second-phase decay was slower, especially in failing patients: 3/3 showed <1 log IU/ml decay between 48 h and 2 weeks, and HCV-RNA >100 IU/ml at week 2. Only one patient experiencing sustained viral response showed similar kinetics.By pyrosequencing, mutational freeze was observed in all 15 patients within the first 24 h, but only in patients with sustained response afterwards. Indeed, 2/2 failing patients showed early resistance, as minor (V36A-T54A: prevalence <26% at 48 h) or major (V36M/A-R155K: prevalence, 99.8% at week 2) variants. Conclusions: Following telaprevir administration, first-phase HCV-RNA decay is consistent with mutational freeze and limited/no viral replication, while second-phase is significantly slower in failing patients (with appearance of resistance), suggesting the usefulness of early HCV-RNA monitoring.© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Modelling hepatitis C therapy—predicting effects of treatment

“…35,37,41–43 Results obtained in studies involving small patient populations found a much slower second phase of viral decline in cirrhotic or treatment experienced patients, than non-cirrhotic treatment naive patients]. 59,60 More data are now needed to precisely evaluate the second phase of viral kinetics with DAAs in “real life” where the proportion of patients with unfavorable characteristics (cirrhosis or treatment experienced) is often larger than in clinical trials. […”

Exploring resistance pathways for first-generation NS3/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning

“…As such, treatment-associated variants may have been missed, since it has been reported that NS3 variants tend to disappear within one year after end of therapy (Barnard et al, 2013;Sullivan et al, 2013), and even shorter in the case of newer generation DAAs (Krishnan et al, 2015). For on-treatment sequences, several samples taken at early time points (b14 days) could not be included in the study since it has been shown that RAVs are only detected in plasma after two weeks when using population-based Sanger sequencing (Cento et al, 2015b). A second limitation was the small overall number of NS3 sequences available for the analysis.…”

“…In cases where more than one PI-experienced sequence was available, the latest on-treatment sequence, or if not available, the first post-treatment sequence was selected. Sequences were excluded when the duration of HCV antiviral treatment during which the sample was taken, was b14 days (Cento et al, 2015a(Cento et al, , 2015b. Table 2 summarizes more detailed information for all samples concerning the time of sampling compared to the start and end date of PI treatment.…”

“…All sequences obtained in the context of this study, were submitted to Genbank (accession numbers KX852142-KX852220 and KX825921-KX825931). Viral sequences originating from Italian patients were published already (Cento et al, 2015a(Cento et al, , 2015b.…”