Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir/pibrentasvir regimen

Abstract

Objectives To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir. Methods Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated. Results We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available. Conclusions One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.

Resistance analysis and treatment outcomes in hepatitis C virus genotype 3‐infected patients within the Italian network VIRONET‐C

“…This RAS confers a high level of resistance to velpatasvir (FC = 724) while has minimal in vitro impact against pibrentasvir (FC = 2.5) in GT3a 20 . Differently, NS5A‐RASs patterns (mostly A30K + Y93H) were frequently observed (55.5%) after G/P failure, as reported by other authors 15,43,44 . This RASs combination confers a high level of resistance to both velpatasvir and pibrentasvir (fold change [>100] and [69] respectively) 9 .…”

“…20 Differently, NS5A-RASs patterns (mostly A30K + Y93H) were frequently observed (55.5%) after G/P failure, as reported by other authors. 15,43,44 This RASs combination confers a high level of resistance to both velpatasvir and pibrentasvir (fold change [>100] and [69] respectively). 9 It can be noted that, according to other published data, the three patients who failed SOF/ LDV ± RBV regimens did not show any presence of NS5A-RASs, 41,45 confirming the suboptimal antiviral activity against GT3 and no selection of resistance.…”

Resistance‐associated substitutions after sofosbuvir/velpatasvir/voxilaprevir triple therapy failure

“…The NS5B C316N and NS5A Y93H substitutions observed in 100% of reads before SOF/VEL/VOX failure in both G1b patients suggest that this combination may have been a major cause of failure, as reported 3,10,11 . None of the G3a‐infected patients had NS5B RAS, but G3a is known to be less sensitive to SOF 12 .…”

Treatment failure with DAA therapy: Importance of resistance

“…2). 16,19,25,29,[33][34][35][36][37][38] Overall, RAS patterns are partially overlapping for the different NS3 and NS5A inhibitors. However, there are also differences with non-overlapping resistance profiles which may be important for selection of rescue DAA regimens.…”

“…Other RASs also have been detected in individual patients. For HCV genotypes 2-6 RASs selected depend substantially on HCV subtypes 16,19,25,29,[33][34][35][36][37][38]. DAA, direct-acting antiviral; DAC, daclatasvir; DSV, dasabuvir; EBV, elbasvir; GLE, glecaprevir; GT, genotype; GZR, grazoprevir; LDV, ledipasvir; Non-NUC, non-nucleosidic NS5B polymerase inhibitor; NUC, nucleotide NS5B polymerase inhibitor; OMV, ombitasvir; PIB, pibrentasvir; PTVr, paritaprevir/ritonavir; RASs, resistance-associated substitutions; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.…”