Systematic review with meta‐analysis: impact of baseline resistance‐associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients

Abstract

Background:The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients receiving the second generation, pan-genotypic glecaprevir/pibrentasvir (G/P) regimen is unclear. Aim:To assess the effect of RAS on the SVR12 in CHC patients treated with G/P regimen. Methods: The EMBASE, MEDLINE and Cochrane central register of controlled trials databases were searched for relevant studies published before 1 March 2019.The principal outcome was to compare the SVR12 in CHC patients with and without baseline RAS, particularly in genotype-1, genotype-3 and direct-acting anti-virals (DAAs) failure patients. The outcomes were pooled using a random-effects model and odds ratio (OR) was calculated. The risk of bias was assessed using the Cochrane risk of bias tools for randomised and nonrandomised interventional studies. Results: After initially identifying 410 studies, 3302 patients from 17 studies were included. Among 50 cases of virologic failures, 48% had genotype-3 infection, 44% genotype-1 infection and 36% DAA-failure patients. Baseline RAS were present in 44(88%) patients. The most common NS5a and NS3 mutations were Y93H and A166S respectively. The odds of SVR12 were significantly reduced in patients with any baseline RAS (NS3 and/or NS5a) (OR 0.32, 95%C I[0.15, 0.65], I 2 = 0%) and NS5a substitutions (OR 0.36, 95%CI [0.18,0.73]). The impact of RAS on SVR12 was significant among genotype-3 patients, but not among genotype-1 or DAA-failure cases. The presence of Y93H and A30K mutations significantly impacted SVR12 rates in genotype-3 patients. Conclusion: Baseline NS3 or NS5a RAS, especially the NS5a substitutions-A30K, Y93H, decrease the odds of achieving SVR12 in genotype-3 CHC patients. | 491 SINGH et al.

Letter: now is the time to remove complexity from HCV guidelines to ensure that elimination remains a priority

“…We read with interest the meta-analysis by Singh and the editorial by Kwong that discussed resistance-associated substitution (RAS) testing in HCV genotype (GT) of 3 patients being considered for glecaprevir/pibrentasvir (GLE/PIB) treatment. 1,2 Singh demonstrated that sustained virological response (SVR) was lower in GT3 patients with baseline RAS than in those without RAS (92.6% versus 99.0%; odds ratio 0.14; 95% confidence intervals 0.05,0.38). 1 They conclude that the management of GT3 patients with GLE/PIB warrants careful consideration.…”

“…1,2 Singh demonstrated that sustained virological response (SVR) was lower in GT3 patients with baseline RAS than in those without RAS (92.6% versus 99.0%; odds ratio 0.14; 95% confidence intervals 0.05,0.38). 1 They conclude that the management of GT3 patients with GLE/PIB warrants careful consideration.…”

Editorial: glecaprevir/pibrentasvir for the treatment of hepatitis C virus—do baseline resistance‐associated substitutions matter? Authors' reply

“…We thank Allison Kwong and Paul Kwo for their editorial on our systematic review. 1,2 Baseline resistance-associated substitution (RAS) testing prior to hepatitis C virus treatment with direct-acting antiviral regimens is still an area of controversy. The objective of our review was to evaluate the impact of baseline RAS on the sustained virologic response at 12 weeks (SVR-12) among patients treated with glecaprevir/pibrentasvir (G/P) regimen.…”

Letter: now is the time to remove complexity from HCV guidelines to ensure that elimination remains a priority—authors' reply

“…We thank Turnes et al for their interest in our systematic review and meta‐analysis 1,2 . Considering widespread hepatitis C virus (HCV) infection and its dire consequences, HCV elimination is the ultimate goal of global treatment strategies 3 .…”

“…In our systematic review, of the 637 patients with HCV genotype 3 infection who were treated with glecaprevir/pibrentasvir (g/p) regimen, only 20 experienced virologic failure with an SVR‐12 of 96.8%. The odds of achieving SVR‐12 were lower in patients with baseline resistance‐associated substitutions (RAS) than those without , OR = 0.14, (95% CI = 0.05, 0.38), number needed to fail was 19 (95% CI = 7, 70) 2 . Considering the high effectiveness of this therapy, pre‐testing for the presence of baseline RAS may only hinder the access to therapy.…”