Pooled Resistance Analysis in HCV Genotype 1-6 Infected Patients Treated With Glecaprevir/Pibrentasvir in Phase 2 and 3 Clinical Trials [PublishAheadOfPrint]

Over 2200 HCV genotype (GT)1-6 infected patients with or without cirrhosis who were treatment-naïve or experienced to interferon, ribavirin and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12 or 16 weeks in 8 registrational phase 2/3 clinical studies. High SVR12 rates were achieved with <1% virologic failure (VF) rate. The prevalence of baseline polymorphisms (BP) in NS3 at amino acid positions 155 or 168 was low (<3%) in GT1, GT2, GT3, GT4, and GT6, while 41.9% of the GT5-infected patients had NS3-D168E; BPs were not detected at position 156 in NS3. The prevalence of NS5A-BPs was high across genotypes, driven by common polymorphisms at amino acid positions 30 or 31 in GT2, 58 in GT4, and 28 in GT6. The prevalence of NS5A T/Y93 polymorphisms was 5.5% in GT1, 4.9% in GT3, and 12.5% in GT6. Consistent with the activity of glecaprevir and pibrentasvir against most amino acid polymorphisms in vitro, BPs in NS3 and/or NS5A did not have an impact on treatment outcome for patients with GT1-6 infection, with the exception of treatment-experienced GT3-infected patients treated for 12 weeks, for whom a 16-week regimen of glecaprevir/pibrentasvir was required to achieve SVR12 rates ≥95%. Among the 22 patients experiencing VF, treatment-emergent substitutions were detected in NS3 in 50% and in NS5A in 82% of patients, frequently as a combination of substitutions that conferred resistance to glecaprevir and/or pibrentasvir. The glecaprevir/pibrentasvir regimen, when using the recommended durations, allows for a pangenotypic treatment option without the need for baseline resistance testing.

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