NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaprevir and pibrentasvir

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Aim: Factors responsible for impaired improvement of liver function despite sustained viral response after direct-acting antiviral agents therapies in cirrhotic patients with hepatitis C virus need to be elucidated.Methods: Liver function and the extent of portosystemic shunting were evaluated for 79 patients with compensated cirrhosis, in whom sustained viral response had been achieved after direct-acting antiviral agents therapies for hepatitis C virus at least 3 years earlier. Conclusions:A large size of portosystemic shunts was found to be a crucial determinant of impaired improvement of liver function, as well as of the development of portal hypertensionrelated events, even after sustained viral response in patients with compensated cirrhosis.

Section: Introductionmentioning

confidence: 99%

Involvement of portosystemic shunts in impaired improvement of liver function after direct‐acting antiviral therapies in cirrhotic patients with hepatitis C virus

Tsuji

Uchida

Uemura

et al. 2020

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“…Uemura et al . classified the extent of resistance against NS5A inhibitor into five groups based on the effective concentration (EC) 50 values obtained in in vitro replicon assays; the coexistence of these RASs was associated with moderate‐to‐severe resistance. However, in the present study, the patients with these RASs who were treated with GLE/PIB achieved an SVR (Table ).…”

Section: Discussionmentioning

confidence: 99%

“…The EC50 in patients with the coexistence of Y93H and L31 or L28/R30 was 1.0–2.3 pmol/L . A phase III study and real‐world data showed that a large percentage of patients with Y93 RASs achieved an SVR . Thus, Y93 RAS seems to be associated with less resistance to GLE/PIB.…”

Section: Discussionmentioning

confidence: 99%

Viral and host factors are associated with retreatment failure in hepatitis C patients receiving all‐oral direct antiviral therapy

Mawatari

Oda

Kumagai

et al. 2020

Aim: Direct-acting antiviral (DAA) therapy for hepatitis C virus is associated with high sustained virologic response rates. However, patients for whom DAA therapy fails acquire resistanceassociated substitutions (RASs). We therefore evaluated the efficacy of DAA retreatment and factors associated with retreatment failure.Methods: Non-structural 5A RASs were investigated at the start of DAA therapy and at treatment failure in 64 patients with hepatitis C virus genotype 1b for whom DAA combination therapy had failed. A total of 59 patients were introduced to DAA retreatment. The factors associated with retreatment failure were investigated.Results: A total of 20 of 43 (46.5%) daclatasvir + asunaprevirtreated patients with virologic failure had no RASs at baseline, and three (15%) acquired P32 deletion RASs. Four of seven sofosbuvir/ledipasvir-treated patients with virologic failure had more than two RASs of NS5A at baseline. The sustained virologic response rates on retreatment were as follows: sofosbuvir/ledipasvir, 81.8%; with elbasvir + grazoprevir, 0%; and glecaprevir/pibrentasvir, 87.5%. Patients for whom sofosbuvir/ledipasvir or elbasvir + grazoprevir failed achieved sustained virologic response with glecaprevir/pibrentasvir. Two of three patients for whom glecaprevir/pibrentasvir retreatment failed had Q24/L28/R30 and A92K RASs; the other had P32 deletion RAS at baseline. Interestingly, 10 of 11 patients with retreatment failure had the interleukin (IL)-28B singlenucleotide polymorphism (SNP) minor allele. A multivariate analysis showed that the IL28B SNP minor allele (P = 0.005, odds ratio 28.291) was an independent risk factor for retreatment failure.Conclusions: In addition to viral factors (e.g. Q24, L28, R30, and A92 or P32 deletion RASs), host factors (e.g. IL28B SNP) are associated with DAA retreatment failure.

“…In recent in vitro and in vivo analyses, emerging genotype 1 HCV RAVs (e.g. NS5A P32 deletion), which showed high resistance to approved NS5A inhibitors, were described . However, this analysis was limited to genotype 1 HCV.…”

Section: Discussionmentioning

confidence: 99%

“…NS5A P32 deletion), which showed high resistance to approved NS5A inhibitors, were described. [26][27][28] However, this analysis was limited to genotype 1 HCV.…”

Section: Discussionmentioning

confidence: 99%

Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs

Suda

Kimura

Shigesawa

et al. 2019

Aims Development of direct‐acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant‐associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non‐structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy. Methods We utilized HCV‐2b/2a (JFH‐1) chimeric virus (genotype 2a), which replicates more robustly than JFH‐1. We constructed various genotype 2a JFH‐1‐based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti‐HCV reagents. Results Genotype 2a‐based HCV with NS5A–P32 deletion could not replicate even in long‐term cultures. Genotype 2a‐based HCV with NS5A‐F28S/M31I showed significantly higher replication ability than the wild‐type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000–10 000 fold‐resistance compared with the wild‐type strain). However, genotype 2a‐based HCV with NA5A‐F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon‐α, and ribavirin. Genotype 2a‐based HCV with NS5B‐S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control. Conclusions When undertaking retreatment for genotype 2a HCV‐infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti‐HCV drugs.