Evolution of simeprevir‐resistant variants over time by ultra‐deep sequencing in HCV genotype 1b

  title={Evolution of simeprevir‐resistant variants over time by ultra‐deep sequencing in HCV genotype 1b},
  author={Norio Akuta and Fumitaka Suzuki and Hitomi Sezaki and Yoshiyuki Suzuki and Tetsuya Hosaka and Masahiro Kobayashi and Mariko Kobayashi and Satoshi Saitoh and Kenji Ikeda and Hiromitsu Kumada},
  journal={Journal of Medical Virology},
Using ultra‐deep sequencing technology, the present study was designed to investigate the evolution of simeprevir‐resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG‐IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B… 

Evolution of simeprevir‐resistant variants in virological non‐responders infected with HCV genotype 1b

The results demonstrated the emergence of simeprevir‐resistant variants during the early stage of triple therapy, and de novo variants of D168 were detected in all of 9 absolute non‐responders.

Deep Sequencing and Phylogenetic Analysis of Variants Resistant to Interferon-Based Protease Inhibitor Therapy in Chronic Hepatitis Induced by Genotype 1b Hepatitis C Virus

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Rapid, Sensitive, and Accurate Evaluation of Drug Resistant Mutant (NS5A-Y93H) Strain Frequency in Genotype 1b HCV by Invader Assay

The NS5A-Y93H mutant strain detection system established in this study may provide important pre-treatment information valuable not only for treatment decisions but also for prediction of disease progression in HCV genotype 1b patients.

Protease Inhibitor Resistance Remains Even After Mutant Strains Become Undetectable by Deep Sequencing.

The virological response to daclatasvir plus asunaprevir treatment was low in patients with simeprevir treatment failure, and PI resistance remains even after disappearance of mutant strains by deep sequencing.

Combination Therapies with Daclatasvir and Asunaprevir on NS3-D168 Mutated HCV in Human Hepatocyte Chimeric Mice

It is necessary to confirm that the frequency of NS3-D168 variants has decreased sufficiently before adopting daclatasvir plus asunaprevir therapy in patients with simeprevir plus PEG-IFN/RBV treatment failure.

Detection of the NS3 Q80K polymorphism by Sanger and deep sequencing in hepatitis C virus genotype 1a strains in the UK.

  • A. BeloukasS. King A. Geretti
  • Biology
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
  • 2015

Quasispecies dynamics and treatment outcome during early hepatitis C infection in a cohort of HIV-infected men

A next generation sequencing approach was developed using 454 pyrosequencing and Illumina-based technology and several mutations conferring resistance were detected in genotype 1a treatment-naive patients, resulting in an improved understanding of HCV quasispecies dynamics.



Emergence of telaprevir‐resistant variants detected by ultra‐deep sequencing after triple therapy in patients infected with HCV genotype 1

It is concluded that it is difficult to predict at baseline the emergence of telaprevir‐resistant variants after commencement of triple therapy in prior non‐responders of HCV genotype 1, even with the use of ultra‐deep sequencing.

Utility of Detection of Telaprevir-Resistant Variants for Prediction of Efficacy of Treatment of Hepatitis C Virus Genotype 1 Infection

It is indicated that the presence of telaprevir-resistant variants at the time of reelevation of viral load can be predicted by a combination of host, viral, and treatment factors.

Genetic Heterogeneity of Hepatitis C Virus in Association with Antiviral Therapy Determined by Ultra-Deep Sequencing

It is demonstrated that clones resistant to direct-acting antivirals for HCV, such as viral protease and polymerase inhibitors, preexist with various abundances in all 27 treatment-naïve patients, suggesting the risk of the development of drug resistance against these agents.

Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo

Using deep sequencing technology and a genetically engineered HCV infection system, it was showed that the rapid emergence of telaprevir‐resistant HCV was induced by mutation from the wildtype strain of HCV in vivo.

Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin

Analysis of genetic variation near the IL28B gene and aa substitution of the core region as predictors of sustained virological response to a triple therapy of telaprevir/PEG‐IFN/ribavirin in Japanese patients infected with HCV genotype 1b identified high sensitivity, specificity, and positive and negative predictive values.

Efficacy of re-treatment with TMC435 as combination therapy in hepatitis C virus-infected patients following TMC435 monotherapy.

Deep sequencing indicated low-level persistence of resistant variants in the remaining 2 patients, which might have affected their response to re-treatment, in the OPERA-1 study.

Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b–infected null responders

Dual therapy with daclatasvir and asunaprevir, without Peg‐IFN and RBV, can achieve high SVR rates in difficult‐to‐treat patients with HCV genotype 1b infection and previous null response to Peg‐ifN andRBV.

Use of Illumina Deep Sequencing Technology To Differentiate Hepatitis C Virus Variants

The successful use of Illumina deep sequencing technology and subsequent analyses to determine the genetic variants and amino acid substitutions in both treatment-naïve and treatment-experienced isolates from HCV-infected patients are demonstrated.

Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial.

In treatment-experienced patients, 12, 24, or 48 weeks simeprevir in combination with 48 weeks PegIFn and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, andRBV and was generally well tolerated.

Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C

Telaprevir in combination with PEG‐IFN/RBV led to a high SVR rate for relapsers and may offer a potential new therapy for nonresponders even with a shorter treatment period.