ArticleAntimicrobial agents and chemotherapy2015
Substitutions at NS3 Residue 155, 156, or 168 of Hepatitis C Virus Genotypes 2 to 6 Induce Complex Patterns of Protease Inhibitor Resistance.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it.
- KASL clinical practice guidelines: management of hepatitis C.Clinical and molecular hepatology · 2016Guideline
- Exploring evolutionary trajectories of drug resistance.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Unveiling the nexus between direct-acting antivirals in hepatitis C virus elimination and immune response.Clinical and experimental medicine · 2025Review
- Article
- Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis.Nature communications · 2023Article
- Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2Antimicrobial agents and chemotherapy · 2021Article
- Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir.ACS chemical biology · 2020Article
- Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants.Hepatology (Baltimore, Md.) · 2019Review
- Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations.Nature communications · 2019Article
- Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors.Critical reviews in biochemistry and molecular biology · 2019Review
- Resistance detection and re-treatment options in hepatitis C virus-related chronic liver diseases after DAA-treatment failure.Infection · 2018Review
- Article
- Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons.Antimicrobial agents and chemotherapy · 2017Article
- Efficient Hepatitis C Virus Genotype 1b Core-NS5A Recombinants Permit Efficacy Testing of Protease and NS5A Inhibitors.Antimicrobial agents and chemotherapy · 2017Article
- Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease.Journal of the American Chemical Society · 2016Article
- Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle.Antimicrobial agents and chemotherapy · 2016Article
- Article
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Various protease inhibitors (PIs) currently are becoming available for treatment of hepatitis C virus (HCV). For genotype 1, substitutions at NS3 protease positions 155, 156, and 168 are the main determinants of PI resistance. For other genotypes, similar substitutions were selected during PI treatment but were not characterized systematically. To elucidate the impact of key PI resistance substitutions on genotypes 2 to 6, we engineered the substitutions R155A/E/G/H/K/Q/T, A156G/S/T/V, and D/Q168A/E/G/H/N/V into HCV recombinants expressing genotype 2 to 6 proteases. We evaluated viral fitness and sensitivity to nine PIs (telaprevir, boceprevir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, deldeprevir, and grazoprevir) in Huh7.5 cells. We found that most variants showed decreased fitness compared to that of the original viruses. Overall, R155K, A156G/S, and D/Q168A/E/H/N/V variants showed the highest fitness; however, genotype 4 position 168 variants showed strong fitness impairment. Most variants tested were resistant to several PIs. Resistance levels varied significantly depending on the specific substitution, genotype, and PI. For telaprevir and boceprevir, specific 155 and 156, but not 168, variants proved resistant. For the remaining PIs, most genotype 2, 4, 5, and 6, but not genotype 3, variants showed various resistance levels. Overall, grazoprevir (MK-5172) had the highest efficacy against original viruses and variants. This is the first comprehensive study revealing the impact of described key PI resistance substitutions on fitness and PI resistance of HCV genotypes 2 to 6. In conclusion, the studied substitutions induced resistance to a panel of clinically relevant PIs, including the newer PIs paritaprevir, deldeprevir, and grazoprevir. We discovered complex patterns of resistance, with the impact of substitutions varying from increased sensitivity to high resistance.
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