ReviewHepatology (Baltimore, Md.)2019
Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants.
Review in Hepatology (Baltimore, Md.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
What it found
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Who cites it
27 citing papers in PubMed.
- The Danish Database for Hepatitis B and C (DANHEP): A Nationwide, Prospective, Ongoing Cohort Study.Clinical epidemiology · 2026Article
- Unraveling the therapeutic landscape of approved non-peptide macrocycles.Acta pharmaceutica Sinica. B · 2025Review
- Advancing high-throughput anti-HCV drug screening: a novel dual-reporter HCV replicon model with real-time monitoring.Research in pharmaceutical sciences · 2025Article
- Effect of direct-acting antivirals on the titers of human pegivirus 1 during treatment of chronic hepatitis C patients.Microbiology spectrum · 2024Article
- An Increase in the Prevalence of Clinically Relevant Resistance-Associated Substitutions in Four Direct-Acting Antiviral Regimens: A Study Using GenBank HCV Sequences.Pathogens (Basel, Switzerland) · 2024Article
- Substitutions in SARS-CoV-2 Mpro Selected by Protease Inhibitor Boceprevir Confer Resistance to Nirmatrelvir.Viruses · 2023Review
- Article
- Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance.Journal of molecular biology · 2022Article
- Article
- High-Titer Hepatitis C Virus Production in a Scalable Single-Use High Cell Density Bioreactor.Vaccines · 2022Article
- Versatile SARS-CoV-2 Reverse-Genetics Systems for the Study of Antiviral Resistance and Replication.Viruses · 2022Article
- Targeting non-structural proteins of Hepatitis C virus for predicting repurposed drugs using QSAR and machine learning approaches.Computational and structural biotechnology journal · 2022Article
- High recombination rate of hepatitis C virus revealed by a green fluorescent protein reconstitution cell system.Virus evolution · 2022Article
- The Role of RASs /RVs in the Current Management of HCV.Viruses · 2021Review
- Characterization of a Novel Hepatitis C Virus Genotype 1 Subtype from a Patient Failing 4 Weeks of Glecaprevir-Pibrentasvir Treatment.Microbiology resource announcements · 2021Article
- Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants.Journal of medicinal chemistry · 2021Article
- Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2Antimicrobial agents and chemotherapy · 2021Article
- Article
- Overcoming Culture Restriction for SARS-CoV-2 in Human Cells Facilitates the Screening of Compounds Inhibiting Viral Replication.Antimicrobial agents and chemotherapy · 2021Article
- Article
Corrections and comments
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Authors and funding
21 authors.
Funding
Abstract
Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance-associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1-4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156-RASs were not maintained. For genotypes 1 and 2, persistence of 156-RASs depended on genome-wide substitution networks, co-selected under continued PI treatment and identified by next-generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156-RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre-existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156-RASs, we observed genome-wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1-6 revealed 156-RASs as key determinants of high-level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1-3 156-variants, which might pose a threat to clinically relevant combination treatments.
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