Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Evaluation of clinical translatability of the diet-induced obese and biopsy-confirmed gubra amylin mouse model of non-alcoholic steatohepatitis

    Research output: Contribution to journalConference abstract in journalResearchpeer-review

  2. Impact of binge drinking on hepatic lipid metabolism: lipidome analysis of liver vein and peripheral blood during acute alcohol intoxication

    Research output: Contribution to journalConference abstract in journalResearchpeer-review

  3. Non‐Alcoholic Fatty Liver Disease Alters Expression Of Genes Governing Hepatic Nitrogen Conversion

    Research output: Contribution to journalConference abstract in journalResearchpeer-review

  4. Preemptive-TIPS improves outcome in high-risk variceal bleeding: An observational study

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Ribavirin inhibition of cell-culture infectious hepatitis C genotype 1-3 viruses is strain-dependent

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. The Consensus Hepatitis C Cascade of Care: standardized reporting to monitor progress toward elimination

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Resistance to piperacillin/tazobactam in Escherichia coli resulting from extensive IS26-associated gene amplification of blaTEM-1

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Hepatitis E during pregnancy: Maternal and foetal case-fatality rates and adverse outcomes—A systematic review

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Genome Sequence of an Unknown Subtype of Hepatitis C Virus Genotype 6: Another Piece for the Taxonomic Puzzle

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

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 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. CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalHepatology (Baltimore, Md.)
Volume70
Issue number3
Pages (from-to)771-787
Number of pages17
ISSN0270-9139
DOIs
Publication statusPublished - Sep 2019

Bibliographical note

© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.

ID: 56978088