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Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes
OBJECTIVES: Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study witho...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228778/ https://www.ncbi.nlm.nih.gov/pubmed/25096075 http://dx.doi.org/10.1093/jac/dku296 |
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author | Sutherland, Katherine A. Mbisa, Jean L. Ghosn, Jade Chaix, Marie-Laure Cohen-Codar, Isabelle Hue, Stephane Delfraissy, Jean-Francois Delaugerre, Constance Gupta, Ravindra K. |
author_facet | Sutherland, Katherine A. Mbisa, Jean L. Ghosn, Jade Chaix, Marie-Laure Cohen-Codar, Isabelle Hue, Stephane Delfraissy, Jean-Francois Delaugerre, Constance Gupta, Ravindra K. |
author_sort | Sutherland, Katherine A. |
collection | PubMed |
description | OBJECTIVES: Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping. METHODS: Phenotypic susceptibility testing and viral infectivity assessments were performed using a single-cycle assay and fold changes (FC) relative to a lopinavir-susceptible reference strain were calculated. RESULTS: >10-fold reduced baseline susceptibility to lopinavir occurred in two of five patients and >5-fold in another two. Four of five patients exhibited phylogenetic evidence of a limited viral evolution between baseline and failure, with amino acid changes at drug resistance-associated positions in one: T81A emerged in Gag with M36I in the protease gene, correlating with a reduction in lopinavir susceptibility from FC 7 (95% CI 6–8.35) to FC 13 (95% CI 8.11–17.8). Reductions in darunavir susceptibility (>5 FC) occurred in three individuals. DISCUSSION: This study suggests both baseline reduced susceptibility and evolution of resistance could be contributing factors to PI failure, despite the absence of classical PI resistance mutations by standard testing methods. Use of phenotyping also reveals lower darunavir susceptibility, warranting further study as this agent is commonly used following lopinavir failure. |
format | Online Article Text |
id | pubmed-4228778 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-42287782014-11-13 Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes Sutherland, Katherine A. Mbisa, Jean L. Ghosn, Jade Chaix, Marie-Laure Cohen-Codar, Isabelle Hue, Stephane Delfraissy, Jean-Francois Delaugerre, Constance Gupta, Ravindra K. J Antimicrob Chemother Original Research OBJECTIVES: Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping. METHODS: Phenotypic susceptibility testing and viral infectivity assessments were performed using a single-cycle assay and fold changes (FC) relative to a lopinavir-susceptible reference strain were calculated. RESULTS: >10-fold reduced baseline susceptibility to lopinavir occurred in two of five patients and >5-fold in another two. Four of five patients exhibited phylogenetic evidence of a limited viral evolution between baseline and failure, with amino acid changes at drug resistance-associated positions in one: T81A emerged in Gag with M36I in the protease gene, correlating with a reduction in lopinavir susceptibility from FC 7 (95% CI 6–8.35) to FC 13 (95% CI 8.11–17.8). Reductions in darunavir susceptibility (>5 FC) occurred in three individuals. DISCUSSION: This study suggests both baseline reduced susceptibility and evolution of resistance could be contributing factors to PI failure, despite the absence of classical PI resistance mutations by standard testing methods. Use of phenotyping also reveals lower darunavir susceptibility, warranting further study as this agent is commonly used following lopinavir failure. Oxford University Press 2014-12 2014-08-04 /pmc/articles/PMC4228778/ /pubmed/25096075 http://dx.doi.org/10.1093/jac/dku296 Text en © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Sutherland, Katherine A. Mbisa, Jean L. Ghosn, Jade Chaix, Marie-Laure Cohen-Codar, Isabelle Hue, Stephane Delfraissy, Jean-Francois Delaugerre, Constance Gupta, Ravindra K. Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes |
title | Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes |
title_full | Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes |
title_fullStr | Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes |
title_full_unstemmed | Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes |
title_short | Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes |
title_sort | phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228778/ https://www.ncbi.nlm.nih.gov/pubmed/25096075 http://dx.doi.org/10.1093/jac/dku296 |
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