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Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial

BACKGROUND: Major protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa follo...

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Autores principales: Sutherland, Katherine A., Parry, Chris M., McCormick, Adele, Kapaata, Anne, Lyagoba, Fred, Kaleebu, Pontiano, Gilks, Charles F., Goodall, Ruth, Spyer, Moira, Kityo, Cissy, Pillay, Deenan, Gupta, Ravindra K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575205/
https://www.ncbi.nlm.nih.gov/pubmed/26382239
http://dx.doi.org/10.1371/journal.pone.0137834
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author Sutherland, Katherine A.
Parry, Chris M.
McCormick, Adele
Kapaata, Anne
Lyagoba, Fred
Kaleebu, Pontiano
Gilks, Charles F.
Goodall, Ruth
Spyer, Moira
Kityo, Cissy
Pillay, Deenan
Gupta, Ravindra K.
author_facet Sutherland, Katherine A.
Parry, Chris M.
McCormick, Adele
Kapaata, Anne
Lyagoba, Fred
Kaleebu, Pontiano
Gilks, Charles F.
Goodall, Ruth
Spyer, Moira
Kityo, Cissy
Pillay, Deenan
Gupta, Ravindra K.
author_sort Sutherland, Katherine A.
collection PubMed
description BACKGROUND: Major protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa following viral rebound on PIs. METHODS: Samples from baseline and treatment failure in patients enrolled in the second line LPV/r trial SARA underwent phenotypic susceptibility testing. Data were expressed as fold-change in susceptibility relative to a LPV-susceptible reference strain. RESULTS: We cloned 48 Gag-Protease containing sequences from seven individuals and performed drug resistance phenotyping from pre-PI and treatment failure timepoints in seven patients. For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC(50) to LPV was 4.07 fold (95% CI, 2.08–6.07) at the pre-PI timepoint. Following viral failure the mean fold-change in EC(50) to LPV was 4.25 fold (95% CI, 1.39–7.11, p = 0.91). All viruses remained susceptible to DRV. In our assay system, the major PI resistance mutation I84V, which emerged in one individual, conferred a 10.5-fold reduction in LPV susceptibility. One of the six patients exhibited a significant reduction in susceptibility between pre-PI and failure timepoints (from 4.7 fold to 9.6 fold) in the absence of known major mutations in protease, but associated with changes in Gag: V7I, G49D, R69Q, A120D, Q127K, N375S and I462S. Phylogenetic analysis provided evidence of the emergence of genetically distinct viruses at the time of treatment failure, indicating ongoing viral evolution in Gag-protease under PI pressure. CONCLUSIONS: Here we observe in one patient the development of significantly reduced susceptibility conferred by changes in Gag which may have contributed to treatment failure on a protease inhibitor containing regimen. Further phenotype-genotype studies are required to elucidate genetic determinants of protease inhibitor failure in those who fail without traditional resistance mutations whilst PI use is being scaled up globally.
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spelling pubmed-45752052015-09-25 Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial Sutherland, Katherine A. Parry, Chris M. McCormick, Adele Kapaata, Anne Lyagoba, Fred Kaleebu, Pontiano Gilks, Charles F. Goodall, Ruth Spyer, Moira Kityo, Cissy Pillay, Deenan Gupta, Ravindra K. PLoS One Research Article BACKGROUND: Major protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa following viral rebound on PIs. METHODS: Samples from baseline and treatment failure in patients enrolled in the second line LPV/r trial SARA underwent phenotypic susceptibility testing. Data were expressed as fold-change in susceptibility relative to a LPV-susceptible reference strain. RESULTS: We cloned 48 Gag-Protease containing sequences from seven individuals and performed drug resistance phenotyping from pre-PI and treatment failure timepoints in seven patients. For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC(50) to LPV was 4.07 fold (95% CI, 2.08–6.07) at the pre-PI timepoint. Following viral failure the mean fold-change in EC(50) to LPV was 4.25 fold (95% CI, 1.39–7.11, p = 0.91). All viruses remained susceptible to DRV. In our assay system, the major PI resistance mutation I84V, which emerged in one individual, conferred a 10.5-fold reduction in LPV susceptibility. One of the six patients exhibited a significant reduction in susceptibility between pre-PI and failure timepoints (from 4.7 fold to 9.6 fold) in the absence of known major mutations in protease, but associated with changes in Gag: V7I, G49D, R69Q, A120D, Q127K, N375S and I462S. Phylogenetic analysis provided evidence of the emergence of genetically distinct viruses at the time of treatment failure, indicating ongoing viral evolution in Gag-protease under PI pressure. CONCLUSIONS: Here we observe in one patient the development of significantly reduced susceptibility conferred by changes in Gag which may have contributed to treatment failure on a protease inhibitor containing regimen. Further phenotype-genotype studies are required to elucidate genetic determinants of protease inhibitor failure in those who fail without traditional resistance mutations whilst PI use is being scaled up globally. Public Library of Science 2015-09-18 /pmc/articles/PMC4575205/ /pubmed/26382239 http://dx.doi.org/10.1371/journal.pone.0137834 Text en © 2015 Sutherland et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sutherland, Katherine A.
Parry, Chris M.
McCormick, Adele
Kapaata, Anne
Lyagoba, Fred
Kaleebu, Pontiano
Gilks, Charles F.
Goodall, Ruth
Spyer, Moira
Kityo, Cissy
Pillay, Deenan
Gupta, Ravindra K.
Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial
title Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial
title_full Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial
title_fullStr Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial
title_full_unstemmed Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial
title_short Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial
title_sort evidence for reduced drug susceptibility without emergence of major protease mutations following protease inhibitor monotherapy failure in the sara trial
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575205/
https://www.ncbi.nlm.nih.gov/pubmed/26382239
http://dx.doi.org/10.1371/journal.pone.0137834
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