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Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy

BACKGROUND: The PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monoth...

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Autores principales: Dunn, David T., Stöhr, Wolfgang, Arenas-Pinto, Alejandro, Tostevin, Anna, Mbisa, Jean L., Paton, Nicholas I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861306/
https://www.ncbi.nlm.nih.gov/pubmed/29428459
http://dx.doi.org/10.1016/j.jcv.2018.02.003
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author Dunn, David T.
Stöhr, Wolfgang
Arenas-Pinto, Alejandro
Tostevin, Anna
Mbisa, Jean L.
Paton, Nicholas I.
author_facet Dunn, David T.
Stöhr, Wolfgang
Arenas-Pinto, Alejandro
Tostevin, Anna
Mbisa, Jean L.
Paton, Nicholas I.
author_sort Dunn, David T.
collection PubMed
description BACKGROUND: The PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monotherapy experienced a loss of drug options due to protease mutations (identified by local Sanger sequencing resistance tests) likely selected by study drug. OBJECTIVES: To assess if we had missed low frequency mutations, using a more sensitive methodology. STUDY DESIGN: We performed next generation sequencing (NGS) on all available frozen plasma samples with VL >1000 copies/ml from patients who were randomised to PI monotherapy. Assays were performed at Public Health England laboratories using a previously described method. Median coverage depth was 76,000 and the threshold for detection of minority variants was 2%. Drug susceptibility was predicted using the Stanford HIVdb algorithm. RESULTS: 17 of 26 potential samples, all from different patients, were identified and successfully tested. The median viral load was 6780 copies/ml and the median time since randomisation was 43 weeks. NGS revealed previously unidentified minority variant protease mutations (G73D, I54T, L89V) in three samples, at frequencies ranging between 2% and 10%. None of these mutations predicted intermediate or high level resistance, the trial primary outcome. DISCUSSION: This report adds to the body of evidence that ritonavir-boosted PI monotherapy, when used as a switch strategy with prompt detection of viral load rebound and early re-introduction of combination therapy, rarely leads to the development of clinically important protease resistance mutations.
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spelling pubmed-58613062018-04-01 Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy Dunn, David T. Stöhr, Wolfgang Arenas-Pinto, Alejandro Tostevin, Anna Mbisa, Jean L. Paton, Nicholas I. J Clin Virol Article BACKGROUND: The PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monotherapy experienced a loss of drug options due to protease mutations (identified by local Sanger sequencing resistance tests) likely selected by study drug. OBJECTIVES: To assess if we had missed low frequency mutations, using a more sensitive methodology. STUDY DESIGN: We performed next generation sequencing (NGS) on all available frozen plasma samples with VL >1000 copies/ml from patients who were randomised to PI monotherapy. Assays were performed at Public Health England laboratories using a previously described method. Median coverage depth was 76,000 and the threshold for detection of minority variants was 2%. Drug susceptibility was predicted using the Stanford HIVdb algorithm. RESULTS: 17 of 26 potential samples, all from different patients, were identified and successfully tested. The median viral load was 6780 copies/ml and the median time since randomisation was 43 weeks. NGS revealed previously unidentified minority variant protease mutations (G73D, I54T, L89V) in three samples, at frequencies ranging between 2% and 10%. None of these mutations predicted intermediate or high level resistance, the trial primary outcome. DISCUSSION: This report adds to the body of evidence that ritonavir-boosted PI monotherapy, when used as a switch strategy with prompt detection of viral load rebound and early re-introduction of combination therapy, rarely leads to the development of clinically important protease resistance mutations. Elsevier Science 2018-04 /pmc/articles/PMC5861306/ /pubmed/29428459 http://dx.doi.org/10.1016/j.jcv.2018.02.003 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dunn, David T.
Stöhr, Wolfgang
Arenas-Pinto, Alejandro
Tostevin, Anna
Mbisa, Jean L.
Paton, Nicholas I.
Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy
title Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy
title_full Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy
title_fullStr Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy
title_full_unstemmed Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy
title_short Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy
title_sort next generation sequencing of hiv-1 protease in the pivot trial of protease inhibitor monotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861306/
https://www.ncbi.nlm.nih.gov/pubmed/29428459
http://dx.doi.org/10.1016/j.jcv.2018.02.003
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