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Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations

BACKGROUND: The declining efficacy of dihydroartemisinin-piperaquine against Plasmodium falciparum in Cambodia, along with increasing numbers of recrudescent cases, suggests resistance to both artemisinin and piperaquine. Available in vitro piperaquine susceptibility assays do not correlate with tre...

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Autores principales: Duru, Valentine, Khim, Nimol, Leang, Rithea, Kim, Saorin, Domergue, Anais, Kloeung, Nimol, Ke, Sopheakvatey, Chy, Sophy, Eam, Rotha, Khean, Chanra, Loch, Kaknika, Ken, Malen, Lek, Dysoley, Beghain, Johann, Ariey, Frédéric, Guerin, Philippe J., Huy, Rekol, Mercereau-Puijalon, Odile, Witkowski, Benoit, Menard, Didier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688949/
https://www.ncbi.nlm.nih.gov/pubmed/26695060
http://dx.doi.org/10.1186/s12916-015-0539-5
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author Duru, Valentine
Khim, Nimol
Leang, Rithea
Kim, Saorin
Domergue, Anais
Kloeung, Nimol
Ke, Sopheakvatey
Chy, Sophy
Eam, Rotha
Khean, Chanra
Loch, Kaknika
Ken, Malen
Lek, Dysoley
Beghain, Johann
Ariey, Frédéric
Guerin, Philippe J.
Huy, Rekol
Mercereau-Puijalon, Odile
Witkowski, Benoit
Menard, Didier
author_facet Duru, Valentine
Khim, Nimol
Leang, Rithea
Kim, Saorin
Domergue, Anais
Kloeung, Nimol
Ke, Sopheakvatey
Chy, Sophy
Eam, Rotha
Khean, Chanra
Loch, Kaknika
Ken, Malen
Lek, Dysoley
Beghain, Johann
Ariey, Frédéric
Guerin, Philippe J.
Huy, Rekol
Mercereau-Puijalon, Odile
Witkowski, Benoit
Menard, Didier
author_sort Duru, Valentine
collection PubMed
description BACKGROUND: The declining efficacy of dihydroartemisinin-piperaquine against Plasmodium falciparum in Cambodia, along with increasing numbers of recrudescent cases, suggests resistance to both artemisinin and piperaquine. Available in vitro piperaquine susceptibility assays do not correlate with treatment outcome. A novel assay using a pharmacologically relevant piperaquine dose/time exposure was designed and its relevance explored in retrospective and prospective studies. METHODS: The piperaquine survival assay (PSA) exposed parasites to 200 nM piperaquine for 48 hours and monitored survival 24 hours later. The retrospective study tested 32 culture-adapted, C580Y-K13 mutant parasites collected at enrolment from patients treated with a 3-day course of dihydroartemisinin-piperaquine and having presented or not with a recrudescence at day 42 (registered ACTRN12615000793516). The prospective study assessed ex vivo PSA survival rate alongside K13 polymorphism of isolates collected from patients enrolled in an open-label study with dihydroartemisinin-piperaquine for uncomplicated P. falciparum malaria in Cambodia (registered ACTRN12615000696594). RESULTS: All parasites from recrudescent cases had in vitro or ex vivo PSA survival rates ≥10 %, a relevant cut-off value for piperaquine-resistance. Ex vivo PSA survival rates were higher for recrudescent than non-recrudescent cases (39.2 % vs. 0.17 %, P <1 × 10(−7)). Artemisinin-resistant K13 mutants with ex vivo PSA survival rates ≥10 % were associated with 32-fold higher risk of recrudescence (95 % CI, 4.5–224; P = 0.0005). CONCLUSION: PSA adequately captures the piperaquine resistance/recrudescence phenotype, a mainstay to identify molecular marker(s) and evaluate efficacy of alternative drugs. Combined ex vivo PSA and K13 genotyping provides a convenient monitor for both artemisinin and piperaquine resistance where dihydroartemisinin-piperaquine is used. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-015-0539-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-46889492015-12-24 Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations Duru, Valentine Khim, Nimol Leang, Rithea Kim, Saorin Domergue, Anais Kloeung, Nimol Ke, Sopheakvatey Chy, Sophy Eam, Rotha Khean, Chanra Loch, Kaknika Ken, Malen Lek, Dysoley Beghain, Johann Ariey, Frédéric Guerin, Philippe J. Huy, Rekol Mercereau-Puijalon, Odile Witkowski, Benoit Menard, Didier BMC Med Research Article BACKGROUND: The declining efficacy of dihydroartemisinin-piperaquine against Plasmodium falciparum in Cambodia, along with increasing numbers of recrudescent cases, suggests resistance to both artemisinin and piperaquine. Available in vitro piperaquine susceptibility assays do not correlate with treatment outcome. A novel assay using a pharmacologically relevant piperaquine dose/time exposure was designed and its relevance explored in retrospective and prospective studies. METHODS: The piperaquine survival assay (PSA) exposed parasites to 200 nM piperaquine for 48 hours and monitored survival 24 hours later. The retrospective study tested 32 culture-adapted, C580Y-K13 mutant parasites collected at enrolment from patients treated with a 3-day course of dihydroartemisinin-piperaquine and having presented or not with a recrudescence at day 42 (registered ACTRN12615000793516). The prospective study assessed ex vivo PSA survival rate alongside K13 polymorphism of isolates collected from patients enrolled in an open-label study with dihydroartemisinin-piperaquine for uncomplicated P. falciparum malaria in Cambodia (registered ACTRN12615000696594). RESULTS: All parasites from recrudescent cases had in vitro or ex vivo PSA survival rates ≥10 %, a relevant cut-off value for piperaquine-resistance. Ex vivo PSA survival rates were higher for recrudescent than non-recrudescent cases (39.2 % vs. 0.17 %, P <1 × 10(−7)). Artemisinin-resistant K13 mutants with ex vivo PSA survival rates ≥10 % were associated with 32-fold higher risk of recrudescence (95 % CI, 4.5–224; P = 0.0005). CONCLUSION: PSA adequately captures the piperaquine resistance/recrudescence phenotype, a mainstay to identify molecular marker(s) and evaluate efficacy of alternative drugs. Combined ex vivo PSA and K13 genotyping provides a convenient monitor for both artemisinin and piperaquine resistance where dihydroartemisinin-piperaquine is used. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-015-0539-5) contains supplementary material, which is available to authorized users. BioMed Central 2015-12-22 /pmc/articles/PMC4688949/ /pubmed/26695060 http://dx.doi.org/10.1186/s12916-015-0539-5 Text en © Duru et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Duru, Valentine
Khim, Nimol
Leang, Rithea
Kim, Saorin
Domergue, Anais
Kloeung, Nimol
Ke, Sopheakvatey
Chy, Sophy
Eam, Rotha
Khean, Chanra
Loch, Kaknika
Ken, Malen
Lek, Dysoley
Beghain, Johann
Ariey, Frédéric
Guerin, Philippe J.
Huy, Rekol
Mercereau-Puijalon, Odile
Witkowski, Benoit
Menard, Didier
Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations
title Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations
title_full Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations
title_fullStr Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations
title_full_unstemmed Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations
title_short Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations
title_sort plasmodium falciparum dihydroartemisinin-piperaquine failures in cambodia are associated with mutant k13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688949/
https://www.ncbi.nlm.nih.gov/pubmed/26695060
http://dx.doi.org/10.1186/s12916-015-0539-5
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