Cargando…

Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs

BACKGROUND: Dihydroartemisinin-piperaquine (DHA-PPQ) is an alternative first-line antimalarial to artemether-lumefantrine in Kenya. However, recent reports on the emergence of PPQ resistance in Southeast Asia threaten its continued use in Kenya and Africa. In line with the policy on continued deploy...

Descripción completa

Detalles Bibliográficos
Autores principales: Wakoli, Dancan M., Ondigo, Bartholomew N., Ochora, Douglas O., Amwoma, Joseph G., Okore, Winnie, Mwakio, Edwin W., Chemwor, Gladys, Juma, Jackeline, Okoth, Raphael, Okudo, Charles, Yeda, Redemptah, Opot, Benjamin H., Cheruiyot, Agnes C., Juma, Dennis, Roth, Amanda, Ogutu, Benhards R., Boudreaux, Daniel, Andagalu, Ben, Akala, Hoseah M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9673313/
https://www.ncbi.nlm.nih.gov/pubmed/36397090
http://dx.doi.org/10.1186/s12916-022-02652-2
_version_ 1784832918145728512
author Wakoli, Dancan M.
Ondigo, Bartholomew N.
Ochora, Douglas O.
Amwoma, Joseph G.
Okore, Winnie
Mwakio, Edwin W.
Chemwor, Gladys
Juma, Jackeline
Okoth, Raphael
Okudo, Charles
Yeda, Redemptah
Opot, Benjamin H.
Cheruiyot, Agnes C.
Juma, Dennis
Roth, Amanda
Ogutu, Benhards R.
Boudreaux, Daniel
Andagalu, Ben
Akala, Hoseah M.
author_facet Wakoli, Dancan M.
Ondigo, Bartholomew N.
Ochora, Douglas O.
Amwoma, Joseph G.
Okore, Winnie
Mwakio, Edwin W.
Chemwor, Gladys
Juma, Jackeline
Okoth, Raphael
Okudo, Charles
Yeda, Redemptah
Opot, Benjamin H.
Cheruiyot, Agnes C.
Juma, Dennis
Roth, Amanda
Ogutu, Benhards R.
Boudreaux, Daniel
Andagalu, Ben
Akala, Hoseah M.
author_sort Wakoli, Dancan M.
collection PubMed
description BACKGROUND: Dihydroartemisinin-piperaquine (DHA-PPQ) is an alternative first-line antimalarial to artemether-lumefantrine in Kenya. However, recent reports on the emergence of PPQ resistance in Southeast Asia threaten its continued use in Kenya and Africa. In line with the policy on continued deployment of DHA-PPQ, it is imperative to monitor the susceptibility of Kenyan parasites to PPQ and other antimalarials. METHODS: Parasite isolates collected between 2008 and 2021 from individuals with naturally acquired P. falciparum infections presenting with uncomplicated malaria were tested for in vitro susceptibility to piperaquine, dihydroartemisinin, lumefantrine, artemether, and chloroquine using the malaria SYBR Green I method. A subset of the 2019–2021 samples was further tested for ex vivo susceptibility to PPQ using piperaquine survival assay (PSA). Each isolate was also characterized for mutations associated with antimalarial resistance in Pfcrt, Pfmdr1, Pfpm2/3, Pfdhfr, and Pfdhps genes using real-time PCR and Agena MassARRAY platform. Associations between phenotype and genotype were also determined. RESULTS: The PPQ median IC(50) interquartile range (IQR) remained stable during the study period, 32.70 nM (IQR 20.2–45.6) in 2008 and 27.30 nM (IQR 6.9–52.8) in 2021 (P=0.1615). The median ex vivo piperaquine survival rate (IQR) was 0% (0–5.27) at 95% CI. Five isolates had a PSA survival rate of ≥10%, consistent with the range of PPQ-resistant parasites, though they lacked polymorphisms in Pfmdr1 and Plasmepsin genes. Lumefantrine and artemether median IC(50)s rose significantly to 62.40 nM (IQR 26.9–100.8) (P = 0.0201); 7.00 nM (IQR 2.4–13.4) (P = 0.0021) in 2021 from 26.30 nM (IQR 5.1–64.3); and 2.70 nM (IQR 1.3–10.4) in 2008, respectively. Conversely, chloroquine median IC(50)s decreased significantly to 10.30 nM (IQR 7.2–20.9) in 2021 from 15.30 nM (IQR 7.6–30.4) in 2008, coinciding with a decline in the prevalence of Pfcrt 76T allele over time (P = 0.0357). The proportions of piperaquine-resistant markers including Pfpm2/3 and Pfmdr1 did not vary significantly. A significant association was observed between PPQ IC(50) and Pfcrt K76T allele (P=0.0026). CONCLUSIONS: Circulating Kenyan parasites have remained sensitive to PPQ and other antimalarials, though the response to artemether (ART) and lumefantrine (LM) is declining. This study forms a baseline for continued surveillance of current antimalarials for timely detection of resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02652-2.
format Online
Article
Text
id pubmed-9673313
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-96733132022-11-19 Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs Wakoli, Dancan M. Ondigo, Bartholomew N. Ochora, Douglas O. Amwoma, Joseph G. Okore, Winnie Mwakio, Edwin W. Chemwor, Gladys Juma, Jackeline Okoth, Raphael Okudo, Charles Yeda, Redemptah Opot, Benjamin H. Cheruiyot, Agnes C. Juma, Dennis Roth, Amanda Ogutu, Benhards R. Boudreaux, Daniel Andagalu, Ben Akala, Hoseah M. BMC Med Research Article BACKGROUND: Dihydroartemisinin-piperaquine (DHA-PPQ) is an alternative first-line antimalarial to artemether-lumefantrine in Kenya. However, recent reports on the emergence of PPQ resistance in Southeast Asia threaten its continued use in Kenya and Africa. In line with the policy on continued deployment of DHA-PPQ, it is imperative to monitor the susceptibility of Kenyan parasites to PPQ and other antimalarials. METHODS: Parasite isolates collected between 2008 and 2021 from individuals with naturally acquired P. falciparum infections presenting with uncomplicated malaria were tested for in vitro susceptibility to piperaquine, dihydroartemisinin, lumefantrine, artemether, and chloroquine using the malaria SYBR Green I method. A subset of the 2019–2021 samples was further tested for ex vivo susceptibility to PPQ using piperaquine survival assay (PSA). Each isolate was also characterized for mutations associated with antimalarial resistance in Pfcrt, Pfmdr1, Pfpm2/3, Pfdhfr, and Pfdhps genes using real-time PCR and Agena MassARRAY platform. Associations between phenotype and genotype were also determined. RESULTS: The PPQ median IC(50) interquartile range (IQR) remained stable during the study period, 32.70 nM (IQR 20.2–45.6) in 2008 and 27.30 nM (IQR 6.9–52.8) in 2021 (P=0.1615). The median ex vivo piperaquine survival rate (IQR) was 0% (0–5.27) at 95% CI. Five isolates had a PSA survival rate of ≥10%, consistent with the range of PPQ-resistant parasites, though they lacked polymorphisms in Pfmdr1 and Plasmepsin genes. Lumefantrine and artemether median IC(50)s rose significantly to 62.40 nM (IQR 26.9–100.8) (P = 0.0201); 7.00 nM (IQR 2.4–13.4) (P = 0.0021) in 2021 from 26.30 nM (IQR 5.1–64.3); and 2.70 nM (IQR 1.3–10.4) in 2008, respectively. Conversely, chloroquine median IC(50)s decreased significantly to 10.30 nM (IQR 7.2–20.9) in 2021 from 15.30 nM (IQR 7.6–30.4) in 2008, coinciding with a decline in the prevalence of Pfcrt 76T allele over time (P = 0.0357). The proportions of piperaquine-resistant markers including Pfpm2/3 and Pfmdr1 did not vary significantly. A significant association was observed between PPQ IC(50) and Pfcrt K76T allele (P=0.0026). CONCLUSIONS: Circulating Kenyan parasites have remained sensitive to PPQ and other antimalarials, though the response to artemether (ART) and lumefantrine (LM) is declining. This study forms a baseline for continued surveillance of current antimalarials for timely detection of resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02652-2. BioMed Central 2022-11-18 /pmc/articles/PMC9673313/ /pubmed/36397090 http://dx.doi.org/10.1186/s12916-022-02652-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Wakoli, Dancan M.
Ondigo, Bartholomew N.
Ochora, Douglas O.
Amwoma, Joseph G.
Okore, Winnie
Mwakio, Edwin W.
Chemwor, Gladys
Juma, Jackeline
Okoth, Raphael
Okudo, Charles
Yeda, Redemptah
Opot, Benjamin H.
Cheruiyot, Agnes C.
Juma, Dennis
Roth, Amanda
Ogutu, Benhards R.
Boudreaux, Daniel
Andagalu, Ben
Akala, Hoseah M.
Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs
title Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs
title_full Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs
title_fullStr Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs
title_full_unstemmed Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs
title_short Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs
title_sort impact of parasite genomic dynamics on the sensitivity of plasmodium falciparum isolates to piperaquine and other antimalarial drugs
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9673313/
https://www.ncbi.nlm.nih.gov/pubmed/36397090
http://dx.doi.org/10.1186/s12916-022-02652-2
work_keys_str_mv AT wakolidancanm impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT ondigobartholomewn impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT ochoradouglaso impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT amwomajosephg impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT okorewinnie impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT mwakioedwinw impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT chemworgladys impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT jumajackeline impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT okothraphael impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT okudocharles impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT yedaredemptah impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT opotbenjaminh impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT cheruiyotagnesc impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT jumadennis impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT rothamanda impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT ogutubenhardsr impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT boudreauxdaniel impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT andagaluben impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs
AT akalahoseahm impactofparasitegenomicdynamicsonthesensitivityofplasmodiumfalciparumisolatestopiperaquineandotherantimalarialdrugs