Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs
Abstract 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 continue...
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-022-02652-2 |
| _version_ | 1798016863024709632 |
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| author | Dancan M. Wakoli Bartholomew N. Ondigo Douglas O. Ochora Joseph G. Amwoma Winnie Okore Edwin W. Mwakio Gladys Chemwor Jackeline Juma Raphael Okoth Charles Okudo Redemptah Yeda Benjamin H. Opot Agnes C. Cheruiyot Dennis Juma Amanda Roth Benhards R. Ogutu Daniel Boudreaux Ben Andagalu Hoseah M. Akala |
| author_facet | Dancan M. Wakoli Bartholomew N. Ondigo Douglas O. Ochora Joseph G. Amwoma Winnie Okore Edwin W. Mwakio Gladys Chemwor Jackeline Juma Raphael Okoth Charles Okudo Redemptah Yeda Benjamin H. Opot Agnes C. Cheruiyot Dennis Juma Amanda Roth Benhards R. Ogutu Daniel Boudreaux Ben Andagalu Hoseah M. Akala |
| author_sort | Dancan M. Wakoli |
| collection | DOAJ |
| description | Abstract 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 IC50 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 IC50s 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 IC50s 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 IC50 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. |
| first_indexed | 2024-04-11T15:57:26Z |
| format | Article |
| id | doaj.art-f4342a5daf924e1da218017f3888927d |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-11T15:57:26Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-f4342a5daf924e1da218017f3888927d2022-12-22T04:15:08ZengBMCBMC Medicine1741-70152022-11-0120111510.1186/s12916-022-02652-2Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugsDancan M. Wakoli0Bartholomew N. Ondigo1Douglas O. Ochora2Joseph G. Amwoma3Winnie Okore4Edwin W. Mwakio5Gladys Chemwor6Jackeline Juma7Raphael Okoth8Charles Okudo9Redemptah Yeda10Benjamin H. Opot11Agnes C. Cheruiyot12Dennis Juma13Amanda Roth14Benhards R. Ogutu15Daniel Boudreaux16Ben Andagalu17Hoseah M. Akala18Department of Biochemistry and Molecular Biology, Egerton UniversityDepartment of Biochemistry and Molecular Biology, Egerton UniversityDepartment of Plant Sciences, Microbiology & Biotechnology, College of Natural Sciences, Makerere UniversityDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectDepartment of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/ Walter Reed ProjectAbstract 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 IC50 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 IC50s 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 IC50s 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 IC50 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.https://doi.org/10.1186/s12916-022-02652-2Artemisinin combined therapyAntimalarialDrug resistanceSensitivityGenomicPlasmodium falciparum |
| spellingShingle | Dancan M. Wakoli Bartholomew N. Ondigo Douglas O. Ochora Joseph G. Amwoma Winnie Okore Edwin W. Mwakio Gladys Chemwor Jackeline Juma Raphael Okoth Charles Okudo Redemptah Yeda Benjamin H. Opot Agnes C. Cheruiyot Dennis Juma Amanda Roth Benhards R. Ogutu Daniel Boudreaux Ben Andagalu Hoseah M. Akala Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs BMC Medicine Artemisinin combined therapy Antimalarial Drug resistance Sensitivity Genomic Plasmodium falciparum |
| 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 | Artemisinin combined therapy Antimalarial Drug resistance Sensitivity Genomic Plasmodium falciparum |
| url | https://doi.org/10.1186/s12916-022-02652-2 |
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