Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana
Abstract Background Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria in Ghana. Artemisinin (ART) tolerance in Plasmodium falciparum has arisen in Southeast Asia and recently, in parts of East Africa. This is ascribed to the survival of ring-stage para...
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Malaria Journal |
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| Online Access: | https://doi.org/10.1186/s12936-023-04482-w |
| _version_ | 1797865519028633600 |
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| author | Samuel Yao Ahorhorlu Neils Ben Quashie Rasmus Weisel Jensen William Kudzi Edmund Tetteh Nartey Nancy Odurowah Duah-Quashie Felix Zoiku Bartholomew Dzudzor Christian William Wang Helle Hansson Michael Alifrangis George Obeng Adjei |
| author_facet | Samuel Yao Ahorhorlu Neils Ben Quashie Rasmus Weisel Jensen William Kudzi Edmund Tetteh Nartey Nancy Odurowah Duah-Quashie Felix Zoiku Bartholomew Dzudzor Christian William Wang Helle Hansson Michael Alifrangis George Obeng Adjei |
| author_sort | Samuel Yao Ahorhorlu |
| collection | DOAJ |
| description | Abstract Background Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria in Ghana. Artemisinin (ART) tolerance in Plasmodium falciparum has arisen in Southeast Asia and recently, in parts of East Africa. This is ascribed to the survival of ring-stage parasites post treatment. The present study sought to assess and characterize correlates of potential ART tolerance based on post-treatment parasite clearance, ex vivo and in vitro drug sensitivity, and molecular markers of drug resistance in P. falciparum isolates from children with uncomplicated malaria in Ghana. Methods Six months to fourteen years old children presenting with acute uncomplicated malaria (n = 115) were enrolled in two hospitals and a Health Centre in Ghana’s Greater Accra region and treated with artemether-lumefantrine (AL) according to body weight. Pre- and post-treatment parasitaemia (day 0 and day 3) was confirmed by microscopy. The ex vivo ring-stage survival assay (RSA) was used to detect percent ring survival while the 72 h SYBR Green I assay was used to measure the 50% inhibition concentration (IC50s) of ART and its derivatives and partner drugs. Genetic markers of drug tolerance /resistance were evaluated using selective whole genome sequencing. Results Of the total of 115 participants, 85 were successfully followed up on day 3 post-treatment and 2/85 (2.4%) had parasitaemia. The IC50 values of ART, artesunate (AS), artemether (AM), dihydroartemisinin (DHA), amodiaquine (AQ), and lumefantrine (LUM) were not indicative of drug tolerance. However, 7/90 (7.8%) pre-treatment isolates had > 10% ring survival rates against DHA. Of the four isolates (2 RSA positive and 2 RSA negative) with high genomic coverage, P. falciparum (Pf) kelch 13 K188* and Pfcoronin V424I mutations were only present in the two RSA positive isolates with > 10% ring survival rates. Conclusions The observed low proportion of participants with day-3 post-treatment parasitaemia is consistent with rapid ART clearance. However, the increased rates of survival observed in the ex vivo RSA against DHA, maybe a pointer of an early start of ART tolerance. Furthermore, the role of two novel mutations in PfK13 and Pfcoronin genes, harboured by the two RSA positive isolates that had high ring survival in the present study, remains to be elucidated. |
| first_indexed | 2024-04-09T23:09:22Z |
| format | Article |
| id | doaj.art-0f1bf3d93df0480cbd14c851c58ddac4 |
| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-04-09T23:09:22Z |
| publishDate | 2023-02-01 |
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| record_format | Article |
| series | Malaria Journal |
| spelling | doaj.art-0f1bf3d93df0480cbd14c851c58ddac42023-03-22T10:28:52ZengBMCMalaria Journal1475-28752023-02-0122111010.1186/s12936-023-04482-wAssessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in GhanaSamuel Yao Ahorhorlu0Neils Ben Quashie1Rasmus Weisel Jensen2William Kudzi3Edmund Tetteh Nartey4Nancy Odurowah Duah-Quashie5Felix Zoiku6Bartholomew Dzudzor7Christian William Wang8Helle Hansson9Michael Alifrangis10George Obeng Adjei11Centre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of GhanaCentre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of GhanaCentre for Medical Parasitology, Department of Immunology and Microbiology, University of CopenhagenCentre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of GhanaCentre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of GhanaDepartment of Epidemiology, Noguchi Memorial Institute for Medical Research, University of GhanaDepartment of Epidemiology, Noguchi Memorial Institute for Medical Research, University of GhanaDepartment of Medical Biochemistry, University of Ghana Medical School, University of GhanaCentre for Medical Parasitology, Department of Immunology and Microbiology, University of CopenhagenCentre for Medical Parasitology, Department of Immunology and Microbiology, University of CopenhagenCentre for Medical Parasitology, Department of Immunology and Microbiology, University of CopenhagenCentre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of GhanaAbstract Background Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria in Ghana. Artemisinin (ART) tolerance in Plasmodium falciparum has arisen in Southeast Asia and recently, in parts of East Africa. This is ascribed to the survival of ring-stage parasites post treatment. The present study sought to assess and characterize correlates of potential ART tolerance based on post-treatment parasite clearance, ex vivo and in vitro drug sensitivity, and molecular markers of drug resistance in P. falciparum isolates from children with uncomplicated malaria in Ghana. Methods Six months to fourteen years old children presenting with acute uncomplicated malaria (n = 115) were enrolled in two hospitals and a Health Centre in Ghana’s Greater Accra region and treated with artemether-lumefantrine (AL) according to body weight. Pre- and post-treatment parasitaemia (day 0 and day 3) was confirmed by microscopy. The ex vivo ring-stage survival assay (RSA) was used to detect percent ring survival while the 72 h SYBR Green I assay was used to measure the 50% inhibition concentration (IC50s) of ART and its derivatives and partner drugs. Genetic markers of drug tolerance /resistance were evaluated using selective whole genome sequencing. Results Of the total of 115 participants, 85 were successfully followed up on day 3 post-treatment and 2/85 (2.4%) had parasitaemia. The IC50 values of ART, artesunate (AS), artemether (AM), dihydroartemisinin (DHA), amodiaquine (AQ), and lumefantrine (LUM) were not indicative of drug tolerance. However, 7/90 (7.8%) pre-treatment isolates had > 10% ring survival rates against DHA. Of the four isolates (2 RSA positive and 2 RSA negative) with high genomic coverage, P. falciparum (Pf) kelch 13 K188* and Pfcoronin V424I mutations were only present in the two RSA positive isolates with > 10% ring survival rates. Conclusions The observed low proportion of participants with day-3 post-treatment parasitaemia is consistent with rapid ART clearance. However, the increased rates of survival observed in the ex vivo RSA against DHA, maybe a pointer of an early start of ART tolerance. Furthermore, the role of two novel mutations in PfK13 and Pfcoronin genes, harboured by the two RSA positive isolates that had high ring survival in the present study, remains to be elucidated.https://doi.org/10.1186/s12936-023-04482-wArtemisinin tolerancePlasmodium falciparumUncomplicated MalariaEx vivo ring-stage survival assayKelch 13Pfcoronin |
| spellingShingle | Samuel Yao Ahorhorlu Neils Ben Quashie Rasmus Weisel Jensen William Kudzi Edmund Tetteh Nartey Nancy Odurowah Duah-Quashie Felix Zoiku Bartholomew Dzudzor Christian William Wang Helle Hansson Michael Alifrangis George Obeng Adjei Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana Malaria Journal Artemisinin tolerance Plasmodium falciparum Uncomplicated Malaria Ex vivo ring-stage survival assay Kelch 13 Pfcoronin |
| title | Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana |
| title_full | Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana |
| title_fullStr | Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana |
| title_full_unstemmed | Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana |
| title_short | Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana |
| title_sort | assessment of artemisinin tolerance in plasmodium falciparum clinical isolates in children with uncomplicated malaria in ghana |
| topic | Artemisinin tolerance Plasmodium falciparum Uncomplicated Malaria Ex vivo ring-stage survival assay Kelch 13 Pfcoronin |
| url | https://doi.org/10.1186/s12936-023-04482-w |
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