Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana

Malaria Journal

Research

Michael Alifrangis¹  Rasmus Weisel Jensen¹  Helle Hansson¹  Christian William Wang¹  George Obeng Adjei²  Edmund Tetteh Nartey²  William Kudzi²  Samuel Yao Ahorhorlu³  Neils Ben Quashie³  Felix Zoiku⁴  Nancy Odurowah Duah-Quashie⁵  Bartholomew Dzudzor⁶ 

[1]Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark

[2]Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark

[3]Centre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of Ghana, P.O. Box 4236, Accra, Ghana

[4]Centre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, University of Ghana, P.O. Box 4236, Accra, Ghana

[5]West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Accra, Ghana

[6]Department of Epidemiology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana

[7]Department of Epidemiology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana

[8]West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Accra, Ghana

[9]Department of Medical Biochemistry, University of Ghana Medical School, University of Ghana, Accra, Ghana

关键词: Artemisinin tolerance;    Plasmodium falciparum;    Uncomplicated Malaria;    Ex vivo ring-stage survival assay;    Kelch 13;    Pfcoronin;    Ghana;   

DOI  :  10.1186/s12936-023-04482-w

 received in 2022-11-22, accepted in 2023-02-04,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundArtemisinin-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.MethodsSix 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.ResultsOf 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.ConclusionsThe 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.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 2