Background The devastating public health impact of malaria has prompted the need for effective interventions. Malaria control gained traction after the introduction of artemisinin-based combination therapy (ACT). However, the emergence of artemisinin (ART) partial resistance in Southeast Asia and emerging reports of delayed parasite sensitivity to ACT in African parasites signal a gradual trend towards treatment failure. Monitoring the prevalence of mutations associated with artemisinin resistance in African populations is necessary to stop resistance in its tracks. Mutations in Plasmodium falciparum genes pfk13, pfcoronin and pfatpase6 have been linked with ART partial resistance. Methods Findings from published research articles on the prevalence of pfk13, pfcoronin and pfatpase6 polymorphisms in Africa were collated. PubMed, Embase and Google Scholar were searched for relevant articles reporting polymorphisms in these genes across Africa from 2014 to August 2021, for pfk13 and pfcoronin. For pfatpase6, relevant articles between 2003 and August 2021 were retrieved. Results Eighty-seven studies passed the inclusion criteria for this analysis and reported 742 single nucleotide polymorphisms in 37,864 P. falciparum isolates from 29 African countries. Five validated-pfk13 partial resistance markers were identified in Africa: R561H in Rwanda and Tanzania, M476I in Tanzania, F446I in Mali, C580Y in Ghana, and P553L in an Angolan isolate. In Tanzania, three (L263E, E431K, S769N) of the four mutations (L263E, E431K, A623E, S769N) in pfatpase6 gene associated with high in vitro IC50 were reported. pfcoronin polymorphisms were reported in Senegal, Gabon, Ghana, Kenya, and Congo, with P76S being the most prevalent mutation. Conclusions This meta-analysis provides an overview of the prevalence and widespread distribution of pfk13, pfcoronin and pfatpase6 mutations in Africa. Understanding the phenotypic consequences of these mutations can provide information on the efficacy status of artemisinin-based treatment of malaria across the continent. Graphical Abstract

The devastating public health impact of malaria has prompted the need for effective interventions. Malaria control gained traction after the introduction of artemisinin-based combination therapies (ACTs). However, the emergence of artemisinin (ART) resistance in South-East Asia and reports of delayed parasite sensitivity to ACTs in African parasites signal an imminent treatment failure. Monitoring the prevalence of mutations associated with artemisinin resistance in African populations is required to stop resistance in its tracks. Plasmodium falciparum Kelch-13 (Pfk13), Pfcoronin and PfATPase6 gene mutations have been associated with ART resistance. In this review, we collated findings from published research articles to establish the prevalence of Pfk13, Pfcoronin and PfATPase6 polymorphisms in Africa. We searched PubMed, Embase and Google Scholar for relevant articles reporting polymorphisms in these genes across Africa between 2014 to 2021. Seventy-two studies which passed the inclusion criteria reported 739 single nucleotide polymorphisms (331 unique variants) from 34,353 samples collected in 26 African countries. Four validated Pfk13 resistant markers linked with delayed parasite clearance were identified in Africa: R561H in Rwanda and Tanzania, M476I in Tanzania, and F446I in Mali, and P553L in Angola. In Tanzania, three (L263E, E431K, and S769N) of the four mutations (L263E, E431K, A623E, and S769N) in PfATPase6 gene previously associated with delayed parasite clearance in presence of artemisinin were reported. Pfcoronin polymorphisms were reported in Senegal, Gabon, Ghana, Kenya and Congo, with P76S being the most prevalent Pfcoronin mutation. Our findings demonstrate independent emergence and widespread distribution of Pfk13, Pfcoronin and PfATPase6 mutations in Africa. Understanding the phenotypic consequences of these mutations can provide information on the efficacy status of artemisinin-based treatment of malaria in Africa.