Prevalence of potential mediators of artemisinin resistance in African isolates of Plasmodium falciparum

Abstract

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.

Keywords: Africa; Artemisinin-based combination therapy; Kelch-13; Mutations; Partial resistance; Pfcoronin; Plasmodium falciparum; pfatpase6.

Fig. 1

Year of publication of research articles reporting Pfk13, Pfcoronin and PfATPase6 gene mutations. The coloured dots represent the number of publications reporting polymorphisms in the Pfk13, Pfcoronin and PfATPase6 genes

Fig. 2

Year of molecular surveillance for Pfk13, Pfcoronin and PfATPase6 gene mutations. The coloured dots represent the number of sites included in the Pfk13, Pfcoronin and PfATPase6 studies

Fig. 3

Demography of research articles reporting Pfk13, Pfcoronin and PfATPase6 gene mutations. a First author affiliation, b Last author affiliation, c Where research funding came from d Sampling technique, e Clinical status, f Parasite detection and/or quantitation assays (PCR = polymerase chain reaction; RT-qPCR = real-time quantitative PCR; PET = photo-induced electron transfer)

Fig. 4

Study selection criteria

Fig. 5

Distribution of unique non-synonymous P. falciparum Kelch-13 single nucleotide polymorphisms (SNPs) in African countries [–, –, , , –, –68, 73, 74]

Fig. 6

Number of P. falciparum isolates with Pfcoronin P76S mutation in Africa [16, 19, 21]