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Background  Efficacy of artemisinin (ART) agents, a critical element of current malaria control efforts is threatened by emergence and spread of resistance. Mutations in  pfkelch13  gene associated with ART-resistance evolved in Southeast Asia (SEA).  k13  mutations whose role in ART-resistance remains unknown, have subsequently emerged independently across all malaria-affected regions. The aim of this systematic review was to determine the prevalence and identify risk factors of  Plasmodium falciparum k13  mutations in malaria-endemic countries.    Methods  An electronic search of studies from 2014 to date was done in MEDLINE via PubMED, SCOPUS, EMBASE and LILACS/VHL databases. Mesh terms and Boolean operators (AND, OR) were used. Two librarians independently conducted this search (RS and AK). The articles were screened for inclusion using a priori criteria set following PRISMA-P and STREGA guidelines. Three independent reviewers (NL, BB, and OM) extracted the data. Data analysis was performed in Open Meta Analyst software. Random effects analysis (DL) was used and heterogeneity established using I 2 -statistic.    Results  A total of 482 articles were retrieved from Pubmed = 302, Lilacs/Vhl = 50, Embase = 80, and Scopus = 37; Bibliography/other searches = 13, of which 374 did not meet the inclusion criteria. The aggregate prevalence of single nucleotide polymorphisms (SNPs) in  pfkelch13  gene was 27.6% (3694/14,827) (95% CI 22.9%, 32.3%). Sub-group analysis showed that aggregate prevalence of non-synonymous SNPs in  pfkelch13  gene was higher, 45.4% (95% CI 35.4%, 55.3%) in Southeast Asia as opposed to 7.6% (95% CI 5.6%, 9.5%) in the African region. A total of 165 independent  k13  mutations were identified across malaria-affected regions globally. A total of 16 non-validated  k13  mutations were associated with increased ART parasite clearance half-life (t 1/2  > 5 h). The majority, 45.5% (75/165), of the mutations were reported in single  P. falciparum  parasite infections. Of the 165  k13 -mutations, over half were reported as new alleles. Twenty (20) non-propeller mutations in the  pfkelch13  gene were identified.    Conclusion  This review identified emergence of potential ART-resistance mediating  k13  mutations in the African region. Diversity of mutations in  pfkelch13  gene is highest in African region compared to SEA. Mutations outside the  pfkelch13  propeller region associated with increased ART parasite clearance half-life occur in malaria-affected regions.

malaria journal

K13-propeller gene polymorphisms in Plasmodium falciparum parasite population in malaria affected countries: a systematic review of prevalence and risk factors