Distribution and Contribution of K13-propeller Gene to Artemisinin Resistance in sub-Saharan Africa: A Systematic Review

Abstract

The observed clinical failure after treatment with artemisinin combination therapy (ACT) has recently been confirmed in western Cambodia. Evidence of declining ACT efficacy has also been reported in Africa. Molecular markers for artemisinin resistance have played an essential role in monitoring the spread of the resistant phenotype and identifying the mechanisms of resistance. Several candidate genes, including the P. falciparum kelch propeller region (K13). However, in sub-Saharan Africa, despite the observed delayed clearance after treatment, the association between ART resistance and K13 gene is questionable as studies have not found significant mutations or an association with the delayed parasite clearance rate following ACT treatment. There is need for more data to clarify the significance of K13-propeller mutations as markers of artemisinin resistance in Africa. An electronic search of studies in sub-Saharan Africa from 2014 to date was done via PubMED, SCOPUS, and EMBASE databases. The search was conducted independently by two librarians. The articles were screened for selection using a priori criteria set following PRISMAP and STREGA guidelines. Data analysis was performed in R-statistics software. A total of 197 articles were identified from Pubmed= 139, Research gate=40, Bibliography/other searches=18, of which 102 did not meet the selection criteria. A total of 74 independent K13 mutations were identified across malaria-affected African countries. Only 7 unconfirmed K13 mutations were associated with delayed parasite clearance half-life (t1/2>3 h). The majority, 47.5% (35/74), of the mutations were reported in single P. falciparum parasite isolate. Of the 74 K13-mutations, nearly two-thirds were reported as new alleles. Twenty-seven (27) non-synonymous mutations in the Pfkelch13 gene were identified. Although artemisinin resistance in SouthEast Asia seems to be a heritable genetic trait, none of the candidate genes suggested by earlier studies confer artemisinin resistance to the observed clinical failure in Africa. Mutations outside the Pfkelch13 propeller region associated with increased ART parasite clearance half-life occur in malaria-affected regions in Africa. The use of a genome-wide approach by whole genome sequencing and gene expression transcriptome studies to identify the molecular basis of artemisinin resistance is warranted to aid in identification potential markers for ACT resistance in Africa.