Review
Spatial and molecular mapping of Pfkelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: a systematic review

https://doi.org/10.1016/S1473-3099(20)30493-XGet rights and content

Summary

The spread of Plasmodium falciparum isolates carrying mutations in the kelch13 (Pfkelch13) gene associated with artemisinin resistance (PfART-R) in southeast Asia threatens malaria control and elimination efforts. Emergence of PfART-R in Africa would result in a major public health problem. In this systematic review, we investigate the frequency and spatial distribution of Pfkelch13 mutants in Africa, including mutants linked to PfART-R in southeast Asia. Seven databases were searched (PubMed, Embase, Scopus, African Journal Online, African Index Medicus, Bioline, and Web of Science) for relevant articles about polymorphisms of the Pfkelch13 gene in Africa before January, 2019. Following PRISMA guidelines, 53 studies that sequenced the Pfkelch13 gene of 23 100 sample isolates in 41 sub-Saharan African countries were included. The Pfkelch13 sequence was highly polymorphic (292 alleles, including 255 in the Pfkelch13-propeller domain) but with mutations occurring at very low relative frequencies. Non-synonymous mutations were found in only 626 isolates (2·7%) from west, central, and east Africa. According to WHO, nine different mutations linked to PfART-R in southeast Asia (Phe446Ile, Cys469Tyr, Met476Ile, Arg515Lys, Ser522Cys, Pro553Leu, Val568Gly, Pro574Leu, and Ala675Val) were detected, mainly in east Africa. Several other Pfkelch13 mutations, such as those structurally similar to southeast Asia PfART-R mutations, were also identified, but their relevance for drug resistance is still unknown. This systematic review shows that Africa, thought to not have established PfART-R, reported resistance-related mutants in the past 5 years. Surveillance using PfART-R molecular markers can provide valuable decision-making information to sustain the effectiveness of artemisinin in Africa.

Introduction

An estimated 219 million new malaria cases and 435 000 deaths occurred globally in 2017, with more than 75% of these cases coming from Africa.1 In the absence of an effective vaccine, reducing the burden of Plasmodium falciparum malaria relies on the effectiveness of artemisinin-based combination therapies (ACTs).1, 2 ACTs combine the rapid antimalarial action (but short half-life) of artemisinin or its derivatives with the slower action (but longer half-life) of partner drugs.3 However, one major challenge for malaria control and elimination efforts is the emergence and spread of P falciparum artemisinin resistance (PfART-R) from the Greater Mekong subregion in southeast Asia over the past decade.4, 5, 6

A reverse migration of PfART-R resistance towards Africa (by comparison with the evolutionary origin and spread of the parasite)7 is a troubling scenario that could have severe consequences on the burden of malaria because alternative therapies are few.8, 9, 10 As this resistance is not yet established in Africa, monitoring PfART-R on the continent is necessary from a global health perspective.9 Therapeutic efficacy trials are the standard method for assessing PfART-R; however, insufficient funding restricts these studies in African countries.3, 11, 12 The delayed parasite clearance obtained in clinical trials and the in-vitro ring-stage (trophozoite) survival assay are also useful for tracking the emergence of artemisinin resistance.5, 13, 14, 15

The association of specific single nucleotide polymorphisms (SNPs) in the P falciparum kelch 13 gene (Pfkelch13) with delayed parasite clearance has raised the potential of molecular markers for the surveillance of PfART-R.14, 16, 17 More than 100 Pfkelch13 mutations have been reported in Africa, but there is still little evidence of PfART-R mutants circulating in the continent.9, 18 In this systematic review, we examine studies reporting Pfkelch13 SNPs across different African countries to determine the relative frequencies and spatial distribution of parasites carrying mutations currently considered to be PfART-R markers.

Section snippets

Search strategy and selection criteria

Our systematic review follows the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.19, 20 Seven electronic medical databases (PubMed, Embase, Scopus, African Journal Online, African Index Medicus, Bioline, and Web of Science) were searched for peer-reviewed articles published before January, 2019, that have the relevant population, intervention, comparator, outcomes, and study design (PICOS) framework (appendix p 2).

A predetermined search strategy used

Results

A list of 3756 records reporting individual SNPs in the Pfkelch13 gene were identified through database searching, including four records found manually. After removal of 2236 duplicated reports, we screened 1520 records of which 1467 were considered ineligible according to the PICOS approach (figure 1). 53 studies remained after exclusion, with P falciparum sample isolates successfully sequenced for Pfkelch13 in 41 African countries;9, 18, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41

Discussion

This paper is the first comprehensive and systematic review specifically focusing on polymorphisms of the Pfkelch13 gene in Africa. Pfkelch13 has exclusively been explored in sub-Saharan African countries, showing a highly polymorphic structure with most allelic variations located in the propeller domain. Despite low relative frequencies of non-synonymous mutations in this domain across the continent, we identified mutant alleles reported to be associated with diminished artemisinin

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