Abstract
The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.
Highlights
The global adoption of artemisinin-based combination treatments (ACTs), consisting of an artemisinin derivative and a partner drug, has played a key role in the worldwide reduction of malaria cases and deaths [1]
In Papua New Guinea, we found three patients infected with parasites carrying the most widespread resistant variant in southeast Asia, and they were confirmed to be artemisinin resistant
We established that the mutations were not imported from southeast Asia, and found other drug resistance variants in their genetic background, including some shared with parasites in Indonesia
Summary
The global adoption of artemisinin-based combination treatments (ACTs), consisting of an artemisinin derivative and a partner drug, has played a key role in the worldwide reduction of malaria cases and deaths [1]. Plasmodium falciparum parasites with decreased sensitivity to artemisinin have emerged at multiple locations in the Greater Mekong Sub-Region (GMS) [2,3,4] These resistant parasites exhibit a reduced clearing rate during treatment [2,3,5], such that treatment efficacy relies more heavily on the partner drug. After an initial period in which many kelch resistant alleles circulated concurrently, diversity has declined dramatically in the eastern part of the GMS (comprising Cambodia, northeast Thailand, southern Laos and Vietnam) where the C580Y allele has become the most prevalent, replacing other circulating mutations [12] This allele is associated with reduced clearing rate western Thailand [5] where it has emerged independently [13]. The C580Y allele has been detected in parasites outside the GMS, in Africa [8] and in Guyana, South America [14]; in these instances the artemisinin clearance rates were not known
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