Slow Clearance of<i>Plasmodium falciparum</i>in Severe Pediatric Malaria, Uganda, 2011–2013

Hawkes, Michael; Conroy, Andrea L.; Opoka, Robert O.; Namasopo, Sophie; Zhong, Kathleen; Liles, W. Conrad; John, Chandy C.; Kain, Kevin C.

doi:10.3201/eid2107.150213

Cited by 53 publications

(62 citation statements)

References 14 publications

(30 reference statements)

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“…In Africa, highly diverse and low-frequent K13 mutant alleles have been observed, with no evidence of selection, and none of these were associated with clinical artemisinin resistance assessed by the presence of parasites on day 3 following artesunate monotherapy or a 3-d ACT course. It is thought that artemisinin resistance has not been established in Africa, supported by the additional absence of evidence of invasion by Asian K13 alleles validated as molecular marker of artemisinin resistance (C580Y, R539T, I543T, Y493H), confirming previous smaller-sized studies (Conrad et al 2014;Torrentino-Madamet et al 2014;Cooper et al 2015;Escobar et al 2015;Hawkes et al 2015;Isozumi et al 2015;Kamau et al 2015;Taylor et al 2015). Haplotyping studies on the most common African mutant 578A !…”

Section: -800 Nmsupporting

confidence: 78%

Antimalarial Drug Resistance: A Threat to Malaria Elimination

Ménard¹,

Dondorp²

2017

Cold Spring Harb Perspect Med

377

339

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Section: -800 Nmsupporting

confidence: 78%

Antimalarial Drug Resistance: A Threat to Malaria Elimination

Ménard¹,

Dondorp²

2017

Cold Spring Harb Perspect Med

377

339

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“…Of these, A569T was previously observed only in Kenya, where it was present in a single sample, as in our analysis (24). In contrast, the A578S polymorphism is present in Africa (8,(24)(25)(26)(27)(28) and Bangladesh (29). Conflicting findings have been reported regarding the role of A578S in artemisinin resistance (8,26,30).…”

Section: Discussioncontrasting

confidence: 52%

“…In contrast, the A578S polymorphism is present in Africa (8,(24)(25)(26)(27)(28) and Bangladesh (29). Conflicting findings have been reported regarding the role of A578S in artemisinin resistance (8,26,30). Previous computational modeling using the betapropeller domain of the btbkelch protein krp1 (PDB ID 2WOZ) suggested that a structural change induced by the A578S mutation potentially disrupts the normal function of the Pfkelch13 protein (29).…”

Section: Discussionmentioning

confidence: 79%

“…Since this mutation is one of the most prevalent mutations in Africa, where emergence of artemisinin resistance has not been observed, this mutation may not be associated with artemisinin resistance (8,25). However, one report has linked this mutation to possible artemisinin resistance, although the sample size was very small (26). Further elucidation of the role of the A578S mutation is warranted.…”

Section: Discussionmentioning

confidence: 95%

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Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

Mita

Culleton

Takahashi

et al. 2016

Antimicrob Agents Chemother

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The emergence and spread of artemisinin-resistant Plasmodium falciparum is of huge concern for the global effort toward malaria control and elimination. Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in the Pfkelch13 gene of resistant parasites. To date, as many as 60 nonsynonymous mutations have been identified in this gene, but whether these mutations have been selected by artemisinin usage or merely reflect natural polymorphism independent of selection is currently unknown. To clarify this, we sequenced the Pfkelch13 propeller domain in 581 isolates collected before (420 isolates) and after (161 isolates) the implementation of artemisinin combination therapies (ACTs), from various regions of endemicity worldwide. Nonsynonymous mutations were observed in 1% of parasites isolated prior to the introduction of ACTs. Frequencies of mutant isolates, nucleotide diversity, and haplotype diversity were significantly higher in the parasites isolated from populations exposed to artemisinin than in those from populations that had not been exposed to the drug. In the artemisinin-exposed population, a significant excess of dN compared to dS was observed, suggesting the presence of positive selection. In contrast, pairwise comparison of dN and dS and the McDonald and Kreitman test indicate that purifying selection acts on the Pfkelch13 propeller domain in populations not exposed to ACTs. These population genetic analyses reveal a low baseline of Pfkelch13 polymorphism, probably due to purifying selection in the absence of artemisinin selection. In contrast, various Pfkelch13 mutations have been selected under artemisinin pressure.

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“…The K189T variant is common in African isolates [38,39] and is not believed to cause increased clearance times following ACT. While the A578S variant has been associated with increased clearance times [40], this mutation was only observed in a small fraction of our strains. Additionally, strains possessing known resistance mutations in PfK13 are FSM susceptible (R. L. Edwards et al, unpublished data) suggesting that selection for artemisinin resistance does not result in FSM resistance.…”

Section: Genotyping Of Known Resistance Loci Does Not Reveal a Changementioning

confidence: 60%

Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin

et al. 2016

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Novel antimalarial therapies are needed in the face of emerging resistance to artemisinin combination therapies. A previous study found a high cure rate in Mozambican children with uncomplicated Plasmodium falciparum malaria 7 days after combination treatment with fosmidomycin-clindamycin. However, 28-day cure rates were low (45.9%), owing to parasite recrudescence. We sought to identify any genetic changes underlying parasite recrudescence. To this end, we used a selective whole-genome amplification method to amplify parasite genomes from blood spot DNA samples. Parasite genomes from pretreatment and postrecrudescence samples were subjected to whole-genome sequencing to identify nucleotide variants. Our data did not support the existence of a genetic change responsible for recrudescence following fosmidomycin-clindamycin treatment. Additionally, we found that previously described resistance alleles for these drugs do not represent biomarkers of recrudescence. Future studies should continue to optimize fosmidomycin combinations for use as antimalarial therapies.

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Slow Clearance ofPlasmodium falciparumin Severe Pediatric Malaria, Uganda, 2011–2013

Cited by 53 publications

References 14 publications

Antimalarial Drug Resistance: A Threat to Malaria Elimination

Antimalarial Drug Resistance: A Threat to Malaria Elimination

Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin

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