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. 2017 Aug;23(8):1300-1307.
doi: 10.3201/eid2308.161582. Epub 2017 Aug 15.

Genomic Characterization of Recrudescent Plasmodium malariae after Treatment with Artemether/Lumefantrine

Gavin G Rutledge, Ian Marr, G Khai Lin Huang, Sarah Auburn, Jutta Marfurt, Mandy Sanders, Nicholas J White, Matthew Berriman, Chris I Newbold, Nicholas M Anstey, Thomas D Otto, Ric N Price

Genomic Characterization of Recrudescent Plasmodium malariae after Treatment with Artemether/Lumefantrine

Gavin G Rutledge et al. Emerg Infect Dis. 2017 Aug.

Abstract

Plasmodium malariae is the only human malaria parasite species with a 72-hour intraerythrocytic cycle and the ability to persist in the host for life. We present a case of a P. malariae infection with clinical recrudescence after directly observed administration of artemether/lumefantrine. By using whole-genome sequencing, we show that the initial infection was polyclonal and the recrudescent isolate was a single clone present at low density in the initial infection. Haplotypic analysis of the clones in the initial infection revealed that they were all closely related and were presumably recombinant progeny originating from the same infective mosquito bite. We review possible explanations for the P. malariae treatment failure and conclude that a 3-day artemether/lumefantrine regimen is suboptimal for this species because of its long asexual life cycle.

Keywords: Australia; Plasmodium malariae; artemether/lumefantrine; haplotype; malaria; parasitemia; parasites; recrudescence.

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Figures

Figure 1
Figure 1
Timeline of the clinical case of a patient with Plasmodium malariae infection diagnosed and treated at Royal Darwin Hospital, Darwin, Northern Territory, Australia, March–April 2015, showing the timing (A), treatment (B), parasite’s genotype as inferred from whole-genome sequencing (C), clinical presentation (D), and location (E). The rounded arrow indicates the recrudescence of the minor haplotype 2 in the initial infection to dominate monoclonally in the second infection. AL, artemether/lumefantrine; H1, haplotype 1; H2; haplotype 2; MP Ag, pan-malarial antigen; R1, reference haplotype.
Figure 2
Figure 2
Analysis of the minor haplotype (H2) that caused recrudescence of Plasmodium malariae infection in a patient at Royal Darwin Hospital, Darwin, Northern Territory, Australia, March–April 2015, showing distribution of SNP alternative (nonreference) allele frequencies across the 14 chromosomes (boxes in the middle and dotted vertical lines) in the initial infection (bottom plot) and the recrudescence (top plot). The SNP colors (green, increasing in frequency; red, decreasing in frequency) form 2 clear bands, corresponding to H1 (yellow box) and H2 (pink box). H2 probably caused the recrudescence given that all of its alleles increase considerably in frequency. Colored boxes in center of chart indicate chromosome sharing. H1, haplotype 1; H2; haplotype 2; R1, reference genome; SNP, single-nucleotide polymorphism.
Figure 3
Figure 3
The different scenarios under which a second Plasmodium malariae infection could have occurred from the initial infection diagnosed in a patient at Royal Darwin Hospital, Darwin, Northern Territory, Australia, March–April 2015. Initial infection is shown in the inner circle. A) A completely new infection might have caused the second malaria onset. B) The drug might not have been absorbed at sufficient levels to kill all the parasites in the blood (pharmacokinetic cause). C) The longer intraerythrocytic life cycle of P. malariae (72 hours) might have enabled some parasites to survive the drug action until lumefantrine concentrations became subtherapeutic (pharmacokinetic cause). D) H2 parasites might have differentially sequestered with a biomass out of proportion with the peripheral parasitemia. E) Some parasites might have formed dormant stages in the liver, blood, or elsewhere (pharmacodynamic cause). F) An immune response might have been differentially primed against haplotypes at higher biomass. G) A haplotype within the initial infection might have been relatively drug resistant (fitness advantage). H1, haplotype 1; H2, haplotype 2; R1, reference genome.
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