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Abstract
BackgroundArtemisinin resistance in falciparum malaria is associated with kelch13 propeller mutations, reduced ring stage parasite killing, and, consequently, slow parasite clearance. We assessed how parasite age affects parasite clearance in artemisinin resistance.MethodsDevelopmental stages of Plasmodium falciparum parasites on blood films performed at hospital admission and their kelch13 genotypes were assessed for 816 patients enrolled in a multinational clinical trial of artemisinin combination therapy.ResultsEarly changes in parasitemia level (ie, 0–6 hours after admission) were determined mainly by modal stage of asexual parasite development, whereas the subsequent log-linear decline was determined mainly by kelch13 propeller mutations. Older circulating parasites on admission were associated with more-rapid parasite clearance, particularly in kelch13 mutant infections. The geometric mean parasite clearance half-life decreased by 11.6% (95% CI 3.4%–19.1%) in kelch13 wild-type infections and by 30% (95% CI 17.8%–40.4%) in kelch13 mutant infections as the mean age of circulating parasites rose from 3 to 21 hours.ConclusionFollowing the start of antimalarial treatment, ongoing parasite sequestration and schizogony both affect initial changes in parasitemia. The greater dependency of parasite clearance half-life on parasite age in artemisinin resistant infections is consistent with ring stage resistance and consequent parasite clearance by sequestration. The stage of parasite development should be incorporated in individual assessments of artemisinin resistance.
Highlights
Artemisinin resistance in falciparum malaria is associated with kelch13 propeller mutations, reduced ring stage parasite killing, and, slow parasite clearance
The geometric mean parasite clearance half-life decreased by 11.6% in kelch13 wild-type infections and by 30% in kelch13 mutant infections as the mean age of circulating parasites rose from 3 to 21 hours
The greater dependency of parasite clearance half-life on parasite age in artemisinin resistant infections is consistent with ring stage resistance and consequent parasite clearance by sequestration
Summary
Developmental stages of Plasmodium falciparum parasites on blood films performed at hospital admission and their kelch genotypes were assessed for 816 patients enrolled in a multinational clinical trial of artemisinin combination therapy. Differences in relative parasitemia at time points grouped by modal stage or genotype were compared using linear regression that adjusted for site and treatment. Because the age of circulating parasites is a circular quantity (ie, the schizont stage is adjacent to the tiny ring stage), the circular mean age of the parasites staged on each patient’s baseline blood film was calculated for each patient, assuming the following ages: TR stage, 3 hours; SR stage, 11 hours; LR stage, 21 hours; ET stage, 28 hours; MT stage, 32 hours; LT stage, 36 hours; and Sh stage, 43 hours [16]
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