Journal Article

Artemisinin Resistance and Stage Dependency of Parasite Clearance in Falciparum Malaria

Imwong, Mallika, Ashley, Elizabeth A., Dhorda, Mehul, White, Nicholas J., Srinamon, Ketsanee, Intharabut, Benjamas, Kingston, Hugh W., Stepniewska, Kasia, Woodrow, Charles, Day, Nicholas P.J., Dondorp, Arjen M., Silamut, Kamolrat

2019

Overview

Abstract Background Artemisinin 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. Methods Developmental 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. Results Early 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. Conclusion Following 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. The effect of parasite stage of development on the parasite clearance curve was investigated in areas affected by artemisinin resistance. Parasite stage shapes the early part of the clearance curve and also influences the subsequent log-linear decline.

• Publisher: Oxford University Press
• Subject: Age / Antimalarials - pharmacology / Antimalarials - therapeutic use / Artemisinin / Artemisinins - pharmacology / Artemisinins - therapeutic use / Developmental stages / Drug Resistance - genetics / Drug Therapy, Combination / Genotype / Genotypes / Humans / Infections / Life Cycle Stages / Major and Brief Reports / Malaria / Malaria, Falciparum - drug therapy / Mutants / Mutation / Parasitemia / Parasitemia - drug therapy / Parasitemia - parasitology / PARASITES / Plasmodium falciparum / Plasmodium falciparum - drug effects / Plasmodium falciparum - genetics / Plasmodium falciparum - growth & development / Protozoan Proteins - genetics / Schizogony