Artemisinin Resistance and Stage Dependency of Parasite Clearance in Falciparum Malaria.

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.

• Authors: Benjamas Intharabut, Hugh W Kingston, Ketsanee Srinamon, Elizabeth A Ashley, Mallika Imwong, Mehul Dhorda, Charles Woodrow, Kasia Stepniewska, Kamolrat Silamut, Nicholas P J Day, Arjen M Dondorp, Nicholas J White, Tracking Resistance to Artemisinin Collaboration
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 219 Issue 9 Pg. 1483-1489 (04 16 2019) ISSN: 1537-6613 [Electronic] United States
• PMID: 30657916 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Chemical References

• Antimalarials
• Artemisinins
• Protozoan Proteins
• artemisinin

Topics

• Antimalarials (pharmacology, therapeutic use)
• Artemisinins (pharmacology, therapeutic use)
• Drug Resistance (genetics)
• Drug Therapy, Combination
• Genotype
• Humans
• Life Cycle Stages
• Malaria, Falciparum (drug therapy)
• Mutation
• Parasitemia (drug therapy, parasitology)
• Plasmodium falciparum (drug effects, genetics, growth & development)
• Protozoan Proteins (genetics)