The impact of sequestration on artemisinin-induced parasite clearance in Plasmodium falciparum malaria in Africa


 
 
 Artemisinin-resistant Plasmodium falciparum is spreading in Southeast Asia and Africa. In vivo susceptibility to artemisinin is studied by looking at the rate of decline of peripheral parasitemia (parasite clearance half-life). However, parasites that are adhered/sequestered to the endothelium and undetectable in the peripheral blood are not considered in the estimation of parasite clearance. Here we evaluated the influence of sequestration on in vivo artemisinin efficacy in Uganda, where artemisinin resistance is spreading.
 
 
 
 We analyzed 133 P. falciparum malaria patients included in an in vivo study on artemisinin efficacy in northern Uganda in 2018 and 2019. The parasite clearance half-life was estimated from peripheral parasitemia after artemisinin monotherapy. P. falciparum histidine-rich protein 2 (PfHRP2) was measured in pre-treatment plasma. The number of sequestered parasites was estimated from PfHRP2 concentration and peripheral parasitemia.
 
 
 
 The estimated number of sequestered parasites per plasma volume ranged from 0 to 2,564,000/μL. Inflammation, thrombocytopenia, and dyslipidemia were significantly associated with sequestration independently of peripheral parasitemia. The median parasite clearance half-lives were 1.65 h in patients infected with Pfkelch13 wild-type parasites (N = 104) and 3.95 h in those with A675V artemisinin-resistant mutant (N = 18). In the multivariable model for the wild-type population, 1,000,000/μL of sequestered parasites were estimated to delay parasite clearance by 16.8% (95% CI: 5.1%–28.5%) although it was not clear in the A675V population.
 
 
 
 In P. falciparum malaria patients without artemisinin-resistant mutations, intensive sequestration delays parasite clearance after treatment, which may contribute to reduced artemisinin efficacy.
