The Impact of Sequestration on Artemisinin-induced Parasite Clearance in Plasmodium falciparum Malaria in Africa

Mature Plasmodium falciparum parasites are rarely found in the peripheral blood because they are sequestered and attached to the endothelium. We demonstrated that intensive sequestration was associated with a delay in parasite clearance after artemisinin-based treatment, independent of artemisinin-resistant mutations Background 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. Methods We analyzed 133 patients with P. falciparum malaria 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 pretreatment plasma. The number of sequestered parasites was estimated from PfHRP2 concentration and peripheral parasitemia. Results The estimated number of sequestered parasites per plasma volume ranged from 0 to 2 564 000/mu L. Inflammation, thrombocytopenia, and dyslipidemia were significantly associated with sequestration independent of peripheral parasitemia. The median parasite clearance half-lives were 1.65 hours in patients infected with Pfkelch13 wild-type parasites (n = 104) and 3.95 hours in those with A675V artemisinin-resistant mutant (n = 18). In the multivariable model for the wild-type population, 1 000 000/mu L of sequestered parasites were estimated to delay parasite clearance by 16.8% (95% confidence interval, 5.1%-28.5%), although it was not clear in the A675V population. Conclusions In patients with P. falciparum malaria without artemisinin-resistant mutations, intensive sequestration delays parasite clearance after treatment, which may contribute to reduced artemisinin efficacy.