Aims
Resistance to artemisinin antimalarials threatens malaria control. Understanding how artemisinin-resistant parasites respond to drug treatment is critical to the development of new antimalarial. We conducted a clinical trial using the induced blood stage malaria (IBSM) model with a P. falciparum artemisinin-resistant isolate harbouring the R539T mutation on the kelch13 gene (K13). The objectives of this study were to evaluate the safety and infectivity of artemisinin-resistant P. falciparum K13 in healthy subjects, and to define the parasite clearance profile of P. falciparum K13 after treatment.
Methods
Two healthy subjects in two cohorts were intravenously inoculated (Day 0) with ~2,800 P. falciparum K13 parasite-infected erythrocytes. Nine days later the subjects received a single oral dose of artesunate (~2 mg/kg). Recrudescent parasitemia was treated with dihydroartemisinin-piperaquin. All subjects were treated with atovaquone/proguanil and primaquine by the end of the study. Safety was determined by monitoring adverse events. Infectivity was determined measuring parasitemia by quantitative PCR targeting the P. falciparum 18S rRNA gene. Parasite reduction ratio and clearance half-life were estimated by log-linear regression.
Results
Thirty-six adverse events were reported during the study, most of them mild (64%; 23/36) and attributed to malaria (81%; 29/36). Four adverse events (11%) were related to drug treatments (related to both atovaquone/proguanil and primaquine, n=3; related only to atovaquone/proguanil, n=1). No serious adverse events were reported. Mean parasitemia before artesunate treatment was 75,331 parasites/mL (range 21,861-128,800 parasites/mL). The parasite reduction ratio was 497 (95% CI 266-926) and the parasite clearance half-life was 5.36 h (95% CI 4.87-5.96). All parasites were cleared by the end of study.
Conclusions
Experimental infection with P. falciparum parasites carrying the K13 mutation was safe, well-tolerated, and treatable with antimalarials. We have established an artemisinin-resistant IBSM model that can be used to investigate the activity of licensed and novel treatments against artemisinin-resistant parasites.