Different Plasmodium falciparum clearance times in two Malian villages following artesunate monotherapy

Abstract

Background: Artemisinin resistance described as increased parasite clearance time (PCT) is rare in Africa. More sensitive methods such as qPCR might better characterize the clearance phenotype in sub-Saharan Africa. Methods: PCT is explored in Mali using light microscopy and qPCR after artesunate for uncomplicated malaria. In two villages, patients were followed for 28 days. Blood smears and spots were collected respectively for microscopy and qPCR. Parasitemia slope half-life was calculated after microscopy. Patient residual parasitemia were measured by qPCR. Results: Uncorrected adequate clinical and parasitological responses (ACPR) observed in Faladje and Bougoula-Hameau were 78% and 92%, respectively (p = 0.01). This reached 100% for both after molecular correction. Proportions of 24H microscopy positive patients in Faladje and Bougoula-Hameau were 97.2% and 72%, respectively (p < 0.0001). Slope half-life was 2.8 h in Faladje vs 2H in Bougoula-Hameau (p < 0.001) and Proportions of 72H patients with residual parasitemia were 68.5% and 40% in Faladje and Bougoula-Hameau, respectively (p = 0.003). The mean residual parasitemia was 2.9 in Faladje vs. 0.008 in Bougoula-Hameau (p = 0.002). Although artesunate is efficacious in Mali, the longer parasite clearance time with submicroscopic parasitemia observed may represent early signs of developing P. falciparum resistance to artemisinins.

Persistence of P. Falciparum Ring-Stage Parasites 42 Days After Artemisinin and Non-Artemisinin Combination Therapy in Naturally Infected Malians

“…Whilst repeated assessments of parasite density shortly after initiation of treatment provide the most conclusive evidence on (changes in) parasite responsiveness (16), alternative metrics are used to compare the early effects of antimalarials. These include the proportion of individuals with residual parasitemia by microscopy (17) or PCR (3,7) or the concentration of the histidine rich protein-2 parasite antigen (18). The current study, examining the kinetics of mRNA transcripts indicative of ring-stage parasitemia following treatment (10,19), explicitly does not aim to present this measure as a proxy for parasite clearance half-lives or direct evidence of reduced susceptibility of parasites to treatment.…”

“…At present, artemisinin derivatives retain excellent e cacy throughout Africa despite reports of decreased sensitivity to some of its partner drugs (2). Whilst recent antimalarial e cacy trials in Africa have shown overwhelmingly high treatment success after ACT (≥ 95%) (2), parasites may persist shortly after initiation of treatment (3). Though this parasite persistence may not necessarily re ect drug resistance, which also depends on initial parasite density, host immunity, and drug absorption (4,5), it is important to better understand what parasite populations persist and whether parasite persistence has consequences for later recrudescence (5).…”

Persistence of P. Falciparum Ring-stage Parasites 42 Days After Artemisinin and Non-artemisinin Combination Therapy in Naturally Infected Malians

“…Whilst repeated assessments of parasite density shortly after initiation of treatment provide the most conclusive evidence on (changes in) parasite responsiveness [18], alternative metrics are used to compare the early effects of antimalarials. These include the proportion of individuals with residual parasitemia by microscopy [19] or PCR [4,8] or the concentration of the histidine rich protein-2 parasite antigen [20]. The current study, examining the kinetics of mRNA transcripts indicative of ring-stage parasitemia following treatment [11,21], explicitly does not aim to present this measure as a proxy for parasite clearance half-lives or evidence of reduced susceptibility of parasites to treatment.…”

“…The current study, examining the kinetics of mRNA transcripts indicative of ring-stage parasitemia following treatment [11,21], explicitly does not aim to present this measure as a proxy for parasite clearance half-lives or evidence of reduced susceptibility of parasites to treatment. A recent study from Mali that was speci cally designed to assess parasite clearance half-lives following artesunate monotherapy observed indications for delayed clearance in one setting [4], highlighting the need for monitoring of (early) parasite clearance following ACTs. Here, the aim was to examine a previously reported phenomenon of persisting sbp1 ring-stage transcripts following ACT treatment in more detail [7,11].…”

“…At present, artemisinin derivatives retain excellent e cacy in most of Africa despite reports of decreased sensitivity to some of its partner drugs [2] and recent evidence for the emergence of artemisinin resistance in East Africa [3]. Whilst recent antimalarial e cacy trials in Africa have shown overwhelmingly high treatment success after ACT (≥95%) [2], parasites may persist shortly after initiation of treatment [4]. Though this parasite persistence may not necessarily re ect drug resistance, which also depends on initial parasite density, host immunity, and drug absorption [5,6], it is important to better understand what parasite populations persist and whether parasite persistence has consequences for later recrudescence [6].…”