Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis

Abstract

Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up.

Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive.

Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007.

Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

Fig. 1

Study profile

Fig. 2

Map of study sites included in the parasite clearance data analysis

Fig. 3

Distribution of PC_1/2 by treatment group in areas with artemisinin-sensitive parasite population. Figure in red shows PC_1/2 values in all western Cambodian sites for comparison

Fig. 4

Relationship between initial parasitaemia and estimated PC_1/2 in patients in areas with artemisinin-sensitive parasite populations. Red line shows locally weighted scatterplot smoothing estimator (LOWESS)

Fig. 5

Relationship between patient age and PC_1/2 in patients in areas with artemisinin-sensitive parasites. (1) Observed data in Africa (a) and Asia (b) with red line showing locally weighted scatter-plot smoothing estimator (LOWESS); only patients with 6-h sampling and enough data points for the full Parasite Clearance Estimator model to be fitted are presented; (2) predicted relationship from multivariate model using fractional polynomials (c); adjusted for treatment group, region, initial parasitaemia, presence of lag phase and study design characteristics

Fig. 6

Meta-analysis of dose effect in randomized studies with artesunate alone in the first 72 h. ¹geometric mean of PC_1/2 in 2 mg/kg treatment arm