Abstract
BackgroundA significant reduction in parasite clearance rates following artesunate treatment of falciparum malaria, and increased failure rates following artemisinin combination treatments (ACT), signaled emergent artemisinin resistance in Western Cambodia. Accurate measurement of parasite clearance is therefore essential to assess the spread of artemisinin resistance in Plasmodium falciparum. The slope of the log-parasitaemia versus time relationship is considered to be the most robust measure of anti-malarial effect. However, an initial lag phase of numerical instability often precedes a steady exponential decline in the parasite count after the start of anti-malarial treatment. This lag complicates the clearance estimation, introduces observer subjectivity, and may influence the accuracy and consistency of reported results.MethodsTo address this problem, a new approach to modelling clearance of malaria parasites from parasitaemia-time profiles has been explored and validated. The methodology detects when a lag phase is present, selects the most appropriate model (linear, quadratic or cubic) to fit log-transformed parasite data, and calculates estimates of parasite clearance adjusted for this lag phase. Departing from previous approaches, parasite counts below the level of detection are accounted for and not excluded from the calculation.ResultsData from large clinical studies with frequent parasite counts were examined. The effect of a lag phase on parasite clearance rate estimates is discussed, using individual patient data examples. As part of the World Wide Antimalarial Resistance Network's (WWARN) efforts to make innovative approaches available to the malaria community, an automated informatics tool: the parasite clearance estimator has been developed.ConclusionsThe parasite clearance estimator provides a consistent, reliable and accurate method to estimate the lag phase and malaria parasite clearance rate. It could be used to detect early signs of emerging resistance to artemisinin derivatives and other compounds which affect ring-stage clearance.
Highlights
A significant reduction in parasite clearance rates following artesunate treatment of falciparum malaria, and increased failure rates following artemisinin combination treatments (ACT), signaled emergent artemisinin resistance in Western Cambodia
The detection limit was 16, 25 or 40 parasites per microlitre. Within this large data-set, 4,008 profiles had their parasite clearance rates calculated, of which 294 profiles were best fitted with a quadratic model and a non-zero lag phase, 883 profiles were best fitted with a cubic model, and 2,821 were best fitted with a linear model (either directly (1,146 profiles), or by a quadratic model with zero lag phase (704 profiles) or by a cubic model with zero lag phase (971 profiles))
The algorithm takes into consideration the potentially confounding effects of the lag phase and removes these initial data before calculating the rate constant of the log-linear phase of parasite clearance
Summary
A significant reduction in parasite clearance rates following artesunate treatment of falciparum malaria, and increased failure rates following artemisinin combination treatments (ACT), signaled emergent artemisinin resistance in Western Cambodia. Accurate measurement of parasite clearance is essential to assess the spread of artemisinin resistance in Plasmodium falciparum. The recent emergence of artemisinin resistance in Plasmodium falciparum malaria in Western Cambodia represents a considerable threat to global health [4,5,6]. A significant reduction in the rates of parasite clearance following treatment with artesunate and increased failure rates following artemisinin combination treatments (ACT) provided definitive evidence of resistance in that region [5,7,8]. The clinical phenotype of slow parasite clearance remains to date the only way to define artemisinin resistance reliably [10]
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