Probability of emergence of antimalarial resistance in different stages of the parasite life cycle - PubMed (original) (raw)
Probability of emergence of antimalarial resistance in different stages of the parasite life cycle
Wirichada Pongtavornpinyo et al. Evol Appl. 2009 Feb.
Abstract
Understanding the evolution of drug resistance in malaria is a central area of study at the intersection of evolution and medicine. Antimalarial drug resistance is a major threat to malaria control and directly related to trends in malaria attributable mortality. Artemisinin combination therapies (ACT) are now recommended worldwide as first line treatment for uncomplicated malaria, and losing them to resistance would be a disaster for malaria control. Understanding the emergence and spread of antimalarial drug resistance in the context of different scenarios of antimalarial drug use is essential for the development of strategies protecting ACTs. In this study, we review the basic mechanisms of resistance emergence and describe several simple equations that can be used to estimate the probabilities of de novo resistance mutations at three stages of the parasite life cycle: sporozoite, hepatic merozoite and asexual blood stages; we discuss the factors that affect parasite survival in a single host in the context of different levels of antimalarial drug use, immunity and parasitaemia. We show that in the absence of drug effects, and despite very different parasite numbers, the probability of resistance emerging at each stage is very low and similar in all stages (for example per-infection probability of 10(-10)-10(-9) if the per-parasite chance of mutation is 10(-10) per asexual division). However, under the selective pressure provided by antimalarial treatment and particularly in the presence of hyperparasitaemia, the probability of resistance emerging in the blood stage of the parasite can be approximately five orders of magnitude higher than in the absence of drugs. Detailed models built upon these basic methods should allow us to assess the relative probabilities of resistance emergence in the different phases of the parasite life cycle.
Figures
Figure 1
The various stages at which resistance can emerge during the blood stage. The model is implemented in Microsoft Excel.
Figure 2
The baseline scenarios for the low (black) and high (red) transmission intensity setting respectively. In the absence of treatment, the parasite biomass of a nonimmune person would increase lethally over time. For a host with some immunity, the parasite biomass could be suppressed around the detectable or pyrogenic levels. Parameter estimates are given in Appendix D.
Figure 3
The probability of artemisinin-resistance emerging at different stages. The dots show the probability of resistance emerging from the sporozoite (_P_s), the hepatic merozoite (_P_h) and blood stage (_P_b). The dotted line represents the range for the probability of resistance emerging in the hepatic merozoite stage (_P_h) in the presence of some residual drugs. For the blood stage, the probability of resistance emerging is calculated at cycle 10 when total parasite biomass is equal or above 108.
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