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Understanding genetic variation in in vivo tolerance to artesunate: implications for treatment efficacy and resistance monitoring.

Pollitt LC, Sim D, Salathé R, Read AF - Evol Appl (2014)

Bottom Line: Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment.Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system.This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University University Park, PA, USA ; Centre for Immunity, Infection and Evolution, University of Edinburgh Edinburgh, UK.

ABSTRACT
Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment. In the absence of molecular markers for resistance, current efforts to monitor drug efficacy are based on the rate at which parasites are cleared from infections. However, some knowledge of the standing variation in parasite susceptibility is needed to identify a meaningful increase in infection half-life. Here, we show that five previously unexposed genotypes of the rodent malaria parasite Plasmodium chabaudi differ substantially in their in vivo response to treatment. Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system. The level of variation observed here in a relatively small number of genotypes suggests existing 'resistant' parasites could be present in the population and therefore, increased parasite clearance rates could represent selection on pre-existing variation rather than de novo resistance events. This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

No MeSH data available.


Related in: MedlinePlus

Genetic variation in the response to drug treatment, deteriorating within-host environment and post-treatment recrudescence. (A) Parasite clearance curves for treated infections over the period of drug treatment controlling for density at the time of first drug dose. Lines show the mean clearance curve across four or five replicate infections and the shaded area shows the standard error. (B) Clearance rates from A transformed into an infection half-life. (C) Infection half-life in untreated infections for days 6–11 postinfection. (D) Mean cumulative parasite densities in treated infections between the end of drug treatment and day 26. Bars show the means of four or five infections, and bars show the standard error of the means.
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fig02: Genetic variation in the response to drug treatment, deteriorating within-host environment and post-treatment recrudescence. (A) Parasite clearance curves for treated infections over the period of drug treatment controlling for density at the time of first drug dose. Lines show the mean clearance curve across four or five replicate infections and the shaded area shows the standard error. (B) Clearance rates from A transformed into an infection half-life. (C) Infection half-life in untreated infections for days 6–11 postinfection. (D) Mean cumulative parasite densities in treated infections between the end of drug treatment and day 26. Bars show the means of four or five infections, and bars show the standard error of the means.

Mentions: In drug-treated infections, clearance rates significantly correlated with parasite density at the onset of treatment, and this effect was independent of parasite line (parasite half-life ∼ density at day 6 PI; = 5.58, P = 0.03); infections with a higher density cleared at a faster rate and this was controlled for in subsequent analyses. In addition clearance, rates differed significantly between parasite lines (Fig.2B) with the least susceptible parasite genotype (AQ; mean = 7.31 h) having a half-life of over 3 h (1.71-fold increase) more than the most susceptible (AJ; mean = 4.28 h) (Fig.2B; parasite half-life ∼ parasite line; = 10.75, P < 0.0005; Table S1.2). A Tukey post hoc test revealed that the two AS lines and ER had similar half-lives under drug treatment, but AQ had a significantly longer half-life than all other lines, and AJ had a significantly shorter half-life (Table S1.2). Extrapolating clearance curves to the predicted time to full clearance showed that infections with ER would take 58 h (2.4 days) longer to clear than infections with AJ (a 1.7-fold increase).


Understanding genetic variation in in vivo tolerance to artesunate: implications for treatment efficacy and resistance monitoring.

Pollitt LC, Sim D, Salathé R, Read AF - Evol Appl (2014)

Genetic variation in the response to drug treatment, deteriorating within-host environment and post-treatment recrudescence. (A) Parasite clearance curves for treated infections over the period of drug treatment controlling for density at the time of first drug dose. Lines show the mean clearance curve across four or five replicate infections and the shaded area shows the standard error. (B) Clearance rates from A transformed into an infection half-life. (C) Infection half-life in untreated infections for days 6–11 postinfection. (D) Mean cumulative parasite densities in treated infections between the end of drug treatment and day 26. Bars show the means of four or five infections, and bars show the standard error of the means.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380923&req=5

fig02: Genetic variation in the response to drug treatment, deteriorating within-host environment and post-treatment recrudescence. (A) Parasite clearance curves for treated infections over the period of drug treatment controlling for density at the time of first drug dose. Lines show the mean clearance curve across four or five replicate infections and the shaded area shows the standard error. (B) Clearance rates from A transformed into an infection half-life. (C) Infection half-life in untreated infections for days 6–11 postinfection. (D) Mean cumulative parasite densities in treated infections between the end of drug treatment and day 26. Bars show the means of four or five infections, and bars show the standard error of the means.
Mentions: In drug-treated infections, clearance rates significantly correlated with parasite density at the onset of treatment, and this effect was independent of parasite line (parasite half-life ∼ density at day 6 PI; = 5.58, P = 0.03); infections with a higher density cleared at a faster rate and this was controlled for in subsequent analyses. In addition clearance, rates differed significantly between parasite lines (Fig.2B) with the least susceptible parasite genotype (AQ; mean = 7.31 h) having a half-life of over 3 h (1.71-fold increase) more than the most susceptible (AJ; mean = 4.28 h) (Fig.2B; parasite half-life ∼ parasite line; = 10.75, P < 0.0005; Table S1.2). A Tukey post hoc test revealed that the two AS lines and ER had similar half-lives under drug treatment, but AQ had a significantly longer half-life than all other lines, and AJ had a significantly shorter half-life (Table S1.2). Extrapolating clearance curves to the predicted time to full clearance showed that infections with ER would take 58 h (2.4 days) longer to clear than infections with AJ (a 1.7-fold increase).

Bottom Line: Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment.Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system.This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University University Park, PA, USA ; Centre for Immunity, Infection and Evolution, University of Edinburgh Edinburgh, UK.

ABSTRACT
Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment. In the absence of molecular markers for resistance, current efforts to monitor drug efficacy are based on the rate at which parasites are cleared from infections. However, some knowledge of the standing variation in parasite susceptibility is needed to identify a meaningful increase in infection half-life. Here, we show that five previously unexposed genotypes of the rodent malaria parasite Plasmodium chabaudi differ substantially in their in vivo response to treatment. Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system. The level of variation observed here in a relatively small number of genotypes suggests existing 'resistant' parasites could be present in the population and therefore, increased parasite clearance rates could represent selection on pre-existing variation rather than de novo resistance events. This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

No MeSH data available.


Related in: MedlinePlus