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Parasite clearance after malaria therapy: staying a step ahead of drug resistance.

Karunajeewa HA - BMC Med (2015)

Bottom Line: The discovery and development of the artemisinin class of antimalarial drugs is one of the great recent success stories of global health.However, after at least two decades of successful use, resistance has finally emerged and appears to be spreading rapidly throughout South-East Asia in spite of our best efforts at containment.The earliest indications of incipient artemisinin resistance may be a slowing of the rate at which parasites are cleared from the blood following treatment.

View Article: PubMed Central - PubMed

Affiliation: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Vic, 3052, Australia. karunajeewa.h@wehi.edu.au.

ABSTRACT
The discovery and development of the artemisinin class of antimalarial drugs is one of the great recent success stories of global health. However, after at least two decades of successful use, resistance has finally emerged and appears to be spreading rapidly throughout South-East Asia in spite of our best efforts at containment. If this were also to occur in Africa, it would have disastrous implications for the continent subject to the world's greatest burden of Plasmodium falciparum. The earliest indications of incipient artemisinin resistance may be a slowing of the rate at which parasites are cleared from the blood following treatment. The Worldwide Antimalarial Resistance Network have analysed data from 29,493 patients from 84 clinical trials in order to define the nature and determinants of early parasite clearance following artemisinin-based treatment in African populations. In doing so, they lay the foundation for systems intended to enable the earliest possible detection of emerging artemisinin resistance in Africa. Please see related article: http://www.biomedcentral.com/1741-7015/13/212.

No MeSH data available.


Related in: MedlinePlus

The parasite positivity rate (PPR) as a parasite clearance metric. The PPR at day 3 is defined by the proportion of a population with detectable parasitemia 3 days following treatment initiation. Therefore, for each individual, it reflects a binary outcome according to whether the X-intercept of the parasite clearance curve (also defined as the parasite clearance time) occurs before or after day 3 (dashed line). Whether this occurs or not will depend on the Y intercept (P: the parasite density at treatment commencement) and the gradient of the parasite clearance curve (k: the rate at which parasites are cleared). k will be determined by intrinsic parasite sensitivity (and therefore decrease when drug resistance develops) but may also be affected by pharmacological (e.g. pharmacokinetic variability) and host factors (acquired malaria-specific immunity will augment parasite killing and therefore increase the gradient)
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Fig2: The parasite positivity rate (PPR) as a parasite clearance metric. The PPR at day 3 is defined by the proportion of a population with detectable parasitemia 3 days following treatment initiation. Therefore, for each individual, it reflects a binary outcome according to whether the X-intercept of the parasite clearance curve (also defined as the parasite clearance time) occurs before or after day 3 (dashed line). Whether this occurs or not will depend on the Y intercept (P: the parasite density at treatment commencement) and the gradient of the parasite clearance curve (k: the rate at which parasites are cleared). k will be determined by intrinsic parasite sensitivity (and therefore decrease when drug resistance develops) but may also be affected by pharmacological (e.g. pharmacokinetic variability) and host factors (acquired malaria-specific immunity will augment parasite killing and therefore increase the gradient)

Mentions: FigureĀ 2 shows how PPR will be dependent on two main factors, namely (1) how high the total body parasite burden is prior to treatment and (2) the rate of parasite clearance. Unfortunately, the relationship between parasite clearance rate and drug-resistance may be confounded by factors other than parasite drug-susceptibility. These include pharmacologic factors (including pharmacokinetic variability and patient non-compliance) and host factors, specifically pre-existing malaria-specific immunity that can augment parasite killing. In a research article published in BMC Medicine [15], the WWARN investigators identify a number of factors associated with the PPR at day 3, many of which (age, fever, severe anaemia, and low transmission settings) probably represent separate proxies for malaria-specific immunity. The gradual acquisition of malaria immunity following repeated infections mean that, in high transmission settings, population immunity is higher so parasite clearance should be more rapid. The clinico-epidemiologic context should therefore be considered when determining the all-important threshold values for triggering a more intensive investigative response. The authors make an excellent case that existing WHO-recommended thresholds may be insufficiently sensitive for this purpose if applied in high transmission settings in Africa, risking the delayed identification of future new foci of artemisinin resistance.Fig. 2


Parasite clearance after malaria therapy: staying a step ahead of drug resistance.

Karunajeewa HA - BMC Med (2015)

The parasite positivity rate (PPR) as a parasite clearance metric. The PPR at day 3 is defined by the proportion of a population with detectable parasitemia 3 days following treatment initiation. Therefore, for each individual, it reflects a binary outcome according to whether the X-intercept of the parasite clearance curve (also defined as the parasite clearance time) occurs before or after day 3 (dashed line). Whether this occurs or not will depend on the Y intercept (P: the parasite density at treatment commencement) and the gradient of the parasite clearance curve (k: the rate at which parasites are cleared). k will be determined by intrinsic parasite sensitivity (and therefore decrease when drug resistance develops) but may also be affected by pharmacological (e.g. pharmacokinetic variability) and host factors (acquired malaria-specific immunity will augment parasite killing and therefore increase the gradient)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4591708&req=5

Fig2: The parasite positivity rate (PPR) as a parasite clearance metric. The PPR at day 3 is defined by the proportion of a population with detectable parasitemia 3 days following treatment initiation. Therefore, for each individual, it reflects a binary outcome according to whether the X-intercept of the parasite clearance curve (also defined as the parasite clearance time) occurs before or after day 3 (dashed line). Whether this occurs or not will depend on the Y intercept (P: the parasite density at treatment commencement) and the gradient of the parasite clearance curve (k: the rate at which parasites are cleared). k will be determined by intrinsic parasite sensitivity (and therefore decrease when drug resistance develops) but may also be affected by pharmacological (e.g. pharmacokinetic variability) and host factors (acquired malaria-specific immunity will augment parasite killing and therefore increase the gradient)
Mentions: FigureĀ 2 shows how PPR will be dependent on two main factors, namely (1) how high the total body parasite burden is prior to treatment and (2) the rate of parasite clearance. Unfortunately, the relationship between parasite clearance rate and drug-resistance may be confounded by factors other than parasite drug-susceptibility. These include pharmacologic factors (including pharmacokinetic variability and patient non-compliance) and host factors, specifically pre-existing malaria-specific immunity that can augment parasite killing. In a research article published in BMC Medicine [15], the WWARN investigators identify a number of factors associated with the PPR at day 3, many of which (age, fever, severe anaemia, and low transmission settings) probably represent separate proxies for malaria-specific immunity. The gradual acquisition of malaria immunity following repeated infections mean that, in high transmission settings, population immunity is higher so parasite clearance should be more rapid. The clinico-epidemiologic context should therefore be considered when determining the all-important threshold values for triggering a more intensive investigative response. The authors make an excellent case that existing WHO-recommended thresholds may be insufficiently sensitive for this purpose if applied in high transmission settings in Africa, risking the delayed identification of future new foci of artemisinin resistance.Fig. 2

Bottom Line: The discovery and development of the artemisinin class of antimalarial drugs is one of the great recent success stories of global health.However, after at least two decades of successful use, resistance has finally emerged and appears to be spreading rapidly throughout South-East Asia in spite of our best efforts at containment.The earliest indications of incipient artemisinin resistance may be a slowing of the rate at which parasites are cleared from the blood following treatment.

View Article: PubMed Central - PubMed

Affiliation: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Vic, 3052, Australia. karunajeewa.h@wehi.edu.au.

ABSTRACT
The discovery and development of the artemisinin class of antimalarial drugs is one of the great recent success stories of global health. However, after at least two decades of successful use, resistance has finally emerged and appears to be spreading rapidly throughout South-East Asia in spite of our best efforts at containment. If this were also to occur in Africa, it would have disastrous implications for the continent subject to the world's greatest burden of Plasmodium falciparum. The earliest indications of incipient artemisinin resistance may be a slowing of the rate at which parasites are cleared from the blood following treatment. The Worldwide Antimalarial Resistance Network have analysed data from 29,493 patients from 84 clinical trials in order to define the nature and determinants of early parasite clearance following artemisinin-based treatment in African populations. In doing so, they lay the foundation for systems intended to enable the earliest possible detection of emerging artemisinin resistance in Africa. Please see related article: http://www.biomedcentral.com/1741-7015/13/212.

No MeSH data available.


Related in: MedlinePlus