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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

Relationship between early parasite clearance and drug resistance. This hypothetical example shows how the parasite clearance curve might change as drug resistance progressively compromises an artemisinin-based combination therapy (ACT). Parasite clearance curves are shown for fully sensitive (blue), early resistance (green), established resistance (orange), and advanced resistance (red) scenarios. The earliest event in the progression of resistance is delayed early parasite clearance – but drug activity may still be sufficient to clear the total body parasite burden and achieve cure. As resistance becomes established, initial parasite killing may be sufficient for parasitemia to fall below the threshold of microscopic detectability (dashed line) but not to eliminate the entire body parasite burden – leading to recrudescence and late treatment failure. Complete failure to clear parasites (early treatment failure) will only occur once resistance to both drugs in an ACT combination has become very advanced
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Fig1: Relationship between early parasite clearance and drug resistance. This hypothetical example shows how the parasite clearance curve might change as drug resistance progressively compromises an artemisinin-based combination therapy (ACT). Parasite clearance curves are shown for fully sensitive (blue), early resistance (green), established resistance (orange), and advanced resistance (red) scenarios. The earliest event in the progression of resistance is delayed early parasite clearance – but drug activity may still be sufficient to clear the total body parasite burden and achieve cure. As resistance becomes established, initial parasite killing may be sufficient for parasitemia to fall below the threshold of microscopic detectability (dashed line) but not to eliminate the entire body parasite burden – leading to recrudescence and late treatment failure. Complete failure to clear parasites (early treatment failure) will only occur once resistance to both drugs in an ACT combination has become very advanced

Mentions: Early detection of drug resistance in malaria is problematic. In vitro parasite culture-based assays are generally poorly predictive of in vivo drug susceptibility phenotype, especially for the artemisinin derivatives. An exception is a “ring stage assay” used to characterize the South-East Asian artemisinin-resistant phenotype [10]. However, future foci of artemisinin resistance may arise through alternative, as yet unknown, biological pathways so may not be amenable to detection using this assay, nor to molecular methods for detecting associated mutations in the Kelch-13 propeller gene [11]. Therefore, in the foreseeable future, early detection of future foci of artemisinin resistance will probably still rely on “old-fashioned” methods of characterizing drug susceptibility by post-treatment clinical evaluation. The South-East Asian experience demonstrates the importance of early parasite clearance as the earliest sign of incipient artemisinin resistance (Fig. 1).Fig. 1


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

Karunajeewa HA - BMC Med (2015)

Relationship between early parasite clearance and drug resistance. This hypothetical example shows how the parasite clearance curve might change as drug resistance progressively compromises an artemisinin-based combination therapy (ACT). Parasite clearance curves are shown for fully sensitive (blue), early resistance (green), established resistance (orange), and advanced resistance (red) scenarios. The earliest event in the progression of resistance is delayed early parasite clearance – but drug activity may still be sufficient to clear the total body parasite burden and achieve cure. As resistance becomes established, initial parasite killing may be sufficient for parasitemia to fall below the threshold of microscopic detectability (dashed line) but not to eliminate the entire body parasite burden – leading to recrudescence and late treatment failure. Complete failure to clear parasites (early treatment failure) will only occur once resistance to both drugs in an ACT combination has become very advanced
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Relationship between early parasite clearance and drug resistance. This hypothetical example shows how the parasite clearance curve might change as drug resistance progressively compromises an artemisinin-based combination therapy (ACT). Parasite clearance curves are shown for fully sensitive (blue), early resistance (green), established resistance (orange), and advanced resistance (red) scenarios. The earliest event in the progression of resistance is delayed early parasite clearance – but drug activity may still be sufficient to clear the total body parasite burden and achieve cure. As resistance becomes established, initial parasite killing may be sufficient for parasitemia to fall below the threshold of microscopic detectability (dashed line) but not to eliminate the entire body parasite burden – leading to recrudescence and late treatment failure. Complete failure to clear parasites (early treatment failure) will only occur once resistance to both drugs in an ACT combination has become very advanced
Mentions: Early detection of drug resistance in malaria is problematic. In vitro parasite culture-based assays are generally poorly predictive of in vivo drug susceptibility phenotype, especially for the artemisinin derivatives. An exception is a “ring stage assay” used to characterize the South-East Asian artemisinin-resistant phenotype [10]. However, future foci of artemisinin resistance may arise through alternative, as yet unknown, biological pathways so may not be amenable to detection using this assay, nor to molecular methods for detecting associated mutations in the Kelch-13 propeller gene [11]. Therefore, in the foreseeable future, early detection of future foci of artemisinin resistance will probably still rely on “old-fashioned” methods of characterizing drug susceptibility by post-treatment clinical evaluation. The South-East Asian experience demonstrates the importance of early parasite clearance as the earliest sign of incipient artemisinin resistance (Fig. 1).Fig. 1

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