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Emergence of artemisinin-resistant malaria on the Western border of Thailand: a longitudinal study.
Lancet. 2012 Apr 5
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26 Apr 2012
New Finding
DOI: 10.3410/f.14267067.15779197
Plasmodium falciparum has shown a remarkable ability to evolve resistance mechanisms to most antimalarial drugs it has been exposed to. In 2010, artemisinin-resistant strains of the parasite were first reported on the western border of Cambodia {1,2}. As with resistance to chloroquine, antifolates, and...Continue reading
Plasmodium falciparum has shown a remarkable ability to evolve resistance mechanisms to most antimalarial drugs it has been exposed to. In 2010, artemisinin-resistant strains of the parasite were first reported on the western border of Cambodia {1,2}. As with resistance to chloroquine, antifolates, and mefloquine in the 1990s, the fear is that under intense selective pressure these resistant isolates will spread rapidly across Asia and into Africa, threatening the current global treatment strategy of artemisinin combination therapy.
The study by Phyo and colleagues conducted on the western border of Thailand (almost a 1000km from the original studies in Cambodia), demonstrates a marked increase in artemisinin-resistant infections over the last 10 years. The results highlight that the current containment efforts may be “too little too late”, and that current strategies need to be reconsidered.
Artemisinin resistance is characterised by slow parasite clearance. This is best gauged by intense blood sampling to define the parasite reduction rate, or in patients with hyperparasitaemia (>4% parasite red blood cells). The study from Thailand used data gathered over a 10-year period on patients with hyperparasitaemia treated with a 7-day regimen of artesunate +/- mefloquine. During the study period parasite clearance times lengthened from a geometric mean half life of 2.6 hours to 3.7 hours, the proportion of slow responders rising from 0.6% in 2001 to 20% in 2010. Genetic analysis of 96 single nucleotide polymorphisms in more than 1500 parasite isolates demonstrated that the heritability of slow parasite clearance increased almost two-fold in the study period, suggesting a genetic basis for the temporal changes in parasite response.
Parasites with identical genotype were not recorded in either Thai or Cambodian isolates, nor were slow responders in Thailand more related to Cambodian isolates than fast responders. Hence, for now it remains unclear whether resistant alleles in Cambodia and Thailand have a common origin or have emerged de novo at both sites.
The study from this well-established malaria research unit highlights the importance of longitudinal clinical studies in monitoring emerging patterns of resistance. The depressing, although perhaps unsurprising, finding is that artemisinin resistance has already spread beyond the borders of Cambodia. Control and containment efforts need to be reinforced to retard further spread, and alternative treatment strategies reviewed.
The study by Phyo and colleagues conducted on the western border of Thailand (almost a 1000km from the original studies in Cambodia), demonstrates a marked increase in artemisinin-resistant infections over the last 10 years. The results highlight that the current containment efforts may be “too little too late”, and that current strategies need to be reconsidered.
Artemisinin resistance is characterised by slow parasite clearance. This is best gauged by intense blood sampling to define the parasite reduction rate, or in patients with hyperparasitaemia (>4% parasite red blood cells). The study from Thailand used data gathered over a 10-year period on patients with hyperparasitaemia treated with a 7-day regimen of artesunate +/- mefloquine. During the study period parasite clearance times lengthened from a geometric mean half life of 2.6 hours to 3.7 hours, the proportion of slow responders rising from 0.6% in 2001 to 20% in 2010. Genetic analysis of 96 single nucleotide polymorphisms in more than 1500 parasite isolates demonstrated that the heritability of slow parasite clearance increased almost two-fold in the study period, suggesting a genetic basis for the temporal changes in parasite response.
Parasites with identical genotype were not recorded in either Thai or Cambodian isolates, nor were slow responders in Thailand more related to Cambodian isolates than fast responders. Hence, for now it remains unclear whether resistant alleles in Cambodia and Thailand have a common origin or have emerged de novo at both sites.
The study from this well-established malaria research unit highlights the importance of longitudinal clinical studies in monitoring emerging patterns of resistance. The depressing, although perhaps unsurprising, finding is that artemisinin resistance has already spread beyond the borders of Cambodia. Control and containment efforts need to be reinforced to retard further spread, and alternative treatment strategies reviewed.
References
1.
Evidence of artemisinin-resistant malaria in western Cambodia.
The New England journal of medicine 2008 Dec 11; 359(24): 2619-20
PMID: 19064625
DOI: 10.1056/NEJMc0805011
2.
Artemisinin resistance in Plasmodium falciparum malaria.
N Engl J Med 2009 Jul 30; 361(5): 455-67
PMID: 19641202
DOI: 10.1056/NEJMoa0808859
Disclosures
None declared
Add Comment
Price R: F1000Prime Recommendation of [Phyo AP et al., Lancet 2012]. In F1000Prime, 26 Apr 2012; DOI: 10.3410/f.14267067.15779197. F1000Prime.com/14267067#eval15779197
08 Jun 2012
New Finding
DOI: 10.3410/f.14267067.791902854
The issue of delayed clearance phenotype to artemisinins ('artemisinin resistance') could become a public health disaster if it spreads. Artemisinin combination therapy (ACT) has become the treatment of choice throughout much of the world, including Asia and Sub-Saharan Africa. 'Artemisinin resistance'...Continue reading
The issue of delayed clearance phenotype to artemisinins ('artemisinin resistance') could become a public health disaster if it spreads. Artemisinin combination therapy (ACT) has become the treatment of choice throughout much of the world, including Asia and Sub-Saharan Africa. 'Artemisinin resistance' is associated with increased treatment failures with ACT. 'Artemisinin resistance' has been known for some time in Western Cambodia and this article in the Lancet demonstrates that the phenotype has spread to Thailand as well and is associated with the genotype of the malaria parasite Plasmodium falciparum. Of note, a recent article in Science {1} links the phenotype to a region of chromosome 13 of P. falciparum.
References
1.
A major genome region underlying artemisinin resistance in malaria.
Science. 2012 Apr 6; 336(6077): 79-82
PMID: 22491853
DOI: 10.1126/science.1215966
Disclosures
None declared
Van Voorhis W: F1000Prime Recommendation of [Phyo AP et al., Lancet 2012]. In F1000Prime, 08 Jun 2012; DOI: 10.3410/f.14267067.791902854. F1000Prime.com/14267067#eval791902854
F1000Prime Recommendations, Dissents and Comments for [Phyo AP et al., Lancet 2012]. In F1000Prime, 20 May 2013; F1000Prime.com/14267067
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BACKGROUND: Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border.
METHODS: In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms.
FINDINGS: 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. INTERPRETATION: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years. FUNDING: The Wellcome Trust and National Institutes of Health.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(12)60484-X
PMID: 22484134
