Declining Efficacy of Artemisinin Combination Therapy Against<i>P. Falciparum</i>Malaria on the Thai–Myanmar Border (2003–2013): The Role of Parasite Genetic Factors

Phyo, Aung Pyae; Ashley, Elizabeth A.; Anderson, Tim; Bozdech, Zbynek; Carrara, Verena I.; Sriprawat, Kanlaya; Nair, Shalini; White, Marina; Dziekan, Jerzy Michał; Ling, Clare; Proux, Stéphane; Konghahong, Kamonchanok; Jeeyapant, Atthanee; Woodrow, Charles J.; Imwong, Mallika; McGready, Rose; Lwin, Khin Maung; Day, Nicholas P. J.; White, Nicholas J.; Nosten, François

doi:10.1093/cid/ciw388

Cited by 187 publications

(197 citation statements)

References 38 publications

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“…Overall, these data suggest that multicopy mdr1 genotypes are prevalent in areas of malaria endemicity of Colombia and that future studies are needed to determine whether (i) the prevalence of increased mdr1 copy numbers is rising, (ii) parasites are evolving decreased susceptibility to LF in vitro, and (iii) AL therapeutic efficacy is dropping. Importantly, a recent study (31) found that mdr1 amplification-even in the absence of K13 propeller mutation-is a risk factor for AS-MQ failure along the Thailand-Myanmar border, further justifying continued monitoring for this genetic change in Colombia.…”

Section: Discussionmentioning

confidence: 99%

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

Montenegro

Neal

Posada

et al. 2017

Antimicrob Agents Chemother

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High treatment failure rates for Plasmodium falciparum malaria have been reported in Colombia for chloroquine, amodiaquine, and sulfadoxine-pyrimethamine. Artemisinin combination therapies were introduced in 2006 in Colombia, where artemether-lumefantrine (AL) is currently used to treat uncomplicated P. falciparum malaria. Artemisinin (ART) resistance was initially observed in Southeast Asia as an increased parasite clearance time, manifesting as a positive thick-blood smear on day 3 after treatment (D3 positivity). Recently, mutations in the propeller domain of the P. falciparum kelch13 gene (K13 propeller) have been associated with ART resistance. In this study, we surveyed AL effectiveness at D3 and molecular markers of drug resistance among 187 uncomplicated P. falciparum cases in 4 regions of Colombia from June 2014 to July 2015. We found that 3.2% (4/125) of patients showed D3 positivity, 100% (163/163) of isolates carried wild-type K13 propeller alleles, 12.9% (23/178) of isolates had multiple copies of the multidrug resistance 1 gene (mdr1), and 75.8% (113/149) of isolates harbored the double mutant NFSDD mdr1 haplotype (the underlining indicates mutant alleles). These data suggest that ART resistance is not currently suspected in Colombia but that monitoring for lumefantrine resistance and AL failures should continue.

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Section: Discussionmentioning

confidence: 99%

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

Montenegro

Neal

Posada

et al. 2017

Antimicrob Agents Chemother

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“…Slower parasite clearance results in a higher parasite burden requiring to be eliminated by the ACT partner drug and an increased probability of selecting resistance. High failure rates have been observed recently after dihydroartemisinin-piperaquine treatment in Cambodia and Vietnam and after artesunatemefloquine on the Thailand-Myanmar borders (11,12). Strategies to restore high cure rates include increasing dosage, duration, and frequency of artemisinin administration and use of triple combinations.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

Das

Dondorp

Nosten

et al. 2017

AAPS J

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Abstract.Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroartemisinin, and microscopy-based parasite densities were measured and evaluated using nonlinear mixed-effects modeling. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had substantially slower parasite clearance compared to patients in Thailand. The pharmacokinetic properties of artesunate and dihydroartemisinin were well described by transit-compartment absorption followed by one-compartment disposition models. Parasite density was a significant covariate, and higher parasite densities were associated with increased absorption. Dihydroartemisinin-dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixture function was implemented to differentiate between sensitive and resistant infections. This predicted that 84% and 16% of infections in Cambodia and Thailand, respectively, were artemisinin resistant. The final model was used to develop a simple diagnostic nomogram to identify patients with artemisinin-resistant infections. The nomogram showed > 80% specificity and sensitivity, and outperformed the current practice of day 3 positivity testing.

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“…

TO THE EDITOR-We read with interest the article by Phyo et al [1] on the role of K13 mutations (markers of partial artemisinin resistance) in artemisininbased combination therapy (ACT) failures in the Greater Mekong Subregion (GMS). Though we agree that Plasmodium falciparum parasites carrying both K13 mutations and genomic signatures of partner drug resistance have a multiplicative effect on ACT failure rates, we have a different interpretation of the apparent role of K13 mutation alone in ACT failures.

Artesunate-mefloquine (ASMQ) was implemented in Cambodia in 2001 in

…”

mentioning

confidence: 99%

“…To this end, the World Health Organization has supported the development of a malaria elimination strategy for this region, and is currently integrating it into the national malaria control programs of all GMS countries [9]. Charlotte Rasmussen, 1 Frédéric Ariey, 2 Rick M. Fairhurst, 3 Pascal Ringwald, 1 and Didier Ménard 4,5,6 …”

mentioning

confidence: 99%

Role of K13 Mutations in Artemisinin-Based Combination Therapy

et al. 2016

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Declining Efficacy of Artemisinin Combination Therapy AgainstP. FalciparumMalaria on the Thai–Myanmar Border (2003–2013): The Role of Parasite Genetic Factors

Cited by 187 publications

References 38 publications

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

Role of K13 Mutations in Artemisinin-Based Combination Therapy

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