Association Between the pfmdr1 Gene and In Vitro Artemether and Lumefantrine Sensitivity in Thai Isolates of Plasmodium falciparum

Mungthin, Mathirut; Khositnithikul, Rommanee; Sitthichot, Naruemon; Suwandittakul, Nantana; Wattanaveeradej, Veerachai; Ward, Stephen A.; Na‐Bangchang, Kesara

doi:10.4269/ajtmh.2010.10-0339

Cited by 51 publications

(52 citation statements)

References 31 publications

(43 reference statements)

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“…Given the widespread nature of samples with K13-propeller mutations and slow clearance following artesunate treatment [5], there is concern that artesunate–mefloquine efficacy will be compromised across a wider area of Thailand in the near future. These data match previously published data from a distinct area of the Thailand–Cambodia border [39, 46]. …”

Section: Discussionsupporting

confidence: 91%

“…Isolates with amplified pfmdr1 were also seen in Ranong (southern Thailand–Myanmar border), consistent with previous data [39–41]. Analysis of genome-wide genetic similarity shows that parasites from the Thailand–Myanmar border and central Myanmar (Shwe Kyin) are related; it is worth noting that most patients enrolled in Mae Sot travelled from Myanmar, with the catchment area extending as far as 40 km inside the border [7].…”

Section: Discussionsupporting

confidence: 86%

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Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration

Srimuang

Miotto

Lim

et al. 2016

Malar J

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BackgroundDeclining anti-malarial efficacy of artemisinin-based combination therapy, and reduced Plasmodium falciparum susceptibility to individual anti-malarials are being documented across an expanding area of Southeast Asia (SEA). Genotypic markers complement phenotypic studies in assessing the efficacy of individual anti-malarials.MethodsThe markers pfmdr1 and pfcrt were genotyped in parasite samples obtained in 2011–2014 at 14 TRAC (Tracking Resistance to Artemisinin Collaboration) sites in mainland Southeast Asia using a combination of PCR and next-generation sequencing methods.Results Pfmdr1 amplification, a marker of mefloquine and lumefantrine resistance, was highly prevalent at Mae Sot on the Thailand–Myanmar border (59.8% of isolates) and common (more than 10%) at sites in central Myanmar, eastern Thailand and western Cambodia; however, its prevalence was lower than previously documented in Pailin, western Cambodia. The pfmdr1 Y184F mutation was common, particularly in and around Cambodia, and the F1226Y mutation was found in about half of samples in Mae Sot. The functional significance of these two mutations remains unclear. Other previously documented pfmdr1 mutations were absent or very rare in the region. The pfcrt mutation K76T associated with chloroquine resistance was found in 98.2% of isolates. The CVIET haplotype made up 95% or more of isolates in western SEA while the CVIDT haplotype was common (30–40% of isolates) in north and northeastern Cambodia, southern Laos, and southern Vietnam.ConclusionsThese findings generate cause for concern regarding the mid-term efficacy of artemether–lumefantrine in Myanmar, while the absence of resistance-conferring pfmdr1 mutations and SVMNT pfcrt haplotypes suggests that amodiaquine could be an efficacious component of anti-malarial regimens in SEA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1598-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 86%

Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration

Srimuang

Miotto

Lim

et al. 2016

Malar J

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“…Studies in South East Asia have shown that the amplification of mdr1 gene is associated with mefloquine [16] and possibly lumefantrine resistance [28]. Our findings support the suggestion that mdr1 amplification is rare in Africa [23].…”

Section: Discussionsupporting

confidence: 88%

Five Years of Antimalarial Resistance Marker Surveillance in Gaza Province, Mozambique, Following Artemisinin-Based Combination Therapy Roll Out

Raman

Mauff

Muianga³

et al. 2011

PLoS ONE

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Antimalarial drug resistance is a major obstacle to malaria control and eventual elimination. The routine surveillance for molecular marker of resistance is an efficient way to assess drug efficacy, which remains feasible in areas where malaria control interventions have succeeded in substantially reducing malaria transmission. Community based asexual parasite prevalence surveys were conducted annually in sentinel sites in Gaza Province, Mozambique from 2006 until 2010, before, during and after antimalarial policy changes to artesunate plus sulfadoxine-pyrimethamine in 2006 and to artemether-lumefantrine in 2008. Genetic analysis of dhfr, dhps, crt, and mdr1 resistant genes was conducted on 3 331 (14.4%) Plasmodium falciparum PCR positive samples collected over the study period from 23 229 children aged 2 to 15 years. The quintuple dhfr/dhps mutation associated with sulfadoxine-pyrimethamine resistance increased from 56.2% at baseline to 75.8% by 2010. At baseline the crt76T and mdr186Y mutants were approaching fixation, 96.1% and 74.7%, respectively. Following the deployment of artemisinin-based combination therapy, prevalence of both these chloroquine-resistance markers began declining, reaching 32.4% and 30.9%, respectively, by 2010. All samples analysed over the 5-year period possessed a single copy of the mdr1 gene. The high and increasing prevalence of the quintuple mutation supports the change in drug policy from artesunate plus sulfadoxine-pyrimethamine to artemether-lumefantrine in Mozambique. As chloroquine related drug pressure decreased in the region, so did the molecular markers associated with chloroquine resistance (crt76T and mdr186Y). However, this reversion to the wild-type mdr186N predisposes parasites towards developing lumefantrine resistance. Close monitoring of artemether-lumefantrine efficacy is therefore essential, particularly given the high drug pressure within the region where most countries now use artemether-lumefantrine as first line treatment.

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“…An investigation of laboratory and adapted Thai isolates identified pfmdr1 184F or 1042N alleles and a copy number of ‡4 to be associated with decreased sensitivity to lumefantrine in vitro [158]. A study in Ghana looked at pfmdr1 copy number over time and, although amplification was observed, this was not associated with any reports of resistance [115].…”

Section: Lumefantrine Resistancementioning

confidence: 99%

The emerging threat of artemisinin resistance in malaria: focus on artemether-lumefantrine

Djimdé

Makanga²,

Kuhen

et al. 2015

Expert Review of Anti-infective Therapy

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The development of artemisinin resistance in the Greater Mekong Subregion poses a significant threat to malaria elimination. Artemisinin-based combination therapies including artemether-lumefantrine (AL) are recommended by WHO as first-line treatment for uncomplicated Plasmodium falciparum malaria. This article provides a comprehensive review of the existing and latest data as a basis for interpretation of observed variability in parasite sensitivity to AL over the last 5 years. Clinical efficacy and preclinical data from a range of endemic countries are summarized, including potential molecular markers of resistance. Overall, AL remains effective in the treatment of uncomplicated P. falciparum malaria in most regions. Establishing validated molecular markers for resistance and strict efficacy monitoring will reinforce timely updates of treatment policies.

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Association Between the pfmdr1 Gene and In Vitro Artemether and Lumefantrine Sensitivity in Thai Isolates of Plasmodium falciparum

Cited by 51 publications

References 31 publications

Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration

Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration

Five Years of Antimalarial Resistance Marker Surveillance in Gaza Province, Mozambique, Following Artemisinin-Based Combination Therapy Roll Out

The emerging threat of artemisinin resistance in malaria: focus on artemether-lumefantrine

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