Selection and Spread of Artemisinin-Resistant Alleles in Thailand Prior to the Global Artemisinin Resistance Containment Campaign

Talundzic, Eldin; Okoth, Sheila; Congpuong, Kanungnit; Pluciński, Mateusz M.; Morton, Lindsay; Goldman, Ira F.; Kachur, Patrick; Wongsrichanalai, Chansuda; Satimai, Wichai; Barnwell, John W.; Udhayakumar, Venkatachalam

doi:10.1371/journal.ppat.1004789

Cited by 101 publications

(128 citation statements)

References 30 publications

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“…pears to be increasing in this region of Kenya, and (iii) gene mutations associated with CQ resistance (Pfcrt CVIET and Pfmdr-1 N86Y) are on the decline. A total of at least 12 polymorphisms in the K13 propeller domain were recently implicated in artemisinin resistance in Southeast Asia (19)(20)(21)37). Similar to previous studies conducted in Africa (38-40), we did not observe any mutations in the propeller domain of the K13 gene that we sequenced.…”

Section: Discussionsupporting

confidence: 87%

“…The reaction mixtures were precipitated in 70% ethanol to clean up dye terminators, rehydrated in 10 l HiDi formamide, and then sequenced on a 3130xl ABI genetic analyzer (ABI Prism, CA, USA). In addition, the K13 propeller domain associated with artemisinin resistance was sequenced as recently described (37). Sequence analysis was performed by using Geneious R7 (Biomatters, Auckland, New Zealand).…”

Section: Methodsmentioning

confidence: 99%

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In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Lucchi

Komino

Okoth

et al. 2015

Antimicrob Agents Chemother

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Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ؎ 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.A ntimalarial drug resistance has hampered progress in malaria control and has led to several changes in drug policies over time. To minimize the potential emergence of drug resistance, the World Health Organization (WHO) recommends the use of artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative coformulated with another class of antimalarial (1). In Kenya, the use of chloroquine (CQ) as the first line of malaria treatment was discontinued in the late 1990s due to a high percentage of treatment failures. CQ was replaced by sulfadoxinepyrimethamine (SP) as the first line of treatment, with amodiaquine (AQ) as a second choice. However, the use of SP was shortlived, as the majority of circulating parasites rapidly developed resistance to SP (reviewed in reference 2). Therefore, in April 2004, the ACT artemether-lumefantrine (AL; Coartem) was recommended as the first-line therapy for the treatment of uncomplicated Plasmodium falciparum malaria in Kenya, although this was not fully implemented until late 2006, when the country was finally able to undertake delivery of large quantities of the drug. Thus, between 2004 and 2006, AQ was briefly used as the first-line treatment for malaria in Kenya. Dihydroartemisinin-piperaquine (DHAP) is the current second-line antimalarial drug treatment, while artesu...

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Lucchi

Komino

Okoth

et al. 2015

Antimicrob Agents Chemother

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“…Recently, another artemisinin resistance gene called kelch k13-propeller domain containing gene was reported (21). The k13-propeller domain was amplified using a nested PCR method previously described (21,22). The sequence data was analyzed using Geneious Pro R8 to identify polymorphisms associated with artemisinin resistance.…”

Section: Drug Resistance Marker Surveillancementioning

confidence: 99%

Malaria Surveillance — United States, 2013

Cullen¹,

Mace²,

Arguin³

2016

MMWR Surveill. Summ.

101

110

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Problem/Condition: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is also occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers.Period Covered: This report summarizes cases in persons with onset of illness in 2013 and summarizes trends during previous years.Description of System: Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are mandated to be reported to local and state health departments by health care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System, National Notifiable Diseases Surveillance System, or direct CDC consultations. CDC conducted antimalarial drug resistance marker testing on blood samples submitted to CDC by health care providers or local/state health departments. Data from these reporting systems serve as the basis for this report.Results: CDC received 1,727 reported cases of malaria, including two congenital cases, with an onset of symptoms in 2013 among persons in the United States. The total number of cases represents a 2% increase from the 1,687 cases reported for 2012. Plasmodium falciparum, P. vivax, P. malariae, and P. ovale were identified in 61%, 14%, 3%, and 4% of cases, respectively. Forty (2%) patients were infected by two species. The infecting species was unreported or undetermined in 17% of cases. Polymerase chain reaction testing determined or corrected the species for 85 of the 137 (62%) samples evaluated for drug resistance marker testing. Of the 904 patients who reported purpose of travel, 635 (70%) were visiting friends or relatives (VFR). Among the 961 cases in U.S. civilians for whom information on chemoprophylaxis use and travel region was known, 42 (4%) patients reported that they had initiated and adhered to a chemoprophylaxis drug regimen recommended by CDC for the regions to which they had traveled. Thirty-six cases were reported in pregnant women, none of whom had adhered to chemoprophylaxis. Among all reported cases, approximately 270 (16%) were classified as severe illnesses in 2013. Of these, 10 persons with malaria died in 2013, the highest number since 2001. In 2013, a total of 137 blood samples submitted to CDC were tested for molecular markers associated with antimalarial drug resistance. Of the 100 P. falciparum-positive samples, 95 were tested for pyrimethamine resistance: 88 (93%) had genetic polymor...

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“…It is possible that mutations within these genes might be necessary for the survival of parasites carrying artemisinin resistance-associated mutations in the Pfkelch13 gene in the absence of artemisinin selection pressure. This could explain the observation that artemisinin-resistant P. falciparum has emerged multiple times in Southeast Asia, where polymorphisms of these loci were prevalent, but not in Africa, where nearly all of these loci are of the wild type (36)(37)(38). Laboratory studies have shown, however, that African parasites can display reduced sensitivity to artemisinin when specific mutations are artificially induced in Pfkelch13 (7).…”

Section: Hap_1 T G G T a G T T T G T A C C A G G C G G A T Gmentioning

confidence: 99%

Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

Mita

Culleton

Takahashi

et al. 2016

Antimicrob Agents Chemother

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The emergence and spread of artemisinin-resistant Plasmodium falciparum is of huge concern for the global effort toward malaria control and elimination. Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in the Pfkelch13 gene of resistant parasites. To date, as many as 60 nonsynonymous mutations have been identified in this gene, but whether these mutations have been selected by artemisinin usage or merely reflect natural polymorphism independent of selection is currently unknown. To clarify this, we sequenced the Pfkelch13 propeller domain in 581 isolates collected before (420 isolates) and after (161 isolates) the implementation of artemisinin combination therapies (ACTs), from various regions of endemicity worldwide. Nonsynonymous mutations were observed in 1% of parasites isolated prior to the introduction of ACTs. Frequencies of mutant isolates, nucleotide diversity, and haplotype diversity were significantly higher in the parasites isolated from populations exposed to artemisinin than in those from populations that had not been exposed to the drug. In the artemisinin-exposed population, a significant excess of dN compared to dS was observed, suggesting the presence of positive selection. In contrast, pairwise comparison of dN and dS and the McDonald and Kreitman test indicate that purifying selection acts on the Pfkelch13 propeller domain in populations not exposed to ACTs. These population genetic analyses reveal a low baseline of Pfkelch13 polymorphism, probably due to purifying selection in the absence of artemisinin selection. In contrast, various Pfkelch13 mutations have been selected under artemisinin pressure.

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Selection and Spread of Artemisinin-Resistant Alleles in Thailand Prior to the Global Artemisinin Resistance Containment Campaign

Cited by 101 publications

References 30 publications

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Malaria Surveillance — United States, 2013

Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

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