The Role of Pfmdr1 and Pfcrt in Changing Chloroquine, Amodiaquine, Mefloquine and Lumefantrine Susceptibility in Western-Kenya P. falciparum Samples during 2008–2011

Eyase, Fredrick; Akala, Hoseah M.; Ingasia, Luiser A.; Cheruiyot, Agnes C.; Omondi, Angela A.; Okudo, Charles; Juma, Dennis W.; Yeda, Redemptah; Andagalu, Ben; Wanja, Elizabeth; Kamau, Edwin; Schnabel, David; Bulimo, Wallace; Waters, Norman C.; Walsh, Douglas S.; Johnson, Jacob

doi:10.1371/journal.pone.0064299

Cited by 87 publications

(107 citation statements)

References 44 publications

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“…In Kenya, this decline was first reported in Kilifi in 2006, 13 years after the discontinuation of CQ use (28), in which the prevalence of the Pfcrt K76T mutation was shown to decrease from ϳ95% in 1993 to ϳ60% in 2006. Studies from western Kenya demonstrated that in 2008, the prevalence of parasites with the Pfcrt CVIET genotype was 72.4%, which was shown to decline to 32.1% by 2011 (44). During our study period, we observed a reduction of the prevalence of this genotype to 7% by 2013, demonstrating that the prevalence of this genotype is on the decline.…”

Section: Discussionsupporting

confidence: 49%

“…In 2007, the prevalence of parasites with the Pfmdr-1 N86Y mutation in western Kenya was shown to be ϳ69% (45). However, a steady decline in the prevalence of this mutation was subsequently observed, from 42% in 2008 to 30% in 2009, 28% in 2010, and 15% in 2011 (44). Our study showed a decline in prevalence from 18% in 2010 to 0% by 2013.…”

Section: Discussionmentioning

confidence: 49%

“…On the other hand, we observed a steady decline in the AQ IC 50 from 2010 to 2012, which slightly increased in 2013. Both the Pfcrt K76T and Pfmdr-1 N86Y mutations are also associated with AQ resistance (3,44). The observed decline in the prevalence of parasites with these mutations suggests that most of the circulating parasites in this region are AQ sensitive.…”

Section: Discussionmentioning

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: 49%

Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

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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“…Most of P. falciparum isolates collected from Thailand carry pfcrt mutations at codons K76T, A220S, Q271E, N326S and R371I [7] . The mutation at codon 86 of pfmdr1 (86Y) related with chlolroquine resistance, while pfmdr1 wild type at the same codon (N86) including increased pfmdr1 gene copy number linked to resistance of the parasite to mefloquine and artesunate [8][9][10] . The aim of the present study was to investigate the distribution and patterns of pfcrt and pfmdr1 polymorphisms in P. falciparum isolates collected from the malaria endemic area of Thailand along Thai-Myanmar border.…”

Section: Introductionmentioning

confidence: 99%

Polymorphic patterns of pfcrt and pfmdr1 in Plasmodium falciparum isolates along the Thai-Myanmar border

Muhamad

Chai่jaroenkul

Phompradit

et al. 2013

Asian Pacific Journal of Tropical Biomedicine

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“…N86 allele in Pfmdr1 has been shown in vitro in conferring less susceptibility to artesunate. 49 Few isolates from Arunachal Pradesh have been 51 Exact association of Pfmdr1 and PfK13 mutations in resistance development cannot be ascertained as study reports including these 2 genes are not sufficiently available. Wild-type N86 allele in Pfmdr1 has been found with increased tolerance to both artemether and lumefantrine separately.…”

Section: Discussionmentioning

confidence: 99%

K13 Kelch Propeller Domain and mdr1 Sequence Polymorphism in Field Isolates From Northeast Region, India

Dutta¹,

Chetry²,

Kalita³

et al. 2017

HPD

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Emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia has made an intense warning to global malaria control programme since Southeast Asia is playing a key role in the evolution of drug resistant malaria parasites. Several polymorphisms in K13 gene have been designated with developing resistance either in vitro or in vivo. In this study, polymorphisms within K13 kelch propeller domain and Pf mdr1 gene were investigated in a total of 134 P. falciparum field isolates circulating in 3 states of Northeast region of India, namely, Assam, Arunachal Pradesh, and Tripura because information regarding this is limited from this region. Six polymorphisms were detected, out of which 2 were new. A481V mutation was found in 4.5% of the total field isolates. A675V and D702N new mutations were present in 3.7% and 1.5% isolates, respectively. Synonymous polymorphism at codon 703 was highly observed (6.7%) than other polymorphisms. N86Y allele in Pf mdr1 gene was also noticed in isolates that contained mutation in K13 propeller domain, but N86 wild-type allele was found comparatively higher in frequency within overall isolates. Moreover, both nucleotide and haplotype diversities in K13 gene were high in Arunachal Pradesh isolates than other 2 states. This is the first report from Northeast region of India with evidence of A675V candidate mutation along with 2 other new mutations which pays attention for further molecular surveillance in this region to document detailed scenario of K13 polymorphism pattern corresponding to artemisinin resistance.

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The Role of Pfmdr1 and Pfcrt in Changing Chloroquine, Amodiaquine, Mefloquine and Lumefantrine Susceptibility in Western-Kenya P. falciparum Samples during 2008–2011

Cited by 87 publications

References 44 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

Polymorphic patterns of pfcrt and pfmdr1 in Plasmodium falciparum isolates along the Thai-Myanmar border

K13 Kelch Propeller Domain and mdr1 Sequence Polymorphism in Field Isolates From Northeast Region, India

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