Different Patterns of pfcrt and pfmdr1 Polymorphisms in P. falciparum Isolates from Nigeria and Brazil: The Potential Role of Antimalarial Drug Selection Pressure

Gbotosho, Grace O.; Folarin, Onikepe A.; Bustamante, Carolina; Silva, Luis Hildebrando Pereira da; Mesquita, Elieth Afonso de; Sowunmi, A.; Zalis, Mariano Gustavo; Oduola, A. M. J.; Happi, Christian T.

doi:10.4269/ajtmh.2012.11-0368

Cited by 20 publications

(23 citation statements)

References 23 publications

(34 reference statements)

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“…1). The fixation of the 76T allele is in agreement with other studies in Brazil [43, 55, 56], despite the withdrawal of CQ from national treatment guidelines in the mid-1980s [57]. The presence of the 76Y allele is in accordance with the description of isolates resistant to CQ in the same regions analysed here [43, 55].…”

Section: Resultssupporting

confidence: 91%

Assessment of copy number variation in genes related to drug resistance in Plasmodium vivax and Plasmodium falciparum isolates from the Brazilian Amazon and a systematic review of the literature

Costa

Amaral

Fontes

et al. 2017

Malar J

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BackgroundParasite resistance to anti-malarials represents a great obstacle for malaria elimination. The majority of studies have investigated the association between single-nucleotide polymorphisms (SNPs) and drug resistance; however, it is becoming clear that the copy number variation (CNV) is also associated with this parasite phenotype. To provide a baseline for molecular surveillance of anti-malarial drug resistance in the Brazilian Amazon, the present study characterized the genetic profile of both markers in the most common genes associated with drug resistance in Plasmodium falciparum and Plasmodium vivax isolates. Additionally, these data were compared to data published elsewhere applying a systematic review of the literature published over a 20-year time period.MethodsThe genomic DNA of 67 patients infected by P. falciparum and P. vivax from three Brazilian States was obtained between 2002 and 2012. CNV in P. falciparum multidrug resistance gene-1 (pfmdr1), GTP cyclohydrolase 1 (pfgch1) and P. vivax multidrug resistance gene-1 (pvmdr1) were assessed by real-time PCR assays. SNPs in the pfmdr1 and pfcrt genes were assessed by PCR–RFLP. A literature search for studies that analysed CNP in the same genes of P. falciparum and P. vivax was conducted between May 2014 and March 2017 across four databases.ResultsAll analysed samples of P. falciparum carried only one copy of pfmdr1 or pfgch1. Although the pfcrt K76T polymorphism, a determinant of CQ resistance, was present in all samples genotyped, the pfmdr1 N86Y was absent. For P. vivax isolates, an amplification rate of 20% was found for the pvmdr1 gene. The results of the study are in agreement with the low amplification rates for pfmdr1 gene evidenced in the Americas and Africa, while higher rates have been described in Southeast Asia. For P. vivax, very low rates of amplification for pvmdr1 have been described worldwide, with exceptions in French Guiana, Cambodia, Thailand and Brazil.ConclusionsThe present study was the first to evaluate gch1 CNV in P. falciparum isolates from Brazil, showing an absence of amplification of this gene more than 20 years after the withdrawal of the Brazilian antifolates therapeutic scheme. Furthermore, the rate of pvmdr1 amplification was significantly higher than that previously reported for isolates circulating in Northern Brazil.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1806-z) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 91%

Assessment of copy number variation in genes related to drug resistance in Plasmodium vivax and Plasmodium falciparum isolates from the Brazilian Amazon and a systematic review of the literature

Costa

Amaral

Fontes

et al. 2017

Malar J

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“…It is noteworthy that despite high grade chloroquine resistance and the association between transporter genes and resistance to chloroquine or amodiaquine in the area,20–24 artesunate-amodiaquine was still effective in the children < 5 years of age. The latter may be a result of the very limited use of amodiaquine monotherapy before the adoption of artesunate-amodiaquine as one of the first-line antimalarial drugs 10,25,26.…”

Section: Discussionmentioning

confidence: 99%

“…This may be caused by the antipyretic effect of the amodiaquine component of artesunate-amodiaquine 24,27. It is generally thought that the lumefantrine component of artemether-lumefantrine has little or no significant antipyretic effect.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Artemisinin-Based Combination Treatments of Uncomplicated Falciparum Malaria in Under-Five-Year-Old Nigerian Children

Oguche¹,

Okafor²,

Watila³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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The efficacy of 3-day regimens of artemether-lumefantrine and artesunate-amodiaquine were evaluated in 747 children < 5 years of age with uncomplicated malaria from six geographical areas of Nigeria. Fever clearance was significantly faster (P = 0.006) and the proportion of children with parasitemia 1 day after treatment began was significantly lower (P = 0.016) in artesunate-amodiaquine—compared with artemether-lumefantrine-treated children. Parasite clearance times were similar with both treatments. Overall efficacy was 96.3% (95% confidence interval [CI] 94.5–97.6%), and was similar for both regimens. Polymerase chain reaction-corrected parasitologic cure rates on Day 28 were 96.9% (95% CI 93.9–98.2%) and 98.3% (95% CI 96.1–99.3%) for artemether-lumefantrine and artesunate-amodiaquine, respectively. Gametocyte carriage post treatment was significantly lower than pretreatment (P < 0.0001). In anemic children, mean time to recovery from anemia was 10 days (95% CI 9.04–10.9) and was similar for both regimens. Both treatments were well tolerated and are safe and efficacious treatments of uncomplicated falciparum malaria in young Nigerian children.

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“…The different pfcrt mutant haplotypes have a consistent geographical distribution: the CQR haplotype CVIET is predominant in southeast Asia and Africa, whereas the AQ-resistant (AQR) haplotype SagtVMNT is predominant in Asia and South America, and StctVMNT, from South America, is very rare in Africa (16).The wild-type haplotype CVMNK is widespread (6,16,29,38). A recent study reported the presence of the StctVMNT haplotype of pfcrt in Angola, but this has not yet been verified by others (15,37).…”

mentioning

confidence: 99%

“…Mutations in this gene have some association with geographic areas. Considering codons 86, 184, 1034, 1042, and 1246, the pfmdr1 CQR haplotype YYSND is common in Asia and Africa, whereas NFCDY has occurred more frequently in CQ-resistant parasites in the Americas (16,24,29,38).…”

mentioning

confidence: 99%

Various pfcrt and pfmdr1 Genotypes of Plasmodium falciparum Cocirculate with P. malariae, P. ovale spp., and P. vivax in Northern Angola

Fançony

Gamboa

Sebastião

et al. 2012

Antimicrob Agents Chemother

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dArtemisinin-based combination therapy for malaria has become widely available across Africa. Populations of Plasmodium falciparum that were previously dominated by chloroquine (CQ)-resistant genotypes are now under different drug selection pressures. P. malariae, P. ovale curtisi, and P. ovale wallikeri are sympatric with P. falciparum across the continent and are frequently present as coinfections. The prevalence of human Plasmodium species was determined by PCR using DNA from blood spots collected during a cross-sectional survey in northern Angola. P. falciparum was genotyped at resistance-associated loci in pfcrt and pfmdr1 by real-time PCR or by direct sequencing of amplicons. Of the 3,316 samples collected, 541 (16.3%) contained Plasmodium species infections; 477 (88.2%) of these were P. falciparum alone, 6.5% were P. falciparum and P. malariae together, and 1.1% were P. vivax alone. The majority of the remainder (3.7%) harbored P. ovale curtisi or P. ovale wallikeri alone or in combination with other species. Of 430 P. falciparum isolates genotyped for pfcrt, 61.6% carried the wild-type allele CVMNK at codons 72 to 76, either alone or in combination with the resistant allele CVIET. No other pfcrt allele was found. Wildtype alleles dominated at codons 86, 184, 1034, 1042, and 1246 of the pfmdr1 locus among the sequenced isolates. In contrast to previous studies, P. falciparum in the study area comprises an approximately equal mix of genotypes associated with CQ sensitivity and with CQ resistance, suggesting either lower drug pressure due to poor access to treatment in rural areas or a rapid impact of the policy change away from the use of standard monotherapies.

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Different Patterns of pfcrt and pfmdr1 Polymorphisms in P. falciparum Isolates from Nigeria and Brazil: The Potential Role of Antimalarial Drug Selection Pressure

Cited by 20 publications

References 23 publications

Assessment of copy number variation in genes related to drug resistance in Plasmodium vivax and Plasmodium falciparum isolates from the Brazilian Amazon and a systematic review of the literature

Assessment of copy number variation in genes related to drug resistance in Plasmodium vivax and Plasmodium falciparum isolates from the Brazilian Amazon and a systematic review of the literature

Efficacy of Artemisinin-Based Combination Treatments of Uncomplicated Falciparum Malaria in Under-Five-Year-Old Nigerian Children

Various pfcrt and pfmdr1 Genotypes of Plasmodium falciparum Cocirculate with P. malariae, P. ovale spp., and P. vivax in Northern Angola

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