Molecular Surveillance as Monitoring Tool for Drug-Resistant Plasmodium falciparum in Suriname

Adhin, Malti R.; Labadie-Bracho, Mergiory; Bretas, Gustavo

doi:10.4269/ajtmh.12-0695

Cited by 15 publications

(15 citation statements)

References 46 publications

(54 reference statements)

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“…In this study, the N86 wild type was detected in almost all samples from periods 1 and 2, in agreement with earlier reports from Suriname [51] and other South American countries [53, 54]. Considering that in period 1 Brazilian national chemotherapy guidelines recommended three different therapeutic approaches, i.e., use of chloroquine, quinine and mefloquine, it is possible to conclude that drug pressure was not able to select a mutant genotype.…”

Section: Discussionsupporting

confidence: 91%

Analysis of polymorphisms in Plasmodium falciparum genes related to drug resistance: a survey over four decades under different treatment policies in Brazil

Inoue

Lopes

Rosário

et al. 2014

Malar J

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BackgroundAnti-malarial resistance in Plasmodium falciparum remains an obstacle for malaria control. Resistance-associated genes were analysed in Brazilian samples over four decades to evaluate the impact of different treatment regimens on the parasite genetic profile.MethodsSamples were collected on filter paper from patients infected in the Amazon region from 1984 to 2011. DNA was extracted with Chelex® 100 and monoinfection confirmed by PCR. SNPs in the pfcrt, pfmdr1, pfdhfr and pfdhps genes were assessed by PCR-RFLP. The pfmdr1 copy number was estimated using real time quantitative PCR with SYBR® Green. Parasite response was assessed ex vivo with seven concentrations of each anti-malarial. Patients were treated according to Brazilian guidelines: quinine plus tetracycline or mefloquine in period 1 and ACT in period 2.ResultsAll 96 samples presented the pfcrt 76T mutant throughout the assessed periods. In addition, all isolates showed ex vivo chloroquine resistance. The pfmdr1 86Y was detected in 1.5% of samples in period 1, and in 25% in period 2. All samples presented the pfmdr1 1246Y. The analysis of pfmdr1 copy number showed amplification in 37.3% in period 1 and in 42% in period 2. Mutations in pfdhfr were shown as follows: 51I in all samples in period 1 and in 81.2% in period 2; 59R in 6.4% in period 2. The pfdhfr 108N and the pfdhps 437G were seen in all samples along time; the pfdhps 540E in 93.7% in period 1 and in 75% in period 2.ConclusionsThe 76T mutation associated to chloroquine resistance is still present in the parasite population, although this anti-malarial was withdrawn from the chemotherapy of P. falciparum in Brazil in the mid-1980s. All isolates assayed ex vivo for chloroquine showed resistant phenotype and 76T. No association was observed between pfmdr1 mutations and resistance to quinine, mefloquine and artemisinin derivatives. Additionally, the pfdhfr 108N mutation was detected in all samples throughout the evaluated periods, demonstrating fixation of the mutant allele in the parasite population. Changes in Brazilian national guidelines for the malaria chemotherapy in the last 27 years yielded a discreet genetic impact in the parasite population.

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Section: Discussionsupporting

confidence: 91%

Analysis of polymorphisms in Plasmodium falciparum genes related to drug resistance: a survey over four decades under different treatment policies in Brazil

Inoue

Lopes

Rosário

et al. 2014

Malar J

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“…These findings have important implications for understanding drug resistance evolution when standard resistance alleles reach fixation and can lose their utility as markers because of adaptive changes at other amino acid positions or loci in the genome. In South America, the prevalence of the CQR marker K76T in the drug efflux transmembrane protein PfCRT has remained high, despite CQ having been abandoned for the treatment of P. falciparum infections (7)(8)(9). This situation contrasts with multiple settings in Africa, where the majority of molecular studies (10)(11)(12)(13) have documented an increase in the prevalence of WT pfcrt after CQ withdrawal.…”

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confidence: 56%

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Moss

Dhingra

Volney

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

131

122

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In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. malaria | drug resistance | evolution | Plasmodium falciparum | PfCRT

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“…The finding in previous studies such as these that there was a decrease in the prevalence of the pfcrt 76T mutated allele and a re-emergence of CQ-sensitive strains some years after abandoning CQ was controversial, particularly as many studies in Africa documented an increase in the re-emergence of the wild type of pfcrt 76 after complete CQ withdrawal ( Laufer et al , 2006 ; Mohammed et al , 2013 ; Mbogo et al , 2014 ; Mekonnen et al , 2014 ). In contrast, South American isolates of P. falciparum have been reported to retain their mutated types despite the cessation of CQ use ( Vieira et al , 2004 ; Griffing et al , 2010 ; Adhin, Labadie-Bracho & Bretas , 2013 ). Similarly, studies conducted in Ethiopia have found a fixation of pfcrt 76T mutations after cessation of CQ use for more than a decade ( Mula et al , 2011 ; Golassa et al , 2014 ).…”

Section: Discussionmentioning

confidence: 97%

Different patterns ofpfcrtandpfmdr1polymorphism inPlasmodium falciparumisolates from Tehama region, Yemen

Atroosh

Al-Mekhlafi

Al-Jasari

et al. 2016

PeerJ

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Introduction. Despite the efforts of the malaria control programme, malaria morbidity is still a common health problem in Yemen, with 60% of the population at risk. Plasmodium falciparum is responsible for 99% of malaria cases. The emergence in Yemen of parasite resistance to chloroquine (CQ) prompted the adoption of artemisinin combination therapy (ACT) in 2009, which involves the use of artesunate plus sulphadoxine-pyrimethamine (AS + SP). However, CQ was retained as the drug of choice for vivax malaria. To assess the impact of the change in the malaria treatment policy five years after its introduction, the present study investigated the mutations in the CQ resistance transporter (pfcrt) and multidrug resistance 1 (pfmdr1) genes.Method. A molecular investigation of 10 codons of pfcrt (72–76, 220, 271, 326, 356, and 371) and five codons of pfmdr1 (86, 184, 1034, 1042, and 1246) was conducted on P. falciparum isolates from districts with the highest malaria endemicity in the Hodeidah and Al-Mahwit governorates in Tehama region, Yemen. A total of 86 positive cases of falciparum monoinfection were investigated for the presence of mutations related to CQ and other antimalarials using a PCR-RFLP assay.Results. There was a wide prevalence of pfcrt gene mutations with the pfcrt 76T CQ resistance marker being predominant (97.7%). The prevalence of other pfcrt mutations varied from high (75E: 88%) to moderate (74I: 79.1%, 220S: 69.8%, 271E and 371I: 53.5%) or low (326S: 36%, 72S: 10.5%). Mutated pfcrt 72–76 amino acids haplotypes were highly prevalent (98.8%). Among these, the CVIET classic, old-world African/Southeast Asian haplotype was the most predominant, and was mostly found in the isolates from the Khamis Bani Saad district of Al-Mahwit (93.1%) and the AdDahi district of Hodeidah (88.9%). However, it was only found in 26.3% of the isolates from the Bajil district of Hodeidah. Surprisingly, the SVMNT new-world South American haplotype was exclusively detected in 9.3% of the isolates from the Bajil district of Hodeidah. Mutations at Y184F of pfmdr1 were found in all isolates (100%) from all districts. The mutation for codons 1034C and 86Y were found only in the isolates from the AdDahi and Khamis Bani Saad districts. Overall, the AdDahi and Khamis Bani Saad districts were similar in terms of carrying most of the mutations in the pfcrt and pfmdr1 genes, while there was a lower prevalence of mutation in the isolates from the Bajil district.Conclusion. The high prevalence of mutations in pfcrt 5 years after the official cessation of CQ use against P. falciparum suggests that there is sustained CQ pressure on P. falciparum isolates in the study area. Moreover, the low prevalence of mutations in the pfmdr1 gene could be a good indicator of the high susceptibility of P. falciparum isolates to antimalarials other than CQ. A new strategy to ensure the complete nationwide withdrawal of CQ from the private drug market is recommended.

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Molecular Surveillance as Monitoring Tool for Drug-Resistant Plasmodium falciparum in Suriname

Cited by 15 publications

References 46 publications

Analysis of polymorphisms in Plasmodium falciparum genes related to drug resistance: a survey over four decades under different treatment policies in Brazil

Analysis of polymorphisms in Plasmodium falciparum genes related to drug resistance: a survey over four decades under different treatment policies in Brazil

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Different patterns ofpfcrtandpfmdr1polymorphism inPlasmodium falciparumisolates from Tehama region, Yemen

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