Occurrence of the Southeast Asian/South American SVMNT Haplotype of the Chloroquine‐Resistance Transporter Gene in<i>Plasmodium falciparum</i>in Tanzania

Alifrangis, Michael; Dalgaard, Michael B.; Lusingu, John; Vestergaard, Lasse S; Staalsøe, Trine; Jensen, Anja T. R.; Enevold, Anders; Rønn, Anita M.; Khalil, Insaf F.; Warhurst, David C.; Lemnge, Martha; Theander, Thor G.; Bygbjerg, Ib Christian

doi:10.1086/504269

Cited by 80 publications

(100 citation statements)

References 18 publications

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“…Consistent with these observations, Mehlotra et al (57) have found that variation in the pfcrt and pfmdr1 loci of Asian and African parasites populations is maintained by substantially different mechanisms than in South American populations where the haplotypes of pfcrt and pfmdr1 both exhibit relatively low levels of diversity. We also note the recent observation of increasingly prevalent SVMNT parasites in Tanzania where AQ pressure has presumably facilitated their spread (51,52). In areas of Africa where AQ is used as monotherapy or in combination with partner antimalarial drugs, CVIET parasites may be under displacement by highly AQ-resistant, CQ-resistant SVMNT parasites that are as advantaged and persistent as in South America.…”

Section: G8mentioning

confidence: 87%

“…4). Worrisomely, an increasing prevalence of SVMNT parasites in Tanzania (7G8-type PfCRT; possibly another new focus) has been associated with a switch from CQ to AQ use (2001) and more frequent observations of AQR from that country in recent years (51,52). * Patterns of pfcrt and pfmdr1 haplotypes in malaria endemic regions also depend on the fitness costs of these haplotypes relative to the advantages they offer to parasite populations.…”

Section: G8mentioning

confidence: 99%

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Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

Sá

Twu

Hayton

et al. 2009

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

247

230

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Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum originated from at least six foci in South America, Asia, and Oceania. Malaria parasites from these locations exhibit contrasting resistance phenotypes that are distinguished by point mutations and microsatellite polymorphisms in and near the CQR transporter gene, pfcrt, and the multidrug resistance transporter gene, pfmdr1. Amodiaquine (AQ), a 4-aminoquinoline related to CQ, is recommended and often used successfully against CQ-resistant P. falciparum in Africa, but it is largely ineffective across large regions of South America. The relationship of different pfcrt and pfmdr1 combinations to these drug-resistant phenotypes has been unclear. In two P. falciparum genetic crosses, particular pfcrt and pfmdr1 alleles from South America interact to yield greater levels of resistance to monodesethylamodiaquine (MDAQ; the active metabolite of AQ) than to CQ, whereas a pfcrt allele from Southeast Asia and Africa is linked to greater CQ than MDAQ resistance with all partner pfmdr1 alleles. These results, together with (i) available haplotype data from other parasites; (ii) evidence for an emerging focus of AQ resistance in Tanzania; and (iii) the persistence of 4-aminoquinoline-resistant parasites in South America, where CQ and AQ use is largely discontinued, suggest that different histories of drug use on the two continents have driven the selection of distinct suites of pfcrt and pfmdr1 mutations. Increasing use of AQ in Africa poses the threat of a selective sweep of highly AQ-resistant, CQ-resistant parasites with pfcrt and pfmdr1 mutations that are as advantaged and persistent as in South America.

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Section: G8mentioning

confidence: 87%

Section: G8mentioning

confidence: 99%

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

Sá

Twu

Hayton

et al. 2009

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

247

230

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“…In recent years, in addition to the conventional in vivo and in vitro methods, the molecular markersbased approach to study and elucidate antimalarial drug resistance has proved useful [22][23][24][25][26]29,30,32]. In this study, we described the distribution of pfcrt K76T and pfmdr1 N86Y mutations in the study area and attempted to evaluate the correlation of these mutations with in vivo clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…In areas that have low levels of complex and multiclonal malaria infections, the inbreeding of malaria parasites having mutant genotypes could spread the antimalarial drug resistance at an extraordinary rate [28]. The prevalence of the SVMNT haplotype in highly malaria-endemic study areas indicates the wide spread of chloroquineresistant P. falciparum, which might have evolved due to prolonged use of antimalarial amodiaquine in malaria chemotherapy [29][30][31]. Studies have shown that P. falciparum mutant pfcrt haplotypes have selective advantage in competitive mosquito infections by protecting immature gametocytes from chloroquine [32].…”

Section: Discussionmentioning

confidence: 99%

Pfcrt mutant haplotypes may not correspond with chloroquine resistance

Goswami

Dhiman

Rabha

et al. 2014

J Infect Dev Ctries

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Introduction: Chloroquine resistance in Plasmodium falciparum is associated with mutations in pfcrt and pfmdr1 genes. The frequency distribution of pfcrt K76T and pfmdr1 N86Y mutations and their association with chloroquine susceptibility was studied in an endemic area along the Indo-Bangladesh border. Methodology: A single-arm prospective study of clinical and parasitological responses in P. falciparum malaria patients to chloroquine was conducted in vivo. PCR-RFLP assay was used to detect pfcrt K76T and pfmdr1 N86Y mutations in P. falciparum. The PCR products of pfcrt gene were sequenced, translated and aligned for haplotyping. Results: Out of 63 cases, 44 (69.8%) responded adequately to chloroquine treatment. Pfcrt K76T mutation was recorded in 100% of the treatment failure cases, whereas pfmdr1 N86Y mutation was found in 52.6% of the cases only. Early treatment failure (84.2%) occurred more frequently than late treatment failure (15.8%). Kaplan-Meier survival analysis showed that the probability estimate for treatment success after 7 and 15 days was 0.84 (95% CI = 0.72-0.92) and 0.70 (95% CI = 0.57-0.80), respectively. Sequence analysis of 72 to 76 pfcrt gene codons revealed the presence of two mutant (CVMNT, CVIET) and two wild (CVMNK, CVIEK) haplotypes. The mutant CVIET haplotype was predominantly distributed (42.1%). Conclusions: The presence of mutations in pfcrt K76T and pfmdr1 N86Y genes is not sufficient to explain the therapeutic efficacy of chloroquine to P. falciparum. Study suggests that pfcrt K76T mutant haplotypes are widely distributed and are spreading diligently, which needs to be taken into account in devising an antimalarial policy.

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“…1,2 Chloroquine-sensitive strains from all geographic regions maintain an invariable wild-type CVMNK (amino acids 72-76) haplotype, whereas there are a number of predominant CQRassociated haplotypes, CVIET allele in parasite population from Southeast Asia and Africa; SVMNT (SVMNT1) in Asia, South America, and Tanzania; S agt VMNT (SVMNT2) in South America; CVMET in Colombia; and CVMNT in South America and the Philippines. [3][4][5][6][7][8] In addition to pfcrt, polymorphisms including copy number variation and point mutations in the multidrug resistance gene, pfmdr1, contribute to parasite susceptibility to a variety of antimalarial drugs. 9,10 Studies have shown that mutations in this gene play a modulatory role in CQR.…”

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confidence: 99%

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

Gbotosho

Folarin²,

Bustamante³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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Abstract. The effect of antimalarial drug selection on pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from two distinct geographical locations was determined in 70 and 18 P. falciparum isolates from Nigeria and Brazil, respectively, using nested polymerase chain reaction and direct DNA sequencing approaches. All isolates from Brazil and 72% from Nigeria harbored the mutant SVMNT and CVIET pfcrt haplotype, respectively. The pfcrt CVMNT haplotype was also observed in (7%) of the Nigerian samples. One hundred percent (100%) and 54% of the parasites from Brazil and Nigeria, respectively, harbored wild-type pfmdr1Asn86. We provide first evidence of emergence of the CVMNT haplotype in West Africa. The high prevalence of pfcrt CVIET and SVMNT haplotypes in Nigeria and Brazil, respectively, is indicative of different selective pressure by chloroquine and amodiaquine. Continuous monitoring of pfcrt SVMNT haplotype is required in endemic areas of Africa, where artesunate-amodiaquine combination is used for treatment of acute uncomplicated malaria.

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Occurrence of the Southeast Asian/South American SVMNT Haplotype of the Chloroquine‐Resistance Transporter Gene inPlasmodium falciparumin Tanzania

Cited by 80 publications

References 18 publications

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

Pfcrt mutant haplotypes may not correspond with chloroquine resistance

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

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