Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

Vargas-Rodríguez, Rosa del Carmen Miluska; Bastos, Melissa da Silva; Menezes, Marcelo Bezerra de; Orjuela-Sánchez, Pamela; Ferreira, Marcelo U.

doi:10.4269/ajtmh.2012.12-0094

Cited by 32 publications

(31 citation statements)

References 33 publications

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“…These results concur with a previous study which used real-time PCR to quantify pvmdr1 CN, identifying CN amplifications in just 2% (1/49) of isolates from Myanmar in 2008 [13]. The survey by Imwong and colleagues found the same genetic background in pvmdr1 CN amplifications from Myanmar, Laos and Thailand, suggesting a common origin, most likely from Thailand, where MQ pressure has historically been greatest and pmvdr1 CN accordingly most prevalent [13, 43]. The pvmdr1 CN amplifications observed in this study most likely also originated from Thailand, but remained at low frequency owing to low levels of MQ pressure on the P. vivax population.…”

Section: Discussionsupporting

confidence: 88%

Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow

Htun

Mon

Aye

et al. 2017

Malar J

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Background Plasmodium vivax malaria remains a major public health burden in Myanmar. Resistance to chloroquine (CQ), the first-line treatment for P. vivax, has been reported in the country and has potential to undermine local control efforts.MethodsPatients over 6 years of age with uncomplicated P. vivax mono-infection were enrolled into clinical efficacy studies in Myawaddy in 2014 and Kawthoung in 2012. Study participants received a standard dose of CQ (25 mg/kg over 3 days) followed by weekly review until day 28. Pvmdr1 copy number (CN) and microsatellite diversity were assessed on samples from the patients enrolled in the clinical study and additional cross-sectional surveys undertaken in Myawaddy and Shwegyin in 2012.ResultsA total of 85 patients were enrolled in the CQ clinical studies, 25 in Myawaddy and 60 in Kawthoung. One patient in Myawaddy (1.2%) had an early treatment failure and two patients (2.3%) in Kawthoung presented with late treatment failures on day 28. The day 28 efficacy was 92.0% (95% CI 71.6–97.9) in Myawaddy and 98.3% (95% CI 88.7–99.8) in Kawthoung. By day 2, 92.2% (23/25) in Myawaddy and 85.0% (51/60) in Kawthoung were aparasitaemic. Genotyping and pvmdr1 CN assessment was undertaken on 43, 52 and 46 clinical isolates from Myawaddy, Kawthoung and Shwegyin respectively. Pvmdr1 amplification was observed in 3.2% (1/31) of isolates in Myawaddy, 0% (0/49) in Kawthoung and 2.5% (1/40) in Shwegyin. Diversity was high in all sites (H E 0.855–0.876), with low inter-population differentiation (F ST 0.016–0.026, P < 0.05).ConclusionsTreatment failures after chloroquine were observed following chloroquine monotherapy, with pvmdr1 amplification present in both Myawaddy and Shwegyin. The results emphasize the importance of ongoing P. vivax drug resistance surveillance in Myanmar, particularly given the potential connectivity between parasite population at different sites.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1912-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 88%

Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow

Htun

Mon

Aye

et al. 2017

Malar J

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“…Therefore, these parasites could potentially be resistant to chloroquine; however, an association with clinical drug response or in vitro susceptibility have not been investigated. This value is similar to the 1.8% prevalence reported in Brazil [41]. …”

Section: Discussionsupporting

confidence: 90%

Plasmodium vivax multidrug resistance-1 gene polymorphism in French Guiana

Faway

Musset

Volney

et al. 2016

Malar J

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Background Plasmodium vivax malaria is a major public health problem in French Guiana. Some cases of resistance to chloroquine, the first-line treatment used against P. vivax malaria, have been described in the Brazilian Amazon region. The aim of this study is to investigate a possible dispersion of chloroquine-resistant P. vivax isolates in French Guiana. The genotype, polymorphism and copy number variation, of the P. vivax multidrug resistance gene-1 (pvmdr1) have been previously associated with modification of the susceptibility to chloroquine.MethodsThe pvmdr1 gene polymorphism was evaluated by sequencing and copy number variation was assessed by real-time PCR, in P. vivax isolates obtained from 591 symptomatic patients from 1997 to 2013.ResultsThe results reveal that 1.0% [95% CI 0.4–2.2] of French Guiana isolates carry the mutations Y976F and F1076L, and that the proportion of isolates with multiple copies of pvmdr1 has significantly decreased over time, from 71.3% (OR = 6.2 [95% CI 62.9–78.7], p < 0.0001) in 1997–2004 to 12.8% (OR = 0.03 [95% CI 9.4–16.9], p < 0.0001) in 2009–2013. A statistically significant relationship was found between Guf-A (harboring the single mutation T958M) and Sal-1 (wild type) alleles and pvmdr1 copy number.ConclusionsFew P. vivax isolates harboring chloroquine-resistant mutations in the pvmdr1 gene are circulating in French Guiana. However, the decrease in the prevalence of isolates carrying multiple copies of pvmdr1 might indicate that the P. vivax population in French Guiana is evolving towards a decreased susceptibility to chloroquine.

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“…Brazil: From 2008 to 2011, patients presenting with malaria symptoms at clinics in Acrelândia and Plácido de Castro [17] were screened by microscopy. Patients with Plasmodium infection provided 15-ml venous blood samples that were further examined for malaria parasites by a quantitative real-time PCR specific for the 18S rRNA gene.…”

Section: Methodsmentioning

confidence: 99%

Independent Origin and Global Distribution of Distinct Plasmodium vivax Duffy Binding Protein Gene Duplications

Hostetler

Kanjee

et al. 2016

PLoS Negl Trop Dis

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BackgroundPlasmodium vivax causes the majority of malaria episodes outside Africa, but remains a relatively understudied pathogen. The pathology of P. vivax infection depends critically on the parasite’s ability to recognize and invade human erythrocytes. This invasion process involves an interaction between P. vivax Duffy Binding Protein (PvDBP) in merozoites and the Duffy antigen receptor for chemokines (DARC) on the erythrocyte surface. Whole-genome sequencing of clinical isolates recently established that some P. vivax genomes contain two copies of the PvDBP gene. The frequency of this duplication is particularly high in Madagascar, where there is also evidence for P. vivax infection in DARC-negative individuals. The functional significance and global prevalence of this duplication, and whether there are other copy number variations at the PvDBP locus, is unknown.Methodology/Principal FindingsUsing whole-genome sequencing and PCR to study the PvDBP locus in P. vivax clinical isolates, we found that PvDBP duplication is widespread in Cambodia. The boundaries of the Cambodian PvDBP duplication differ from those previously identified in Madagascar, meaning that current molecular assays were unable to detect it. The Cambodian PvDBP duplication did not associate with parasite density or DARC genotype, and ranged in prevalence from 20% to 38% over four annual transmission seasons in Cambodia. This duplication was also present in P. vivax isolates from Brazil and Ethiopia, but not India.Conclusions/SignificancePvDBP duplications are much more widespread and complex than previously thought, and at least two distinct duplications are circulating globally. The same duplication boundaries were identified in parasites from three continents, and were found at high prevalence in human populations where DARC-negativity is essentially absent. It is therefore unlikely that PvDBP duplication is associated with infection of DARC-negative individuals, but functional tests will be required to confirm this hypothesis.

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Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

Cited by 32 publications

References 33 publications

Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow

Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow

Plasmodium vivax multidrug resistance-1 gene polymorphism in French Guiana

Independent Origin and Global Distribution of Distinct Plasmodium vivax Duffy Binding Protein Gene Duplications

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