Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

Menegon, Michela; Talha, Albadawi Abdelbagi; Severini, Carlo; Elbushra, S. M.; Mohamedani, Ahmed Abdalla; Malik, Elfatih M.; Mohamed, Tarig Awad; Wernsdorfer, Walther H.; Majori, Giancarlo; Nour, Bakri Y. M.

doi:10.4269/ajtmh.2010.09-0514

Cited by 21 publications

(27 citation statements)

References 53 publications

(49 reference statements)

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“…Many of the haplotypes detected in this study have been reported previously in Africa [28], [29]. Although the most dramatic increase was noted in the septuple mutant, T 76 Y 86 I 51 R 59 N 108 G 437 E 540 , from baseline to the year 5 survey, there was also a substantial increase in isolates containing the pfmdr1-86 sensitive sextuple mutant, T 76 N 86 I 51 R 59 N 108 G 437 E 540 .…”

Section: Discussionsupporting

confidence: 75%

Effect of Transmission Reduction by Insecticide-Treated Bednets (ITNs) on Antimalarial Drug Resistance in Western Kenya

et al. 2011

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Despite the clear public health benefit of insecticide-treated bednets (ITNs), the impact of malaria transmission-reduction by vector control on the spread of drug resistance is not well understood. In the present study, the effect of sustained transmission reduction by ITNs on the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) in children under the age of five years was investigated during an ITN trial in Asembo area, western Kenya. During the ITN trial, the national first line antimalarial treatment changed from CQ to SP. Smear-positive samples collected from cross sectional surveys prior to ITN introduction (baseline, n = 250) and five years post-ITN intervention (year 5 survey, n = 242) were genotyped for single nucleotide polymorphisms (SNPs) at dhfr-51, 59, 108, 164 and dhps-437, 540 (SP resistance), and pfcrt-76 and pfmdr1-86 (CQ resistance). The association between the drug resistance mutations and epidemiological variables was evaluated. There were significant increases in the prevalence of SP dhps mutations and the dhfr/dhps quintuple mutant, and a significant reduction in the proportion of mixed infections detected at dhfr-51, 59 and dhps-437, 540 SNPs from baseline to the year 5 survey. There was no change in the high prevalence of pfcrt-76 and pfmdr1-86 mutations. Multivariable regression analysis further showed that current antifolate use and year of survey were significantly associated with more SP drug resistance mutations. These results suggest that increased antifolate drug use due to drug policy change likely led to the high prevalence of SP mutations 5 years post-ITN intervention and reduced transmission had no apparent effect on the existing high prevalence of CQ mutations. There is no evidence from the current study that sustained transmission reduction by ITNs reduces the prevalence of genes associated with malaria drug resistance.

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Section: Discussionsupporting

confidence: 75%

Effect of Transmission Reduction by Insecticide-Treated Bednets (ITNs) on Antimalarial Drug Resistance in Western Kenya

et al. 2011

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“…falciparum population in eastern Sudan carrying the mutant pfcrt allele CVIET [7]. Lower drug pressure is reflected by more wild type pfcrt where transmission is higher and perennial in central Sudan [53]. Moreover SP has been used intensively in patients where CQ failed.…”

Section: Discussionmentioning

confidence: 99%

Selection of pfdhfr/pfdhps alleles and declining artesunate/sulphadoxine-pyrimethamine efficacy against Plasmodium falciparum eight years after deployment in eastern Sudan

Gadalla

Abdallah

Atwal

et al. 2013

Malar J

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BackgroundArtesunate/sulphadoxine-pyrimethamine (AS/SP) has been the first-line treatment for falciparum malaria in Sudan since 2004. The impact of this combination on anti-malarial resistance-associated molecular markers has not been investigated. In this study, an evaluation of the efficacy and prevalence of drug resistance alleles (pfcrt, pfmdr1, pfdhfr and pfdhps) eight years after the adoption of AS/SP in eastern Sudan is reported.MethodsA 28-day follow-up efficacy trial of AS/SP was conducted in eastern Sudan during the 2012 transmission season. Blood smears were collected from patients on days 0, 1, 2, 3, 7, 14, 21 and 28. Blood spots on filter paper were obtained pre-treatment and on the day the patient was parasite positive by microscopy. Genotyping of alleles was performed by qPCR (pfcrt 72–76 and pfmdr1 copy number) and direct sequencing of pfmdr1, pfdhfr and pfdhps.ResultsSixty-three patients out of 68 (93%) completed the 28-day follow-up, adequate clinical, and parasitological response occurred in 90.5% and 85.3% of the patients in the per-protocol and intent-to-treat analyses, respectively. PCR corrected per-protocol efficacy was 93.7%. The enrolment prevalence of pfcrt-CVMNK was 30.2% and pfmdr1-N86 was 40.3%. The pfmdr1 haplotype NFD occurred in 32.8% of pre-treatment samples and was significantly higher than previous reports (Fisher’s exact p = 0.0001). The pfdhfr-51I/108N combination occurred in all sequenced isolates and 59R was observed in a single individual. pfdhps substitutions 436A, 437G, 540E, 581G and 613S were observed at 7.8, 77.3, 76.9%, 33.8% and 0.0%, respectively. Treatment failures were associated with the pfdhps haplotype SGEGA at these five codons (OR 7.3; 95% CI 0.65 - 368; p = 0.048).ConclusionThe decrease of CQR associated genotypes reflects the formal policy of complete removal of CQ in Sudan. However, the frequency of markers associated with SP failure is increasing in this study area and may be contributing to the treatment efficacy falling below 90%. Further monitoring of AS/SP efficacy and of post-treatment selection of pfdhfr and pfdhps alleles in vivo is required to inform future treatment guidelines.

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“…Different mutations of Pfcrt indicating resistance have been reported in this study with total of 25.8%. However, this percentage is low compared to other areas in the country where Pfcrt mutations ranging from 63 to 100% were reported [7,11,16,30,31]. Chloroquine resistance mutations is not reversible.…”

Section: Discussionmentioning

confidence: 77%

“…Chloroquine resistance emerged worldwide as early as late fifties in Southeast Asia and South America [5]. In Sudan, chloroquine resistance started in late 1970s, and treatment failure became alarmingly high until the introduction of ACT in 2005 [4,6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Single nucleotide polymorphisms (SNPs) in Pfcrt and Pfmdr1 genes have been correlated with chloroquine resistance for P. falciparum around the world [8,9]. Mutations in these genes have been identified in several studies from different parts of the Sudan [7,10,11]. The resistant haplotypes of Pfcrt have been identified as 72-76 CVIET and Pfmdr1 responsible for chloroquine resistance as 86Y [8,9,12].…”

Section: Introductionmentioning

confidence: 99%

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Assessment of Plasmodium falciparum drug resistance molecular markers from the Blue Nile State, Southeast Sudan

Mohamed

Hussien

Mohamed

et al. 2020

Malar J

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Background: Plasmodium falciparum malaria is a public health problem worldwide. Malaria treatment policy has faced periodic changes due to emergence of drug resistant parasites. In Sudan chloroquine has been replaced by artesunate and sulfadoxine/pyrimethamine (AS/SP) in 2005 and to artemether-lumefantrine (AL) in 2017, due to the development of drug resistance. Different molecular markers have been used to monitor the status of drug resistant P. falciparum. This study aimed to determine the frequency of malaria drug resistance molecular markers in Southeast Sudan. Methods:The samples of this study were day zero dried blood spot samples collected from efficacy studies in the Blue Nile State from November 2015 to January 2016. A total of 130 samples were amplified and sequenced using illumina Miseq platform. The molecular markers included were Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, Pfk13, exonuclease and artemisinin resistant (ART-R) genetic background (Pfmdr2, ferroredoxine, Pfcrt and Pfarps10). Results:Resistance markers for chloroquine were detected in 25.8% of the samples as mutant haplotype Pfcrt 72-76 CVIET and 21.7% Pfmdr1 86Y. Pfdhfr mutations were detected in codons 51, 59 and 108. The ICNI double-mutant haplotype was the most prevalent (69%). Pfdhps mutations were detected in codons 436, 437, 540, 581 and 613. The SGEGA triple-mutant haplotype was the most prevalent (43%). In Pfdhfr/Pfdhps combined mutation, quintuple mutation ICNI/SGEGA is the most frequent one (29%). Six of the seven treatment failure samples had quintuple mutation and the seventh was quadruple. This was significantly higher from the adequately responsive group (P < 0.01). Pfk13 novel mutations were found in 7 (8.8%) samples, which were not linked to artemisinin resistance. Mutations in ART-R genetic background genes ranged from zero to 7%. Exonuclease mutation was not detected.

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Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

Cited by 21 publications

References 53 publications

Effect of Transmission Reduction by Insecticide-Treated Bednets (ITNs) on Antimalarial Drug Resistance in Western Kenya

Effect of Transmission Reduction by Insecticide-Treated Bednets (ITNs) on Antimalarial Drug Resistance in Western Kenya

Selection of pfdhfr/pfdhps alleles and declining artesunate/sulphadoxine-pyrimethamine efficacy against Plasmodium falciparum eight years after deployment in eastern Sudan

Assessment of Plasmodium falciparum drug resistance molecular markers from the Blue Nile State, Southeast Sudan

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