Molecular Diagnosis of Resistance to Antimalarial Drugs during Epidemics and in War Zones

University of Maryland, Baltimore, Baltimore, Maryland, United States
The Journal of Infectious Diseases (Impact Factor: 6). 09/2004; 190(4):853-5. DOI: 10.1086/422758
Source: PubMed


Plasmodium falciparum mutations pfcrt K76T and the dhfr/dhps “quintuple mutant” are molecular markers of resistance to chloroquine and sulfadoxine-pyrimethamine, respectively. During
an epidemic of P. falciparum malaria in an area of political unrest in northern Mali, where standard efficacy studies have been impossible, we measured
the prevalence of these markers in a cross-sectional survey. In 80% of cases of infection, pfcrt K76T was detected, but none of the cases carried the dhfr/dhps quintuple mutant. On the basis of these results, chloroquine was replaced by sulfadoxine-pyrimethamine in control efforts.
This example illustrates how molecular markers for drug resistance can provide timely data that inform malaria-control policy
during epidemics and other emergency situations.

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    • "At a time when worrisome reports of reduced parasite sensitivity to ACTs are published from South East Asia and elsewhere [4] [15] [16], limited data is available on the status of resistance to ACTs in the Eastern Africa region since ACTs adoption about 10 years ago. The potential of molecular markers for predicting therapeutic efficacy has already been documented and demonstrated [5] [6] [12] [15] [17] [18]. In this study, we aimed to determine the prevalence of SNPs in the pfatpase6 gene at codons 263, 431, 623, and 769 in four high malaria transmission villages in Bondo ward in Handeni in North Eastern Tanzania, for changes in their frequencies over time between 2010 and 2013. "
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    ABSTRACT: We aimed to determine the current prevalence of four P. falciparum candidate artemisinin resistance biomarkers L263E, E431K, A623E, and S769N in the pfatpase6 gene in a high transmission area in Tanzania in a retrospective cross sectional study using 154 archived samples collected from three previous malaria studies in 2010, 2011 and 2013. Mutations in pfatpase6 gene were detected in parasite DNA isolated from Dried Blood Spots by using PCR-RFLP. We observed overall allelic frequencies for L263E, E431K, A623E, and S769N to be 5.8% (9/154), 16.2% (25/154), 0.0% (0/154), and 3.9% (6/154). The L263E mutation was not detected in 2010 but occurred at 3.9% and 2.6% in 2011 and 2013 respectively. The L263E mutation showed a significant change of frequency between 2010 and 2011, but not between 2011 and 2013 (íµí±ƒ < 0.05). Frequency of E431K was highest of all without any clear trend whereas S769N increased from 2.2% in 2010 to 3.6% in 2011 and 5.1% in 2013. A623E mutation was not detected. The worrisome detection and the increase in the frequency of S769N and other mutations calls for urgent assessment of temporal changes of known artemisinin biomarkers in association with in vivo ACT efficacy.
    Full-text · Article · Jan 2015 · Malaria Research and Treatment
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    • "Genetic association studies have identified and validated genetic markers of resistance for older anti-malarial drugs, such as CQ and SP (Cowman et al 1988; Peterson et al 1988; Sidhu et al 2002). Molecular epidemiology studies of drug resistant markers are a practical means of monitoring dynamic drug resistant parasite populations in different parts of the world and could be useful in planning drug efficacy studies (Djimde et al 2004). The presence of the single S108N mutation in a population is the minimum requirement for pyrimethamine resistance and is the first mutation seen as PYR resistance develops (Cowman et al 1988; Peterson et al 1988; Reeder et al 1996). "
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    ABSTRACT: Parasite drug resistance remains a great hindrance to effective control of malaria. Despite the widespread resistance, Sulphadoxine-Pyrimethamine (SP) is still used as one of the Artemisin-based combination therapies (ACTs). SP resistance has been associated with mutations in the dihydrofolate reductase (DHFR) gene of Plasmodium falciparum. We hypothesized that other factors may contribute to the prevalence of DHFR resistant genotypes in areas of limited use of SP in Ibadan, south-west Nigeria. Blood samples were collected from 100 children presenting with microscopically confirmed P. falciparum. Parasite DNA extracted from dried blood spots by Chelex method was analysed with a primary Polymerase Chain Reaction (PCR) and nested PCR for specific DHFR codons; 108, 51 and 59. Overall, 83% had resistant DHFR 108 genotypes. Mutations in the Ile51 and Arg59 were present in 69% and 76% respectively. The proportion of Ser108 increased significantly with age while the proportion of resistant genotypes Asn108 reduced with age. The prevalence of DHFR alleles differed between genders. Among the females, the prevalence of the Ser108 and Cys59 increased with age while the prevalence of the Asn108 and mixed infections Ser108/Asn108 decreased with age. There was an increased risk of the Asn108 resistant genotypes being present in the females in a 2:1 ratio [OR=2.3, 95% CI=1.2 – 4.5] when compared to the males [OR = 1.0, 95% CI= 0.8 – 2.1]. This study shows that other factors in addition to drug selection, specifically age and sex, may determine the distribution of DHFR resistant genotypes in areas of limited SP usage. Keywords: malaria, drug resistance, sulphadoxine-pyrimethamine, dihydrofolate reductase, artemisinin-based combination therapy.
    Full-text · Article · Aug 2013
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    • "These markers can be easily detected using finger-pricked blood samples collected onto filter papers. In addition, molecular markers may be useful not only in epidemic situations but also in war zones and refugee camps due to difficulties in measuring resistance by other means (Djimdé et al., 2004). Lessons inferred from molecular markers of resistance to formerly efficacious "
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    ABSTRACT: Antimalarial chemotherapy is one of the main pillars in the prevention and control of malaria. Following widespread resistance of Plasmodium falciparum to chloroquine, sulfadoxine-pyrimethamine came to the scene as an alternative to the cheap and well-tolerated chloroquine. However, widespread resistance to sulfadoxine- pyrimethamine has been documented. In vivo efficacy tests are the gold standard for assessing drug resistance and treatment failure. However, they have many disadvantages, such as influence of host immunity and drug pharmacokinetics. In vitro tests of antimalarial drug efficacy also have many technical difficulties. Molecular markers of resistance have emerged as epidemiologic tools to investigate antimalarial drug resistance even before becoming clinically evident. Mutations in P. falciparum dihydrofolate reductase and dihydrofolate synthase have been extensively studied as molecular markers for resistance to pyrimethamine and sulfadoxine, respectively. This review highlights the resistance of P. falciparum at the molecular level presenting both supporting and opposing studies on the utility of molecular markers.
    Full-text · Article · Nov 2012 · Acta Tropica
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