Field-based evidence for the linkage of pfcrt and pfdhfr drug-resistant malaria genotypes and clinical profiles of severe malaria in Niger

Ibrahim, Maman Laminou; Gay-Andrieu, Françoise; Adéhossi, Eric; Lacroix, Veronique; Randrianarivelojosia, Milijaona; Duchemin, Jean‐Bernard

doi:10.1016/j.micinf.2007.02.003

Cited by 15 publications

(15 citation statements)

References 27 publications

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“…This observation must be viewed in light of the results of in vivo tests conducted in Niger a decade ago, for which a treatment success rate of about 85% was reported for CQ. The trend in 2011 (11% of isolates presenting a mutated codon 76) is therefore distinctly different from those reported for molecular studies carried out between 2003 and 2007 in Niger, in which the prevalence of Pfcrt 76T was reported to be between 32.4% and 50.8% (22,32). However, given the limited number of isolates examined and the short time interval between these studies, it is too soon to draw any firm conclusions about a shift toward an improved susceptibility of parasites to CQ in Niger.…”

contrasting

confidence: 60%

Ex Vivo Responses of Plasmodium falciparum Clinical Isolates to Conventional and New Antimalarial Drugs in Niger

Issaka

Salissou

Aliyu

et al. 2013

Antimicrob Agents Chemother

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Little is known about resistance of Plasmodium falciparum to antimalarials in Sahelian countries. Here we investigated the drug susceptibilities of fresh isolates collected in Niger post-deployment of artemisinin-based combination therapies (ACTs). We found that the parasites remained highly susceptible to new (dihydroartemisinin, lumefantrine, pyronaridine, and piperaquine) and conventional (amodiaquine and chloroquine) antimalarial drugs. The introduction of ACTs in 2005 and their further deployment nationwide have therefore not resulted in a decrease in P. falciparum susceptibilities to these antimalarials. The WHO estimates that 50% of the world's population is exposed to malaria. In 2010, 216 million cases and more than 650,000 deaths from malaria were reported. Despite a decrease in the number of confirmed cases in some parts of the world, the situation remains heterogeneous and worrying in Africa (1). Together with respiratory infections and diarrheal diseases, malaria is one of the leading causes of death in Niger. Malaria transmission rates are high, with a mean incidence of 80 cases per 1,000 inhabitants. Despite the complementary nature of interventions in the field, which have strengthened in recent years, the number of cases has steadily risen over the last 20 years, reaching three million in 2010 (2, 3). There are several reasons for the deterioration of the public health situation with regard to malaria, and the increase in resistance to antimalarial drugs is considered a key factor. In Niger, infections are currently treated with combinations of drugs including an artemisinin (ART) derivative (artemisinin-based combination treatment, or ACT) (4). Since 2005, ACT has been proposed as the first-line treatment for the management of uncomplicated malaria. The use of such treatments throughout Niger was greatly expanded in 2010 by the implementation of a Global Fund Affordable Malaria Facility mechanism (5). Thereby, the drug pressure exerted on Plasmodium falciparum increases the risk of selection of parasites with altered susceptibility to antimalarials. This seems to be inevitable, as demonstrated by recent observations in Asia, which have revealed the presence of parasites less sensitive to artemisinins (6). The risk of emerging resistance to ACT makes it necessary to monitor the susceptibilities of parasites to antimalarial drugs, particularly those used in combination with artemisinin derivatives, on a regular basis and to search for new molecules with antimalarial activity.In this context, a study was carried out in Niger in 2011, at Gaya in the Dosso region, 250 km south of Niamey (3.44°N, 11.9°E), to evaluate the response of P. falciparum isolates to lumefantrine (LUM) and amodiaquine diphosphate (AQ), both of which are widely used in the ACTs distributed in Niger. In addition, responses to alternative molecules, such as pyronaridine (PYD) and piperaquine (PIP), both currently not available in Niger, as well as dihydroartemisinin (DHA) and chloroquine (CQ), were investigated. P. falciparum is...

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contrasting

confidence: 60%

Ex Vivo Responses of Plasmodium falciparum Clinical Isolates to Conventional and New Antimalarial Drugs in Niger

Issaka

Salissou

Aliyu

et al. 2013

Antimicrob Agents Chemother

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“…When PfDHPS 540E mutant was joined together with the triple mutation of PfDHFR as the quintuple mutation, it indicates a significant predictor of SP treatment failure. Below 50% prevalence of the PfDHFR 540 mutation is used as a threshold of a parasite genetic marker of SP-resistance, in the program of Intermittent Preventive Treatment (IPT) during infancy in Africa [20,30,34,35]. One isolate containing PfDHPS 540E mutant found in our study with the mutation of PfDHFR 108N and mutation of PfDHPS 437G as the triple mutations.…”

Section: Mutations Of Pfdhfr and Pfdhps Genesmentioning

confidence: 93%

Polymorphism of Plasmodium Falciparum Dihydrofolate Reductase and Dihydropteroate Synthase Genes among Pregnant Women with Falciparum Malaria in Banjar District, South Kalimantan Province, Indonesia

Fitriah¹,

Sulistyawati²,

Riyanto³

et al. 2012

JTLS

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Pregnant women are highly vulnerable to malaria infection in its endemic areas, particularly infection by Plasmodium falciparum that can cause premature, low birth weight, severe anemia in pregnant women, and death. Sulfadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment for pregnant (IPTp) is used for malaria control in pregnancy recommended by the World Health Organization that has already been implemented in Africa. The P. falciparum resistance to SP has been reported in several malarial endemic areas, and mutations in the genes of Plasmodium falciparum Dihydrofolate Reductase (Pfdhfr) and Dihydropteroate Synthase (Pfdhps) are shown to be associated with parasite resistance to SP treatment. Genetic analysis of Pfdhfr and Pfdhps genes in pregnant women infected with P. falciparum has not yet been examined in Indonesia. The cross-sectional study was conducted at two subdistricts, Sungai Pinang and Peramasan, in Banjar district of South Kalimantan Province, where 127 pregnant women were recruited from 2008 to April 2010. Two important mutations in Pfdhfr gene (amino acid positions at N51 and S108) and three in Pfdhps gene (A437, K540 and A581) were analyzed by nested PCR-RFLP method. All of the seven pregnant women samples infected with P. falciparum presented PfDHFR 108N and PfDHPS 437G mutations. One of the samples had the additional mutation at PfDHPS 540, in which Lys is substituted by Glu. These results suggested that P. falciparum might present only some resistance to SP at Sungai Pinang and Peramasan subdistricts, Banjar District, South Kalimantan province, Indonesia. Although there were limited number of samples, this study showed only few mutations of Pfdhfr and Pfdhps genes in P. falciparum at Banjar district, South Kalimantan Province, that suggests SP might be effective for IPTp in this area. Thus, further analysis of the other mutation sites in Pfdhfr and Pfdhps genes and in vivo efficacy study of SP with more sufficient sample numbers will be necessary to confirm this preliminarily result .

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“…A major gene implicated in resistance to CQ, pfcrt, has been identified [16], and the role of another gene, pfmdr1, in augmenting the level of resistance has been proved [17]. Findings of recent studies from Sudan, Niger and France (imported malaria) are suggestive of reduced virulence of parasites carrying pfcrt mutations [18][19][20] and show that CM [20] and fatal CM [19] are preferentially caused by CQ-sensitive parasites. Major limitations in the latter study [19] are the limited study area (the Gedaref area in Eastern Sudan) and sample size.…”

Section: Intermittent Preventive Malaria Treatmentmentioning

confidence: 99%

“…However, in a more recent study from Orissa, in India, where a relatively larger sample size was studied, an association of malaria mortality with the wild variants of pfcrt/pfmdr1 alleles was reported [21]. Although the implications of dhfr/dhps mutations in parasite virulence were not investigated in the Sudanese and French studies, there is evidence for a link between the dhfr/dhps and pfcrt/pfmdr1 mutations [20,22]. In the study from Niger, a codon 108 mutation Article highlights.…”

Section: Intermittent Preventive Malaria Treatmentmentioning

confidence: 99%

Prospects of intermittent preventive treatment of adults against malaria in areas of seasonal and unstable malaria transmission, and a possible role for chloroquine

Giha

2010

Expert Opinion on Pharmacotherapy

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Chloroquine (CQ) is outmoded as an antimalarial drug in most of the malarial world because of the high resistance rate of parasites. The parasite resistance to CQ is attributed to pfcrt/pfmdr1 gene mutations. Recent studies showed that parasites with mutations of pfcrt/pfmdr1 genes are less virulent, and that those with dhfr/dhps mutations are more susceptible to host immune clearance; the former and latter mutations are linked. In the era of artemisinin-based combination therapy, the frequency of pfcrt/pfmdr1 wild variants is expected to rise. In areas of unstable malaria transmission, the unpredictable severe epidemics of malaria and epidemics of severe malaria could result in high mortality rate among the semi-immune population. With this in mind, the use of CQ for intermittent preventive treatment of adults (IPTa) is suggested as a feasible control measure to reduce malaria mortality in adults and older children without reducing uncomplicated malaria morbidity. The above is discussed in a multidisciplinary approach validating the deployment of molecular techniques in malaria control and showing a possible role for CQ as a rescue drug after being abandoned.

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Field-based evidence for the linkage of pfcrt and pfdhfr drug-resistant malaria genotypes and clinical profiles of severe malaria in Niger

Cited by 15 publications

References 27 publications

Ex Vivo Responses of Plasmodium falciparum Clinical Isolates to Conventional and New Antimalarial Drugs in Niger

Ex Vivo Responses of Plasmodium falciparum Clinical Isolates to Conventional and New Antimalarial Drugs in Niger

Polymorphism of Plasmodium Falciparum Dihydrofolate Reductase and Dihydropteroate Synthase Genes among Pregnant Women with Falciparum Malaria in Banjar District, South Kalimantan Province, Indonesia

Prospects of intermittent preventive treatment of adults against malaria in areas of seasonal and unstable malaria transmission, and a possible role for chloroquine

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