Return of Chloroquine Antimalarial Efficacy in Malawi

Laufer, Miriam K.; Thesing, Phillip C.; Eddington, Nicole D.; Masonga, Rhoda; Dzinjalamala, Fraction K.; Takala, Shannon L.; Taylor, Terrie E.; Plowe, Christopher V.

doi:10.1056/nejmoa062032

Cited by 373 publications

(324 citation statements)

References 27 publications

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“…This sharp reduction in the level of in vivo CQ resistance may be explained by the 2005 antimalarial treatment policy change from CQ to artemether-lumefantrine or artesunate-amodiaquine as first lines treatments for acute uncomplicated malaria in Nigeria, although, chloroquine has not been completely withdrawn, despite the change in drug policy. It has been argued that the withdrawal of CQ or SP as first line treatment for uncomplicated malaria in other disease endemic settings of Africa has led to the reemergence of drug sensitive Plasmodium falciparum [8][9][10]. The fact that in-vitro CQ resistance (54%) is higher than in-vivo resistance (38%), may be attributed to immunopotentiation of antimalarial drugs by patients immunity, which would have helped older patients (>5years of age) clear drug CQ resistant parasites.…”

Section: Discussionmentioning

confidence: 99%

“…An earlier report [8] has demonstrated the return of CQ susceptible parasites in Malawi soon after the country switched from CQ to SP as the first line therapy for malaria. Furthermore, a recent clinical trial in Malawi also confirmed that CQ had excellent clinical efficacy, 12 years after it was removed from use [9,10 ]. It is therefore necessary to understand the molecular basis of resistance to already available antimalarial drugs such as CQ, and explore the potentials of the information generated in improving the potency and rational for developing effective drug combinations.…”

Section: Introductionmentioning

confidence: 99%

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Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Folarin

Gbotosho²,

Sowunmi³

et al. 2008

TOTMJ

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This study was designed to evaluate the association between polymorphisms in pfcrt and pfmdr1 genes and in-vitro chloroquine (CQ) sensitivity in fresh isolates of P. falciparum and patients' treatment outcome. The modified schizont inhibition assay was used to determine in-vitro sensitivity of P. falciparum. Polymorphisms in pfcrt and pfmdr1 genes were detected using nested PCR and RFLP techniques in 84 P. falciparum isolates obtained from patients with acute uncomplicated malaria.Eighty five percent (71/84) and 15% (13/84) of the parasites were resistant and sensitive in-vitro to CQ respectively. Molecular analysis showed presence of mutant pfcrtT76, pfmdr1Y86 and pfmdr1F184 alleles in 60%, 33% and 14% of the isolates respectively. There was a significant association between in-vitro and in-vivo CQ resistance (p=0.029) and also between the presence of mutant pfcrtT76+pfmdr1 Y86-Y184 haplotype and in-vitro (p=0.013) or in-vivo CQ resistance (p=0.024).Overall results from this study demonstrates that the presence of pfcrtT76+ pfmdr1 Y86-Y184 haplotype in Nigerian isolates of Plasmodium falciparum is predictive of in-vitro and in-vivo CQ resistance and therefore may be useful for monitoring resistance to this drug.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Folarin

Gbotosho²,

Sowunmi³

et al. 2008

TOTMJ

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“…This mutation in a putative transporter gene is well-associated with chloroquine resistance in P. falciparum (5). The MSS-HTA was compared with a standard allele-restricted PCR (ARPCR) in clinical samples from Malawi, a country where standard PCR analyses and a recent clinical trial have suggested that chloroquine-resistant malaria has disappeared (6)(7)(8)(9).…”

mentioning

confidence: 99%

Minority-Variant pfcrt K76T Mutations and Chloroquine Resistance, Malawi

Juliano

Kwiek

Cappell

et al. 2007

Emerg. Infect. Dis.

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Genotyping of the chloroquine-resistance biomarker pfcrt (Plasmodium falciparum chloroquine resistance transporter gene) suggests that, in the absence of chloroquine pressure, Plasmodium falciparum parasites in Malawi have reverted to chloroquine sensitivity. However, malaria infections in Africa are commonly polyclonal, and standard PCRs cannot detect minority genotypes if present in <20% of the parasites in an individual host. We have developed a multiple site-specifi c heteroduplex tracking assay (MSS-HTA) that can detect pfcrt 76T mutant parasites consisting of as little as 1% of the parasite population. In clinical samples, no pfcrt 76T was detected in 87 pregnant Malawian women by standard PCR. However, 22 (25%) contained minority-variant resistant genotypes detected by the MSS-HTA. These results were confi rmed by subcloning and sequencing. This fi nding suggests that the chloroquine-resistant genotype remains common in Malawians and that PCR-undetectable drug-resistant genotypes may be present in disease-endemic populations. Surveillance for minority-variant drugresistant mutations may be useful in making antimalarial drug policy. D rug-resistant Plasmodium falciparum malaria continues to be a growing health problem throughout most of the world (1). To combat this threat, governments and aid agencies need accurate drug resistance surveillance data. The World Health Organization has stressed the need for methods of detecting molecular markers of drug resistance that will be useful in predicting responses to both clinical and public health interventions (2). This has been diffi cult in highly malaria-endemic areas, where infections are almost always polyclonal (3,4). In patients with polyclonal infections, small drug-resistant parasite populations (minority variants) may be masked by larger drug-sensitive populations because standard PCRs are relatively insensitive to minority variants (2). Therefore, new methods capable of detecting these subpopulations may lead to better drug resistance surveillance and provide a better tool to predict outcome.We describe a new multiple site-specifi c heteroduplex tracking assay (MSS-HTA) for detecting the pfcrt (Plasmodium falciparum chloroquine resistance transporter gene) K76T mutation. This mutation in a putative transporter gene is well-associated with chloroquine resistance in P. falciparum (5). The MSS-HTA was compared with a standard allele-restricted PCR (ARPCR) in clinical samples from Malawi, a country where standard PCR analyses and a recent clinical trial have suggested that chloroquine-resistant malaria has disappeared (6-9). Materials and Methods Study SamplesInformed consent, as approved by the ethics committees of the University of North Carolina and the Malawi College of Medicine/Ministry of Health, was obtained from all participants in this research study. The Malaria and HIV in Pregnancy Study (MHP) patient samples originated from a study of pregnant women attending Queen Elizabeth Central Hospital, an urban hospital in Blantyre. The complete characte...

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“…Pfcrt est également impliqué dans la baisse de sensibilité du parasite à l'amodiaquine et à la quinine [41,42]. Dans les zones où les allèles de résistance ne sont pas fixés, on observe une augmentation de la fréquence de l'allèle sauvage après abandon de la chloroquine [43,44]. L'analyse de ce locus renseigne sur la pression médicamenteuse exercée au sein des populations.…”

Section: Approches Méthodologiquesunclassified

Étude de la résistance dePlasmodium falciparumaux antipaludiques au sein du réseau international des Instituts Pasteur (RIIP-Palu)

2013

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Return of Chloroquine Antimalarial Efficacy in Malawi

Abstract: Chloroquine is again an efficacious treatment for malaria, 12 years after it was withdrawn from use in Malawi. (ClinicalTrials.gov number, NCT00125489 [ClinicalTrials.gov].).

Cited by 373 publications

References 27 publications

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Minority-Variant pfcrt K76T Mutations and Chloroquine Resistance, Malawi

Étude de la résistance dePlasmodium falciparumaux antipaludiques au sein du réseau international des Instituts Pasteur (RIIP-Palu)

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