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Improved Accuracy of Molecular and Immunological Markers for Prediction of Efficacy of Antimalarial Drugs
Closed for proposals
Project Type
Project Code
E15019CRP
1304Approved Date
Status
Start Date
Expected End Date
Completed Date
14 December 2010Description
Drug resistant malaria has been identified as a major public health problem in a large number of developing Member States. Interestingly, malaria parasites with molecular signatures of drug resistance, as determined by radioisotopic methods, infect some people that, despite receiving the resistant medication (chloroquine or fansidar) manage to clear the parasites from their blood after receiving the apparently inappropriate treatment. This is because clinical efficacy depends on the effect of host immunity, both innate and acquired acting in conjunction with the drug. Hence studies need to be designed to investigate influence of host factors on parasite clearance. The selected population for this study will be people infected with parasites presenting drug resistance mutations that receiving either chloroquine or fansidar and, nevertheless, managed to clear the infection. Polymorphisms in promoter regions of cytokine genes, linked to immune response, will be investigated for their association with the host’s ability to clear parasites using molecular nuclear techniques.
Objectives
To enhance Member States’ capability to prevent and control infectious diseases. This project falls within the mission of fostering applied research to the solution of global problems
Specific objectives
To refine and validate molecular markers in the human genome that correlate with clearance of malaria parasites after specific treatment despite the drug resistant profile of the parasite as determined by molecular techniques.
The ultimate aim is to provide control programmes with a cost-effective alternative to in vivo surveillance of drug resistant malaria. Relying solely on drug resistant (molecular or in vitro) profiles may result in premature jettisoning of drugs which remain effective in settings where genetic makeup/profile of the population allows elimination of drug resistant parasites.
Impact
This is the first study to identify human genetic loci associated with clearance of drug –resistant parasites.
Antimalarial drug resistance is a major problem for the effective control of malaria. Surveillance of drug resistance through in vivo efficacy trials is expensive and time-consuming, and may be unethical in areas of high treatment failure. Molecular monitoring of drug resistance provides an alternative, quicker and cheaper method to assess the likely failure rate of existing or new antimalarial drugs. However the results obtained consistently over-estimate the likelihood of treatment failure, because they fail to take into account the ability of some patients to clear drug resistant infections. This project provides evidence that three human SNPs are associated with enhanced clearance of drug-resistant parasites and could be used, in combination with genetic information on parasite molecular markers, to better predict treatment failure rates.
The CRP has enabled counterparts to receive basic and more advanced training in the analysis of genetic data (parasite and human) from the contracted expert.
Standard operating procedures for the genotyping of malaria parasites for drug resistance have been established in all counterpart laboratories. New protocols for different antimalarial drugs and resistance loci have been developed and made available (electronically) to all counterparts, enhancing their capacity for diagnosis of drug resistance. Quality control samples have also been shipped to all counterparts to enable adequate controls for assays to be performed, and a quality assurance scheme was set up.
Relevance
The CRP contributes to the objective of enhancing Member States’ capability to prevent and control the infectious disease malaria. It is also highly relevant to human health, as malaria continues to be a major cause of morbidity and mortality in many countries, and especially in lesser developed areas of the world. Resistance to all antimalarial drugs has now arisen and is increasing. Many countries have moved to artemisinine-combination therapy (ACT), but the first cases of reduced efficacy to artemisinine have recently emerged in Cambodia. Resistance monitoring must therefore remain a priority for effective malaria control.