MALACTRES

Multi-drug resistance in malaria under combination therapy: Assessment of specific markers and development of innovative, rapid and simple diagnostics


Framework programme:: 7
Contract/Grant agreement number:: 201889
EC contribution:: 2.800.000 €
Duration:: 60 months
Funding scheme:: Focused Research Project
Starting date:: 01/01/2008
Web-site:: http://www.malactres.eu

Keywords: malaria, drug resistance, artemisinin-based combination therapy, diagnostics, molecular biology, Plasmodium, rapid tests.

Background

Malaria is the most serious parasitic disease in the world. Approximately one-fourth of the world's population is at risk of contracting the disease, and every year more than 2 million people, mainly young children in sub-Saharan Africa, die because of it. Malaria is caused by single-cell (protozoan) parasites of the genus Plasmodium. Four species can cause human disease: P. falciparum (the most important one and responsible for the majority of deaths), P. vivax, P. ovale and P. malariae. Accurate diagnosis followed by prompt and efficacious treatment is the backbone of any malaria control programme. However, both diagnosis and treatment represent huge challenges, as many laboratory tests to confirm malaria infection lack sensitivity/specificity or are difficult to perform under rural conditions. Most affordable drugs are also losing their effectiveness due to emerging resistance.

Improved diagnostic tools to support the clinical suspicion of malaria are needed. In principle, molecular biology-based tools would provide the most sensitive and accurate tools for diagnosis, but their implementation in resource-poor settings is hampered due to dependency on electricity, and costs of equipment. To circumvent resistance, the World Health Organization recommends for P. falciparum malaria the use of combination therapies, preferably those containing artemisinin derivatives (ACTs – artemisinin-based combination therapies). However, the use of ACTs requires careful monitoring as there is a significant risk of parasites also developing resistance to this new generation of drugs, leaving vulnerable communities without appropriate treatment measures.

Aims and expected results

The main aim of MALACTRES is to develop and evaluate molecular tools for monitoring ACT drug resistance in selected target countries (i.e. Burkina Faso, Nigeria and Tanzania). These will preferably be based on isothermal amplification technology and will have an easy read-out system which can be implemented in routine malaria diagnosis, preferably under resource-poor conditions.

The possible evolution of ACT drug resistance will be monitored along with the molecular principles that confer drug resistance (these could be single nucleotide point mutations or altered gene expression). The consortium hopes in particular to identify alleles of candidate resistance genes associated with increased transmission success of P. falciparum after ACT treatment in completed clinical trials with endpoints at the gametocyte or infected mosquito level.

The commercial value aspects of the developed tests will also be explored with the possibility of bringing developed tools to market at affordable competitive prices.

ACT treatment trials will be conducted with transmission endpoints, and measurement will be made of the impact of resistance-associated alleles of key genes on:

gametocyte prevalence, density and longevity;
infectiousness of gametocyte-positive treated individuals to mosquitoes;
infectiousness of randomly selected treated individuals to mosquitoes;

These activities will help lead to new information on the genetic basis of ACT resistance, new tools for the diagnosis of malaria, new tools to monitor ACT drug resistance, and new insights into the transmission of ACT resistant parasites

Potential applications:

The outcome of the project will lead to an improved diagnosis of malaria. The work will provide more insight into the development of drug resistance and could have wider applications in the field of malaria or other infectious diseases in general.

The developed tools could be implemented in resistance surveillance studies of National Malaria Control Programmes in disease endemic countries. The new knowledge with respect to the molecular basis of ACT resistance and effect on disease transmission will have implications for adjustment of control programmes.

Coordinator:

Dr. Henk Schallig
Royal Tropical Institute
Amsterdam
The Netherlands
h.schallig@kit.nl

Partners: