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Anti-malaria drug resistance is spreading throughout Southeast Asia and we need to find new treatments. Our researchers at MORU use a combination of artemisinin and two partner drugs instead of one. If confirmed safe and tolerable, triple artemisinin combination therapies might be a good option to treat multi-drug resistant malaria, as well as slow down the emergence and spread of anti-malarial resistance.

I’m Rob van der Pluijm, I’m a doctor from the Netherlands and I’m currently the coordinator of the TRAC II project.

Tremendous progress has been made in the fight against malaria, but at the moment we are facing the problem that artemisinin and partner drug resistance have emerged in Southeast Asia and it is spreading. The current treatments don’t work well enough in Cambodia, Thailand and Vietnam, and we are trying to find new treatments.

The TRAC II project is the second phase of the tracking resistance to artemisinin collaboration project, and we currently are mapping the current extent of artemisinin and partner drug resistance in Asia and one country in Africa. When we started this project we already knew that artemisinin and partner drug resistance exists in Southeast Asia and it’s leading to ACT (artemisinin combination therapy) failures.

Therefore we have created the TRAC II project to also be a randomised trial in which we assess the safety, tolerability and efficacy of triple ACTs.

The standard treatment for malaria is ACT which is a combination of an artemisinin, a fast acting short acting drug, and a partner drug which stays in the body for a longer time. Triple ACTs are a combination of a standard ACT with a matching partner drug.

The idea, it’s a little bit like in HIV and tuberculosis, is that by combining drugs in a combination for the treatment of malaria, the treatment might be more effective in areas where artemisinin and partner drug resistance already exists. We also hope that by deploying triple ACTs on a larger scale, for instance in Africa, India and Bangladesh, we might be able to slow down the emergence and spread of anti-malarial resistance.

The project just finished recruitment, we’ve recruited just over 1,100 patients. As you can imagine this has led to a lot of data, over 1 million data points.

Field studies aimed at mapping the current extent of artemisinin and partner drug resistance are very expensive. One of the key findings in recent years was that you can identify parasites that are resistant by looking at genetic markers. One of the important ones is the kelch mutation, and the kelch mutation was validated in the first phase of the TRAC project. Other markers of for instance piperaquine and mefloquine resistance have also been identified.

One of the key findings is that artemisinin and partner drug resistance are clearly established in Southeast Asia. We’ve looked at the genome of the parasites and we see that these genes all originated from Western Cambodia. For a long time there was a suspicion that this was the case, and I think that this study will confirm that the resistance that we find in Vietnam and the resistance we find in Thailand and even northeast Cambodia, actually originated in western Cambodia and has spread from there throughout Southeast Asia.

Another finding in the field has been that parasites that are resistant to piperaquine are less likely to be resistant to mefloquine, and on the other hand parasites that are resistant to mefloquine are less likely to be resistant to piperaquine. This was one of the bases for combining piperaquine with mefloquine in one of the triple ACTs, with the idea that parasites can either be resistant to piperaquine, or resistant to mefloquine.

Even with effective treatment available, over 400,000 people die every year from malaria, predominantly children. You can imagine that if anti-malarial resistance spreads from Asia to Africa, where most of this mortality occurs, this will lead to tremendous increases in mortality. What we hope is that by deploying triple ACTs in Asia, and also in Africa, we might be able to prevent or at least stall the emergence of anti-malarial resistance. Even in areas where most of the ACTs are failing, our triple ACTs are fully effective. This is an indication that once we confirm the safety and tolerability of these drugs, triple ACTs might be a very good option for treatment of multi-drug resistant malaria.

Rob van der Pluijm

Dr Rob van der Pluijm coordinates TRAC II, a project that aims to map resistance to antimalarials and assess the tolerability, safety and efficacy of two new triple artemisinin combination therapies (ACTs). The triple combinations will hopefully restore efficacy in areas where ACTs are currently starting to fail dramatically.

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