Since the 1990s, the World Health Organisation (WHO) has recommended Artemisinin-based Combination Therapies (ACTs) as the first-line treatment of P. Falciparum malaria in endemic areas. The efficacy of this treatment relies on the artemisinin derivative (which rapidly reduces the number of malaria parasites in the patient, but is rapidly cleared from the body) in combination with the more slowly eliminated partner drug, which is important for preventing the re-emergence of the original infection. 

But if the dosage of the drug is not right, the malaria parasites may not be completely eliminated, and/or the infection can re-emerge later. “Both these mechanisms favour the emergence of malaria parasites which are resistant to the drug being used, so getting the drug dosage right is important not just to individual patients, but also to make sure that effective malaria drugs are not lost because of drug resistance’, said IDDO & WWARN Director Professor Phillipe Guerin.

Children under the age of five are particularly vulnerable to treatment failure and developing severe malaria, likely because of their lower immunity, but also because dosing strategies are usually based on weight or age bands determined during early drug development - patients at the margins of these bands can end up receiving a too high or too low a dose of what would be an otherwise effective medication. 

“The issue is compounded because doses of medication for children are usually extrapolated from adult doses, but children are not merely small adults – their responses to medication often differ from those of adults,” said IDDO/WWARN Science Lead Professor Ric Price, who led on this research project. 

To work out how young children with malaria were responding malaria treatment, a WWARN study group identified every single study published between 1960 and February 2013 where patients were treated with a combination of the artemisinin derivative dihydroartemisinin and the partner drug piperaquine. This combination is one of the four existing artemisinin combination therapies.

Rather than relying on just the published results, the team obtained individual patient data from almost 70% of the participants from the studies, including children under the age of five.

The pooled analyses across these 24 studies found that children under the age of five were nearly three times more likely to receive too low a dose of the partner drug piperaquine, compared to children aged 5-12 years. What’s more, the piperaquine dose was a significant predictor of the malaria infection returning: for every 5 mg per kilogram of bodyweight decrease in the dose of piperaquine, the risk of the infection returning increased by 13%. 

Finally, they estimated that the risk of malaria treatment would be halved if if the target dose of children under five was increased to 59 mg per kilogram of body weight, rather than the then WHO-recommended lower limit was 48 mg/kg of body weight. These estimates also showed that 95% of young children with malaria would be cured by using this greater amount of piperaquine in combination with dihydroartemisinin. 

“At the same time, for the 10 studies where we had data about children receiving these slightly higher doses, there was no increase in gastrointestinal toxicity, indicating that increasing the dose is likely to be safe,” said Professor Price, who is based at the Menzies School of Health Research in Australia and an infectious disease physician, in additional to his role within WWARN. 

Writing in a companion piece to the published results in PLoS Medicine, Dr Paul Garner, the-then coordinating Editor for the Cochrane Infectious Diseases Group in malaria, said “By analysing trial arms observationally, Price and colleagues can examine patient factors and directly relate this to individual outcomes. This is innovative and useful, drawing on the rigor of the trial design in standardising data collection, and is complementary to existing efforts.”

The results of this study were published in December 2013 in PLoS Medicine. Following this publication, in June 2015, the World Health Organisation raised the minimum recommended disease for dihydroartemisinin-piperaquine.