WWARN study provides evidence to support changes to the latest WHO malaria treatment guidelines

Since 2000, experts have reported dramatic declines in cases and deaths related to malaria. Despite this encouraging news, close to 600,000 people still die from malaria each year, mainly young children in sub-Saharan Africa. In light of these statistics the World Health Organization (WHO) has released updated guidelines on the use of artemisinin combination therapies (ACTs), the currently recommended treatment against malaria infection.

The aim of the revised guidelines is to promote the optimal use of safe and effective antimalarial treatments to cure and protect patients, and to slow drug resistance. The guidelines provide evidence-based recommendations to assist policy makers to design effective national treatment policies and help healthcare workers reassess treatment protocols.

“Despite the rapidly increasing availability of ACTs, with 392 million artemisinin combination therapy (ACT) courses procured in 2013, millions of children are still not treated appropriately for malaria, primarily because of difficulties in accessing treatment rapidly. These updated guidelines emphasise the importance of treating uncomplicated and severe malaria promptly with appropriate drugs and will help to reduce even further the morbidity and mortality from malaria,” says Prof David Lalloo from the Liverpool School of Tropical Medicine.

Assuring that all patients are treated with effective ACTs at an optimal dose has been a key focus of WWARN study group analyses this year. One overall conclusion is that determining and administering the optimal dose for young children is particularly difficult. To improve dosing among this group, the new guidelines recommend that: “To prolong their useful therapeutic life and ensure that all patients have an equal chance of being cured ….dosage regimens should be based on the patient’s weight and should provide effective concentrations of antimalarial drugs for a sufficient time (also known as adequate drug exposure) to eliminate the infection in all target populations.” Although weighing patients is not routine in all locations, using the new WHO guidelines’ weight-based dosage recommendations would increase the proportion of infants and toddlers who receive the right treatment. 

In 2013, the WWARN DP Dose Impact Study Group published a study suggesting that the dosing regimens for dihydroartemisinin-piperaquine (DP) should be reviewed. Although DP is still overall a highly efficacious drug, the study highlighted that even when the recommended dose was given, children under five years had a higher risk of treatment failure. The study results suggested that patients who received a lower than adequate antimalarial dose are slower to respond to treatment, which is less likely to kill all the parasites they have in their bodies, and they would be more likely to have malaria again a few weeks later.

“Small children may need a higher dosage of some drugs, as compared to adults, since children and adults do not absorb or process some drugs equivalently. Therefore we need to administer a higher dose in small children in order to achieve equivalent drug exposures in all patient groups.” says Associate Professor Joel Tarning, Head of the Pharmacometric Modelling Group at WWARN.

Based on the results from the Study Group and pharmacometric simulations of piperaquine exposures for each weight group, the WHO has revised the recommended dose of dihydroartemisinin-piperaquine for young children. These revised dose regimens are predicted to provide similar piperaquine concentrations across all age groups.

“It is essential to achieve effective antimalarial drug exposure in all patient groups in order to ensure optimal cure rates,” says Prof Karen Barnes, Head of the Pharmacology Group at WWARN. “WWARN showed that sometimes young children were receiving suboptimal doses of DP. The changes to the treatment guidelines should limit the risk of treatment failure for young and vulnerable children, and prolong the useful lifespan of this important treatment.”

“It is exciting to see that WWARN’s work provides supporting evidence to optimise treatment against malaria infection. This is a tribute to the ongoing efforts of the many researchers and institutes who work to determine antimalarial treatment efficacy and optimal dosing, and who participate in the WWARN data sharing platform. These results highlight what research collaboration and individual patient meta-analyses can achieve,” says Prof Philippe Guérin, WWARN Director.

The WWARN DP Dose Impact Study Group is one of three dose impact publications to come from the WWARN Study Groups. The ASAQ Dose Impact Study Group found that that the efficacy of artesunate-amodiaquine can vary due to changes in the formulation of the two parts of the ACT, artesunate and amodiaquine. When both components are combined in a single tablet, this fixed dose formulation shows better treatment efficacy than that observed when separate AS and AQ tablets are just taken at the same time; this is mostly attributed to a lower dosage of AQ.

The AL Dose Impact Study Group confirmed that the current recommended dose of artemether-lumefantrine (AL) is still working very well in patients treated for malaria, but suggests that a higher dose of AL could potentially further improve treatment results for young children in Asia and underweight children in Africa. However, further research is needed to inform improvements to the AL dose in young children, as it is hard for patients to absorb more AL even when they are given extra tablets.

Read the full version of the WHO’s ‘Guidelines for the treatment of malaria’

Related publications:

The Worldwide Antimalarial Resistance Network (WWARN) AS-AQ Study Group. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data. BMC Medicine2015 13:66. Published 31 March 2015 doi: 10.1186/s12916-015-0301-z.

Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group. The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data. The Lancet Infectious Diseases 2015; D-14-00566R1; DOI 10.1016 S1473-3099 (15)70024-1

The Worldwide Antimalarial Resistance Network (WWARN) DP Study Group (2013) The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data. PLOS Med 10(12): e1001564. DOI:10.1371/journal.pmed.1001564