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Contact: Fiona Godwin
Public Library of Science

Malaria treatment could improve in children

An analysis of patients from across the malaria endemic world suggests that a key antimalarial treatment could be improved by better dosing in young children

Antimalarial drug resistance has hampered malaria control programs for almost 60 years. A key factor in combatting this threat is to ensure that all antimalarial drugs are deployed in a way that ensures that the maximum number of patients are completely cured.

A study published this week in PLOS Medicine explores this issue by presenting the results of a large pooled analysis of more than 7,000 patients with malaria from Africa, Asia and South America. It presents a convincing argument for public health policy-makers to pay careful attention to dosing recommendations for artemisinin combination therapies (ACTs) when reviewing current drug treatment protocols, particularly for young children.

The paper examines the combination of piperaquine and dihydroartemisinin, an increasingly common choice of treatment for patients suffering from malaria caused by the malaria parasite Plasmodium falciparum.

The results of the study, coordinated by the WorldWide Antimalarial Resistance Network (WWARN), show that while treatment of malaria with dihydroartemisinin-piperaquine generally results in excellent patient recovery, young children are at higher risk of treatment failure and this may be due to their receiving an insufficient dose of the drug.

WWARN brought together 76 researchers worldwide who contributed individual patient data from 26 clinical studies. These data are being used to analyze the implications of different drug dosing levels of ACTs, for treatment efficacy. The results, which combine almost 70% of all available published data on this treatment, confirm that dihydroartemisinin-piperaquine is highly efficacious curing more than 97% of patients.

However, the study also highlights that one third of children aged 1-5 years received a dose of piperaquine below that recommended by the World Health Organisation. Furthermore, patients receiving a lower dose were slower to respond to treatment and had a greater risk of getting malaria again.

Dr Corine Karema, from the Rwandan National Malaria Control Program and a co-author of the paper, emphasises that "It is very important that treatment guidelines recommend optimal drug dosing levels to maximise their impact and ensure all patients are rapidly and completely cured."

The results suggest that further drug dose optimization of dihydroartemisinin-piperaquine may be warranted in young children.

Professor Ric Price, one of the lead investigators working with WWARN, concludes "This study highlights the ability of researchers from around the world to come together and pool their data for collective gain. The power of such research collaborations will help to support the optimisation of current antimalarial treatments, reduce the spread of antimalarial drug resistance and ultimately save lives"

In a linked Perspective, Paul Garner, from the Liverpool School of Tropical Medicine, UK, discusses some of the issues associated with optimizing ACT dosing.

He says: "There is a balancing act between under-dosing, which increases the risk of resistance developing, and increasing dosing such that toxicity and adverse events increase."


Research Article

Funding: WWARN is funded by a Bill & Melinda Gates Foundation grant. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: EAA has worked as an investigator on studies of dihydroartemisinin-piperaquine sponsored by both Holley-Cotec and Medicines for Malaria Venture. EAA and FN have received research funding from Holley-Cotec. KIB serves as a member of a number of malaria-related World Health Organization committees, including the Malaria Chemotherapy Technical Expert Group. KIB is a recipient of a research grant from the Medicines for Malaria Venture and is a sub-recipient of grants from the Bill & Melinda Gates Foundation. QB has received speaker fees and travel grants from Sigma Tau. UDA has received research funding and several travel grants from Sigma Tau; UDA has been a consultant for Sigma Tau on dihydroartemisinin-piperaquine. CMeneŽndez and NJW are members of the Editorial Board of PLOS Medicine. RNP served on the Data Safety Monitoring Board for the Sigma Tau DP multicentered clinical trials and received reimbursements for travel expenses to attend these meetings. ET, NV, and NJW are members of the WHO antimalarial treatment guidelines committee. All other authors have declared that no competing interests exist.

Citation: 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




Andrea Stewart

Perspective Article

Funding: No funding was received for the writing of this article.

Competing Interests: The author is Director of Evidence Building and Synthesis Research Consortium, which receives money to increase the number of evidence-informed decisions by intermediary organizations, including WHO and national decision makers that benefit the poor in middle- and low-income countries. The author is the coordinator of a WHO Collaborating Centre for Evidence Synthesis for Infectious and Tropical Diseases (http://apps.who.int/whocc/default.aspx; UNK234). One of the Centre's aims is to help WHO in its role as an infomediary in communicating reliable summaries of research evidence to policymakers, clinicians, teachers, and the public in developing countries. Technical advice was sought from Dr. Dianne J. Terlouw on the pharmacokinetic background to these drugs. Dr. Terlouw is the Principal Investigator on a trial examining dose optimisation with DHAP. Dr. Terlouw had no part in writing the manuscript and the views expressed are entirely those of the author.

Citation: Garner P (2013) Artemisinin Combination Therapy: A Good Antimalarial, but Is the Dose Right? PLoS Med 10(12): e1001565. doi:10.1371/journal.pmed.1001565




Paul Garner
Liverpool School of Tropical Medicine
+44 (0)151 708 9393

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