Malnourishment and malaria in children – how does it affect treatment outcomes?

Almost three million children under the age of five die each year in sub-Saharan Africa. Two of the key causes of premature death is malnutrition and malaria infection. As such, both frequently coexist at the same time, but little research has been undertaken to determine how well antimalarial treatments work in severely malnourished children. Severe malnutrition affects almost all organs and it reduces the body’s absorption of medicines through the intestinal tract.

The current protocol for determining the efficacy of antimalarials in young children excludes those with severe acute malnutrition (SAM). As such there is a dearth of information on how malnutrition affects the efficacy and outcomes of antimalarials in small children.

For the first time, researchers have investigated the efficacy and pharmacology parameters of the commonly used artemisinin combination therapy, artemether-lumefantrine (AL), in children with severe malnutrition and compared it with those who were not malnourished. The study, recently published in BMC Medicine,was led by Epicentre in Paris and Maradi, Niger, in collaboration with the Malaria Research and Training Centre, University of Bamako, Mali, the Department of Clinical Pharmacology, University of Cape Town, South Africa, and WWARN.

The analysis found that when malnourished children were treated with AL alongside ready to use therapeutic foods such as Plumpy’Nut®, the therapeutic efficacy was the same as children treated with AL who were not malnourished. However, the team also found that older malnourished children were at higher risk of reinfection after treatment than those children without nourishment problems. Adapting the dose or prolonging the treatment regimen for malnourished children could reduce the risk of reinfection.

Lead author Dr Lise Denoeud-Ndam from Epicentre, Paris highlights: “This study is another step towards understanding the interplay between malnutrition and malaria treatment results. However, further studies are needed to urgently answer the question of whether ACT dosing strategies are adequate in children with severe acute malnutrition, especially in countries such as Mali and Niger where it causes widespread morbidity and mortality in small children.”

This study used the WWARN Parasite Clearance Estimator to measure the parasite clearance slope half-life to help determine the efficacy of AL. The tool offers researchers a consistent and reliable method to estimate the rate of parasite clearance from patients - vital for assessing signs of change in antimalarial drug efficacy.

The research team showed that there was no difference in treatment failures and parasite clearance rates in malnourished and non-malnourished children. In older children, where reinfections were more frequent than in younger children, severe malnutrition was associated with a two-fold higher risk of reinfection by day 28.

The results from this study reflect the findings from two previous WWARN Study Groups. The AL Dose Impact Study Group found that although AL is still efficacious for the vast majority of the population, a higher risk of recurrence is observed in underweight children in Africa.

The Lumefantrine PK/PD Study Group measured day 7 concentration of AL levels in the body to determine that underweight children could benefit from either higher, more frequent, or prolonged dosage regimens. Both studies recommended that further assessment is required to assess the effects of increasing the dose of AL in malnourished children.

Going forward, the study of analysing and improving treatment outcomes of malnourished children in Africa with malaria infection is a WWARN research priority together with our partners. A Malaria and Malnutrition Study Group is currently assessing the effect of various nutritional indicators in treatment outcome in children aged 6-59 months treated with artemisinin based combination therapies for uncomplicated Plasmodium falciparum malaria. The statistical analysis for this study is underway.

“There is a serious knowledge gap in associations between malnutrition and antimalarial drug efficacy,” says Prof Philippe Guérin*, WWARN and IDDO Director. “By working together with our research partners like Epicentre, MSF, the MRTC and the University of Cape Town we are tackling the knowledge gaps. This study is providing key information to better understand how malaria treatment is impacted by malnutrition. A Population pharmacokinetics of lumefantrine in children with severe acute malnutrition is underway on the same population. These data will provide important evidence for public health workers and policy makers.”

Publication

Lise Denoeud-Ndam, et al. Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali. BMC Medicine 2016. 14:167. DOI: 10.1186/s12916-016-0716-1

Reference

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* Prof Guérin is Director of WWARN and the Infectious Diseases Data Observatory (IDDO).