Malaria drug less effective in malnourished children

Researchers have found that the most-prescribed antimalarial drug is less effective in severely malnourished children than in those that are adequately nourished. The study calls for further research into optimising treatment for undernourished children – who are particularly vulnerable to contracting malaria and dying from the disease.

“Although one in three children under five years old in sub-Saharan Africa is malnourished, they are usually excluded from studies on malaria treatment,” explains Professor Karen Barnes from the University of Cape Town’s (UCT) Division of Clinical Pharmacology. She, along with UCT Associate Professor Lubbe Wiesner and Michiel Smit, previously part of Wiesner’s lab in the same division, collaborated with international partners on the research.

“The dosage regimens recommended for these children don’t seem to be optimal and this increases the chances that treatment will fail for them – which is what we showed in this study.”

Young children are particularly vulnerable to malaria infection; 61% of those who die from malaria worldwide are less than five years old.

Barnes is also head of the Worldwide Antimalarial Resistance Network (WWARN) Pharmacology Group and the founding director of the South African Medical Research Council’s (SAMRC) Collaborating Centre for Optimising Antimalarial Therapy (CCOAT).

Malaria & malnutrition: a bad combination

Young children are particularly vulnerable to malaria infection; 61% of those who die from malaria worldwide are less than five years old. Young children who are malnourished are at an even higher risk of contracting the disease and dying from it.

Sub-Saharan Africa – where one in three young children is malnourished – also sees more than 90% of the world’s malaria cases and deaths.

The physiology of malnourished children, which is different from that of adequately-nourished children, may change the way antimalarial drugs are taken up and distributed by their bodies. Malnutrition could, for instance, reduce the absorption of drugs in children, but there has been little research into how well the treatments work for them. The information available seems to be contradictory.

What the researchers did

Artemether-lumefantrine is the most commonly used antimalarial drug worldwide. Scientists have already recorded, though, that levels of the drug – which is recommended by the World Health Organization – are lower in children’s blood, compared to adults’, after treatment. Despite this, children are currently given the same dose as adults (adjusted for their body weight).

The research team worked to understand how malnutrition might further compromise this treatment, as well as testing whether the current treatment is effective for malnourished children.

“Malaria and malnutrition are both potentially life-threatening conditions and are both most common in young children in sub-Saharan Africa, so studies to understand how best to treat malaria in malnourished, young children are long overdue,” says Barnes.

The researchers investigated the absorption of lumefantrine and the effectiveness of artemether-lumefantrine in treating severely malnourished children with uncomplicated – or not severe – malaria.

“This study is the first to address the challenge of treating malaria in severely malnourished children, specifically.”

Specifically, the team analysed how the drug behaved over time in terms of absorption, distribution, metabolism and excretion (its pharmacokinetics) as well as its effectiveness (its pharmacodynamics). To do this, they looked at data for 399 children (all with malaria, 131 of them severely malnourished) involved in a clinical trial at two hospitals in Mali and Niger. The concentrations of the drug were measured by Wiesner’s team using an assay developed and validated by Smit.

“This study is the first to address the challenge of treating malaria in severely malnourished children, specifically,” says Barnes. “It highlights how important it is to make sure that optimised drug doses are developed for undernourished children and other vulnerable groups – such as pregnant women – who are usually excluded from studies to decide treatment doses.”

These groups are often excluded from clinical trials, as they may not represent the main target group, they are difficult to recruit and their participation can raise ethical concerns.

Key insights

The results showed that not only were the levels of lumefantrine lower in children’s blood compared to adults’, but that among severely malnourished children there was even less of the drug – about 19% less – than in other children. This lower exposure also meant these children acquired new malaria infections sooner.

“There are serious knowledge gaps in associations between malnutrition and antimalarial drug efficacy, and this study provides key insights,” said Professor Joel Tarning, head of WWARN Pharmacometrics, which led the study with numerous collaborators, including UCT, Epicentre, the Mahidol-Oxford Tropical Medicine Research Unit, the University of Bamako in Mali, Médecins Sans Frontières and the Ministry of Health of Niger.

To evaluate three alternative dosing regimens the researchers used a model they had developed to see if they could improve lumefantrine exposure among severely malnourished children. Standard treatment involves administering the drug twice a day for three days.

Among severely malnourished children there was even less of the drug – about 19% less – than in other children.

The researchers explored increasing, intensifying and extending this treatment.

The model showed that increasing the dosage would not result in increased exposure, because of the limited ability of severely malnourished children to absorb the drug. However, both the intensified regimen (three times a day for three days) and an extended regimen (twice a day for five days) brought the exposure up to levels similar to those in the other children.

“Now we need to test these in malnourished young children,” Barnes concludes. “This is so that treatment guidelines can align with the optimal malaria treatment for the very many young and malnourished children living in malaria areas in sub-Saharan Africa.”

• Chotsiri P et al. (2019) Severe acute malnutrition results in lower lumefantrine exposure in children treated with artemether-lumefantrine for uncomplicated malaria. Clinical Pharmacology & Therapeutics. doi:10.1002/cpt.1531