DISCUSSION
stunting, malaria, PK/PD, drug‐based malaria, malnutrition
MALARIA, MALNUTRITION, MALNOURISHED, MALNUTRITION
Using parametric survival and growth modeling, we quantified the interplay between malaria and malnutrition in Ugandan children in a high perennial malaria transmission setting. Our findings indicate that improved malaria control in high transmission settings could improve overall health by reducing malnutrition, but that even when a child receives active malaria chemoprevention the risk of malaria is increased in malnourished children compared with nourished children. This indicates that further optimization of malaria chemoprevention is needed for malnourished children. In addition, we show that clinical trials and associated pharmacokinetic/pharmacodynamic (PK/PD) studies of drug‐based malaria prevention interventions should prioritize enrolling malnourished children and they should also incorporate outcomes, such as measures of malnutrition to best evaluate the intervention's health impacts.Malnutrition is highly prevalent in Africa, including in this cohort of Ugandan children. The estimated national prevalence of stunting in Ugandan children less than 5 years of age is 28.5%,Multiple potential mechanisms for an association between malnutrition and malaria have been proposed, including malnutrition leading to reduced immunity to malaria by lowering anti‐Complementary to this finding, the Weibull distribution (increasing hazard of malaria over time) best predicted malaria hazard in the TS and DP arms, whereas in the no chemoprevention and SP arms, the hazard was constant. These differences in malaria risk trajectory by the chemoprevention arm may have been due to lower adherence to the study drugs as the study progressed or insufficient weight‐based doses as the child aged resulting in suboptimal drug exposure. PQ concentrations decreased over time as efficacy decreased in the DP arm. Dose optimization to compensate for developmental changes in drug metabolism as well as adherence interventions could be needed to improve malaria chemoprevention.Other studies have suggested malnutrition could be a confounder for socioeconomic factors that could increase malaria risk (e.g., housing construction, parental access to LLINs, or education).Although HIV‐exposed and ‐unexposed children received their care at the same study clinic and were enrolled over a similar period of time, HIV‐exposed children had a 21% lower risk of malaria compared to HIV‐unexposed children throughout the study period. A biological cause for decreased risk of malaria associated with HIV exposure is unlikely. Prior studies have found no difference in the burden of malaria between HIV‐exposed and HIV‐unexposed infants.We found each additional malaria episode was associated with a decreased subsequent growth rate for height by 0.4%. As malaria episodes increased, so did the risk of stunting by 3 years of age. Consistent with this finding, effective malaria prevention with LLIN has been associated with significant weight and length gains in children.This study has some limitations. First, we could not independently assess the role of breastfeeding on growth, due to confounding with HIV‐exposure. As measured, breast‐feeding did not improve growth predictions in our models, although this has been an important predictor in prior studies which assessed growth in sub‐Saharan African infants.In conclusion, this analysis supports a bidirectional relationship between malnutrition, as measured by ZHA, and an increased risk of recurrent malaria. We found that the relationship between increased risk of malaria with lower ZHA persisted despite the choice of chemoprevention regimen, even when the most efficacious malaria chemoprevention regimen (DP) was used. Our findings suggest that optimizing chemoprevention regimens for high‐risk groups like malnourished young children, will be essential to maximize efficacy of any chemoprevention option. Further research is needed to identify the optimal chemoprevention regimens for young children with malnutrition and to evaluate how treating chronic malnutrition during infancy could improve the burden of malaria and overall health outcomes in young children.