The relationship between malnutrition and malaria in young children is under debate, and no studies evaluating the association between malnutrition and response to artemisinin-based combination therapies (ACTs) have been published. We evaluated the association between malnutrition and response to antimalarial therapy in Ugandan children treated with ACTs for repeated episodes of malaria. Children aged 4 to 12 months diagnosed with uncomplicated malaria were randomized to dihydroartemisinin-piperaquine (DP) or artemether-lumefantrine (AL) and followed for up to 2 years. All HIV-exposed and HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis (TS). The primary exposure variables included height-for-age and weight-for-age z scores. Outcomes included parasite clearance at days 2 and 3 and risk of recurrent parasitemia after 42 days of follow-up. Two hundred ninety-two children were randomized to DP or AL, resulting in 2,013 malaria treatments. Fewer than 1% of patients had a positive blood smear by day 3 (DP, 0.2%; AL, 0.6% [P = 0.18]). There was no significant association between height-for-age or weight-for-age z scores and a positive blood smear 2 days following treatment. For children treated with DP but not on TS, decreasing height-for-age z scores of <−1 were associated with a higher risk of recurrent parasitemia than a height-for-age z score of >0 (hazard ratio [HR] for height-for-age z score of <−1 and ≥−2 = 2.89 [P = 0.039]; HR for height-for-age z score of <−2 = 3.18 [P = 0.022]). DP and AL are effective antimalarial therapies in chronically malnourished children in a high-transmission setting. However, children with mild to moderate chronic malnutrition not taking TS are at higher risk for recurrent parasitemia and may be considered a target for chemoprevention
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