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Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia

Abstract

Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg/day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events, clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N=104) or placebo (N=103). Malaria incidence did not differ between children on hydroxyurea [0.05 episodes/child/year, 95% CI (0.02, 0.13)] versus placebo [0.07 episodes/child/year (0.03, 0.16)]; the hydroxyurea/placebo malaria incidence rate ratio was 0.7 [(0.2, 2.7), p=0.61]. Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%, p=0.001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious adverse events, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (two hydroxyurea, one placebo, none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or adverse events. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined.

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