Abstract
AbstractHydroxyurea 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 (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), 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 per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .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 = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416.
Highlights
Sickle cell anemia (SCA) is a life-threatening hematological disorder and among the world’s most prevalent hereditary diseases, with more than 300 000 affected babies born each year.[1]
Over the 1-year study period, malaria testing was done for 235 episodes of measured fever or history of fever in study participants, with only 12 fever episodes because of malaria
Medication adherence, assessed by careful questioning at each clinic visit, was deemed excellent in both treatment arms. In this prospective randomized double-blinded placebo-controlled trial of young children with SCA living in Uganda, hydroxyurea therapy was both safe and efficacious
Summary
Sickle cell anemia (SCA) is a life-threatening hematological disorder and among the world’s most prevalent hereditary diseases, with more than 300 000 affected babies born each year.[1]. Hydroxyurea has proven laboratory and clinical efficacy for both children and adults with SCA.[4,5,6,7] Its mechanisms of action are multiple and incompletely understood, but fetal hemoglobin (HbF) induction in erythroid cells is critical for the inhibition of intracellular sickling. Treatment has salutary effects on blood cell adhesion, morphology, and rheology.[8] Further, hydroxyurea is a safe drug for SCA, with low incidence of treatment-related toxicity and no serious long-term effects observed to date. Hydroxyurea is currently approved by the US Food and Drug Administration for adults with severe symptoms and by the European Medicines Agency for affected adults and children above age 2 years.
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