Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia
- 14 December 2017
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 130 (24), 2585-2593
- https://doi.org/10.1182/blood-2017-06-788935
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 (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. Publisher9s Note: There is an Inside Blood Commentary on this article in this issue. Key Points Compared with placebo, hydroxyurea did not increase the incidence or severity of malaria events in Ugandan children with SCA. Hydroxyurea provided significant clinical and laboratory benefits, suggesting it will be safe and effective across sub-Saharan Africa.Keywords
This publication has 28 references indexed in Scilit:
- Inhaled Nitric Oxide Reduces Endothelial Activation and Parasite Accumulation in the Brain, and Enhances Survival in Experimental Cerebral MalariaPLOS ONE, 2011
- Nitric Oxide Protection Against Murine Cerebral Malaria Is Associated With Improved Cerebral Microcirculatory PhysiologyThe Journal of Infectious Diseases, 2011
- Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG)The Lancet, 2011
- A Role for Fetal Hemoglobin and Maternal Immune IgG in Infant Resistance to Plasmodium falciparum MalariaPLOS ONE, 2011
- Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesisNature Communications, 2010
- High mortality from Plasmodium falciparum malaria in children living with sickle cell anemia on the coast of KenyaBlood, 2010
- How I use hydroxyurea to treat young patients with sickle cell anemiaBlood, 2010
- Malaria in patients with sickle cell anemia: burden, risk factors, and outcome at the outpatient clinic and during hospitalizationBlood, 2010
- Malaria as a Cause of Morbidity and Mortality in Children with Homozygous Sickle Cell Disease on the Coast of KenyaClinical Infectious Diseases, 2009
- Tumor Necrosis Factor and Disease Severity in Children with Falciparum MalariaNew England Journal of Medicine, 1989