Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa

Abstract

BACKGROUND Hydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hydroxyurea in low-resource settings. METHODS We enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell–related events, transfusions, and survival). RESULTS A total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient-years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88). CONCLUSIONS Hydroxyurea treatment was feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. Hydroxyurea use reduced the incidence of vaso-occlusive events, infections, malaria, transfusions, and death, which supports the need for wider access to treatment. (Funded by the National Heart, Lung, and Blood Institute and others; REACH ClinicalTrials.gov number, NCT01966731.)

Sickle cell screening in Uganda: High burden, human immunodeficiency virus comorbidity, and genetic modifiers

“…One suggested intervention for screening and diagnosis includes introducing other techniques for screening, such as new point‐of‐care devices that hold promise for widespread testing in low‐resource settings . For treatment, disease‐modifying therapy with hydroxyurea should also be included in any national strategy for the management of sickle cell disease, since recent data suggest that daily oral hydroxyurea is both safe and effective in malaria endemic regions within Africa …”

“…29,30 For treatment, disease-modifying therapy with hydroxyurea should also be included in any national strategy for the management of sickle cell disease, 10,31 since recent data suggest that daily oral hydroxyurea is both safe and effective in malaria endemic regions within Africa. 32,33 Overall, formation of a practical continuum of care for sickle cell dis-…”

Sickle cell disease: Reducing the global disease burden

“…The randomized NOHARM study in malaria‐endemic Uganda carried out in children with SCD reported no increased frequency of clinical malaria on hydroxyurea treatment compared with placebo, helping address the safety concerns in relation to malaria infection in the region . The REACH trial, an open‐label study conducted in four African countries demonstrated the safety, feasibility, and efficacy of hydroxyurea in children with sickle cell disease . Interestingly, a reduced incidence of clinical malaria in this cohort of children treated with hydroxyurea was unexpectedly observed.…”

Pharmacy hydroxyurea education materials for patients with sickle cell disease: An environmental scan and assessment of accuracy

“…Recent evidence suggests a robust increase in HU prescription to children with SCD; however, the prescription rates for all ages are still inadequate (below 50% in pediatrics and close to 10% in adults) . In light of the expanding global application of HU in the care of patients with SCD given recent demonstration of efficacy in patients living in regions of sub‐Saharan Africa, efforts in understanding barriers to HU acceptance in SCD are becoming increasingly relevant.…”