In this trial involving children with sickle cell anemia living in sub-Saharan Africa, we found that hydroxyurea treatment was feasible, reasonably safe, and had both laboratory and clinical benefits. Specifically, as compared with pretreatment rates, the rates of clinical events, including vaso-occlusive pain, infection, malaria, transfusion, and death, declined after 1 year of hydroxyurea treatment.
Enrollment was robust at all the clinical trial sites, with enthusiasm and support from local clinical research teams and populations of patients, which showed the feasibility of conducting a large-scale clinical trial in sub-Saharan Africa. Hematologic dose-limiting toxic effects during the first 3 months of treatment (the primary safety end point) occurred in only a small number of participants, and the hydroxyurea dose was then safely escalated toward a maximum tolerated dose, similar to treatment protocols in the United States.15 Expected hematologic benefits occurred, with significant increases in the hemoglobin and fetal hemoglobin levels. Significant reductions were observed in the incidence rates of sickle cell–related clinical events, including vaso-occlusive pain, and major clinical events including infection, malaria, transfusion, and death. No serious adverse events or deaths were considered by the investigators to be related to hydroxyurea treatment (Tables S3 and S4 in the Supplementary Appendix).
In the United States and Europe, hydroxyurea has emerged as a potent, disease-modifying therapy with regulatory approvals for use in both children and adults. Although the primary mode of action of hydroxyurea is through the induction of fetal hemoglobin, this drug has multiple salutary effects on erythrocytes, leukocytes, and even endothelium that make it a beneficial oral treatment for this life-threatening disease, especially at the maximum tolerated dose.18 The WHO includes hydroxyurea on its Model Lists of Essential Medicines for children and adults for the treatment of sickle hemoglobinopathies,19,20 which provides an impetus for widespread use on a global scale. To date, however, few studies have been completed in sub-Saharan Africa or other low-income settings where the burden of sickle cell disease is greatest.21 In addition to several small studies of hydroxyurea conducted in Nigeria,22-24 the Novel Use of Hydroxyurea in an African Region with Malaria (NOHARM) trial was a randomized, double-blinded, placebo-controlled trial that was conducted at a single, large, urban site in Uganda, which showed that the rates of malaria were not higher with hydroxyurea than with placebo.25 However, the overall incidence of malaria in the NOHARM trial was very low, whereas the participants in the REACH trial lived in urban and rural areas of Africa that have a much higher incidence of malaria than Kampala, Uganda, where the NOHARM trial was conducted.
With full enrollment, high rates of adherence to trial visits and medication use, and a retention rate of nearly 95% in the trial over a period of 3 years, our trial showed that hydroxyurea treatment was both feasible and safe in sub-Saharan Africa. Despite frequent laboratory monitoring, dose-limiting toxic effects were uncommon in the first 3 months of treatment, and then the incidence did not increase further (Table 1). After 6 months of fixed-dose hydroxyurea therapy, dose escalation was not associated with unacceptable side effects or with toxic effects regarding laboratory variables and reached daily doses that were similar to those reported in the United States.26,27 Our results indicate that a daily dose of approximately 20 mg per kilogram per day was reasonably effective and not associated with dose-limiting toxic effects. The trial was not designed to determine the appropriate amount or frequency of laboratory monitoring.
The laboratory benefits of hydroxyurea treatment were evident, despite relative malnutrition in the REACH cohort, as compared with WHO child-growth standards and with populations of patients with sickle cell disease in the United States and Europe. Expected significant increases were observed in both the hemoglobin and fetal hemoglobin levels, along with significant decreases in the absolute neutrophil and reticulocyte counts, and these changes were sustained over time (Table 2). The mean increase in the hemoglobin level of 1 g per deciliter, despite suboptimal nutrition and ongoing risks of malaria and other infections, is important because the hemoglobin level is a well-established predictor of adverse outcomes in children with sickle cell anemia.28 Within 6 months after the start of treatment, expected clinical benefits were also observed with regard to sickle cell–related events such as pain and the acute chest syndrome, as well as all severe (grade ≥3) adverse events.
The benefits of hydroxyurea therapy with regard to malaria infections were significant — with a rate reduction of more than 50% — and were not predicted before the trial (Table 1), despite the lack of malaria chemoprophylaxis programs at all the clinical sites. This benefit was especially notable after 12 months of treatment, so it may reflect known inhibitory effects of fetal hemoglobin,29 more than direct effects by hydroxyurea,30 on parasite growth. The importance of this effect should be evident for sub-Saharan Africa, where Plasmodium falciparum malaria is a major killer of children and is especially lethal in those with sickle cell anemia.31 In a finding that perhaps reflects the decrease in the incidence of malaria, there was a significant reduction in the incidence of transfusions (Table 1), which is important because of the general lack of safe blood supply across Africa.32
This trial showed a significant reduction in all-cause mortality in this young cohort (Table 1). This effect reflects the combined effect of fewer severe sickle cell–related clinical complications, infections, malaria, and possibly transfusions. However, because the REACH trial did not include a placebo control, the survival benefit could be due to hydroxyurea use but also to better overall care, since the participants had frequent visits while they were receiving treatment. However, these findings are similar to those of previous reports that have shown an effect of hydroxyurea therapy on survival.13,14,33,34
A limitation of this trial was the open-label treatment design without randomization or a placebo control, which was a decision that was based on strong opinions from the local ethics boards. However, the design fully addressed the key end points of feasibility and safety, showing that hydroxyurea could be administered in low-resource settings. All the participants received good care with close monitoring, which probably contributed to better outcomes that were unrelated to hydroxyurea treatment; additional studies will be needed to confirm sustained benefits with less monitoring. Strengths of this trial included the following: the international design; the dosing algorithm of a fixed dose followed by escalation to the maximum tolerated dose; the use of an electronic-capture system for data entry; and the availability of an online dose calculator to help ensure the safety of the participants. Long-term follow-up of this African cohort is ongoing for the investigation of growth and development and possible effects on organ function and fertility.
In conclusion, our results show that daily hydroxyurea treatment was feasible and safe for children with sickle cell anemia in sub-Saharan Africa. Moreover, hydroxyurea treatment reduced the rates of painful events, infection, malaria, transfusion, and death. Despite the recognition that 50 to 90% of affected children in Africa die before the age of 5 years,35 sickle cell anemia remains a neglected disease for which safe and effective treatment options are needed.36 As countries in sub-Saharan Africa begin newborn screening programs to identify children with sickle cell anemia,37-39 wider access to hydroxyurea may provide a simple and inexpensive oral medication that can alter the disease course and prolong survival.