March-April 2019, Volume 16, Issue 2
Hydroxyurea for Children With Sickle Cell Anemia in Sub-Saharan Africa: The Child That Comes and Goes Away Can Come to Stay With Hydroxyurea
Published on: February 07, 2019
Tshilolo L, Tomlinson G, Williams TN, et al. Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa. N Engl J Med. 2019;380:121-131.
Sickle cell disease (SCD) was first reported in the United States in 1910; however, the condition has been present in Africa for more than 5,000 years. An estimated 100,000 Americans struggle with SCD, which causes recurrent unpredictable episodes of acute debilitating pain, chronic organ damage, poor quality of life, and a two- to three-decade reduction in life expectancy compared to unaffected individuals. Globally, SCD is much more prevalent, with more than a quarter of a million births annually in sub-Saharan Africa alone. Among the Igbo tribe in Nigeria (the most populous country in Africa), these children were often called ogbanje, meaning “the child that comes and goes away,” or simply, “the child who dies young.”1,2 The high death rate among children ascribed as ogbanjes was reported by Nzewi to correlate strongly with symptoms and a hematologic profile consistent with a diagnosis of SCD among 70 of 100 children studied.2
Decades of work in the United States has allowed some progress to be made in this disease, with advances to reduce the incredibly high infant and childhood mortality. But there is a dearth of interventions successfully implemented in African countries where SCD is more prevalent and extremely lethal in children. Hydroxyurea therapy has been incorporated into the standard of care for children and adults with SCD in the United States since the U.S. Food and Drug Administration (FDA) approval in 1998.3 The National Heart, Lung, and Blood Institute’s evidence-based report published in 2014 recommended offering hydroxyurea treatment to persons nine months and older with sickle cell anemia to ameliorate recurrent pain crises and acute chest syndrome and to improve anemia.4
Until recently, there have been very few studies of hydroxyurea use for SCD in sub-Saharan Africa, where the impact of this drug could potentially be greatest. The high cost of hydroxyurea in resource-poor countries creates challenges and there are also quality-assurance concerns with local manufacturing of hydroxyurea.5 Most families cannot afford the frequent blood monitoring required to achieve the maximum tolerated dose (MTD) recommended when using hydroxyurea in the United States. It is unknown whether hydroxyurea use in patients with co-existing malnutrition; nutritional deficiencies; or bacterial, parasite, or helminth infections will cause more severe cytopenias. Lastly, conducting rigorous clinical trials is uniquely difficult in resource-poor countries and requires careful planning as well as robust stakeholder engagement to determine the most pragmatic study design that is both feasible and cost-effective.
In 2018, Dr. Léon Tshilolo and colleagues published results of a large prospective phase I/II study titled Realizing Effectiveness Across Continents with Hydroxyurea (REACH) to demonstrate the safety and efficacy of hydroxyurea use among children in four sub-Saharan African countries including Angola, Democratic Republic of Congo, Kenya, and Uganda. This study was birthed from a partnership between U.S., Canadian, and sub-Saharan African investigators convened under the umbrella of the Global Sickle Cell Disease Network (GSCDN). The REACH study investigated the safety and feasibility of using open-label hydroxyurea in children with SCD aged one to ten years in sub-Saharan Africa, across four clinical sites with a target enrollment of 150 children per site. Consented subjects were screened during a two-month period to obtain baseline laboratory data and clinical history. Oral hydroxyurea was then initiated at a dose of 15 to 20 mg/kg/d for the first six months before any dose escalation was attempted. The dose of hydroxyurea was escalated every two months thereafter if the absolute neutrophil count was greater than 4,000/cm3, hemoglobin was more than 6.5g/dL, absolute reticulocyte count was higher than 150 × 10–9, and platelet count was lower than 150 × 10–9. Subjects were seen every month to assess for safety and efficacy for the first year and every two months afterward.
It is unusual in a clinical trial to incorporate and monitor standard-of-care guidelines for disease management; however, the REACH study provided an umbrella protocol guidance to address the a priori concern about the potential impact of co-existing malnutrition, nutritional deficiencies, and infections on the response to hydroxyurea. During the screening period, the protocol called for vaccination against measles and PCV13 (if not completed), PCV23 (if older than 2 years), nutritional supplementation based on dietary and anthropometry parameters, vitamin A supplementation with 200,000 IU orally (if younger than 5 years and not documented within the past 6 months), folate and iron supplementation, and malaria prophylaxis per local standards. Treatment for helminth infection with albendazole or mebendazole was required at study entry and repeated every six months, while vitamin A supplementation was repeated annually until completion of study.
A total of 606 subjects completed screening and initiated study treatment, and 90 percent of subjects documented no missed medication doses. While this study was not designed to assess clinical benefit, it did show a reduction in overall rates of SCD-related events (114.5 vs. 53.0 events per 100 patient-years; incidence rate ratio, 0.47; 95% CI, 0.38 to 0.57) with reduction in both acute pain and acute chest syndrome rates. Surprisingly, the rates of infection also declined, including rates of nonmalarial infections (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72) and severe (grade 3 or higher) infections (28.9 vs. 8.0 events per 100 patient-years; incidence rate ratio, 0.28; 95% CI, 0.19 to 0.42). This study also noted significant reductions in rates of malarial infections (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), blood 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 events per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88).
The REACH study began enrollment in June 2014 and successfully enrolled 635 subjects in 30 months. Nearly 95 percent of participants were retained on study for more than three years despite having to comply with monthly study visits for a year and bimonthly study visits thereafter.6,7 This is remarkably impressive and demonstrates the feasibility of conducting large clinical trials in SCD in resource-poor countries. It also implies that study participants and their families perceived value in their study visits, whether access to hydroxyurea alone or access to the supportive care associated with being on the study. Hydroxyurea use led to a 50 percent reduction in malaria infection and consequently a reduction in transfusion rates. These findings are noteworthy because malarial infections have a high lethality rate among infants and children in sub-Saharan Africa, where transfusion safety is a persistent challenge.
It is not clear why there was a dramatic reduction in the rates of malarial and nonmalarial infections or if it had anything to do with hydroxyurea use specifically. The benefits of being a part of a clinical trial and receiving what should be standard of care (malaria and helminth prophylaxis, vitamin supplementation, etc.) could very well be responsible for this detected effect. Overall, the REACH study lays to rest several of the initial concerns with dosing hydroxyurea to MTD in countries where infections and malnutrition are prevalent. The answer to financial access to the medication and required monitoring in a nonclinical trial setting remains elusive. The REACH investigators and the GSCDN are committed to working with national governments to identify optimal dissemination strategies that will afford broader uptake of this disease-modifying therapy for patients with SCD.
Onwubalili JK. Sickle-cell anaemia: an explanation for the ancient myth of reincarnation in Nigeria. Lancet. 1983;2:503-505.
Nzewi E. Malevolent ogbanje: recurrent reincarnation of sickle cell disease?. Soc Sci Med. 2001;52:1403-1416.
Wong TE, Brandow AM, Lim W, et al. Update on the use of hydroxyurea therapy in sickle cell disease. Blood. 2014;124:3850-3857.
National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: Expert Panel Report, 2014. NHLBI. Sep 2014.
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312:1033-1048.
McGann PT, Tshilolo L, Santos B, et al. Hydroxyurea therapy for children with sickle cell anemia in sub-Saharan Africa: rationale and design of the REACH Trial. Pediatr Blood Cancer. 2016;63:98-104.
McGann PT, Williams TN, Olupot-Olupot P, et al. Realizing effectiveness across continents with hydroxyurea: enrollment and baseline characteristics of the multicenter REACH study in sub-Saharan Africa. Am J Hematol. 2018;93:537-545.
Conflict of Interests
Dr. Osunkwo indicated no relevant conflicts of interest.
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