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Cited by 380Hemoglobinopathies and Related DisordersBlood groups and transfusionMalaria Research and Control

Hydroxyurea for children with sickle cell anemia in Sub-Saharan Africa

Open access
Tshilolo, Léon, Tomlinson, George, Williams, Thomas N., Santos, Brígida, Olupot-Olupot, Peter, Lane, Adam, Aygun, Banu, Stuber, Susan E. +3 more·2019·New England Journal of Medicine
DOI 10.1056/nejmoa1813598PMC PMC6454575
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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 .).

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Crossref · 10.1056/nejmoa1813598

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  • An open-label trial in 606 African children aged 1 to 10 years treated with hydroxyurea found that HbF increased from 10.9% to 23.4%.

    “Nevertheless, an open-label trial in 606 African children aged 1 to 10 years treated with hydroxyurea found that HbF increased from 10.9% to 23.4%.”

    From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [73]

    Methods > Trial Design describes an open-label trial recruiting children aged 1 to 10 in sub-Saharan Africa, and Results > Enrollment and Retention says 606 began hydroxyurea. Results > Laboratory Benefits reports a 12.5-percentage-point increase in fetal hemoglobin after one year, but the passages in our copy do not give the claimed starting and ending values of 10.9% and 23.4%. (LLM, conf=0.85)

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  • The increase in HbF in the open-label hydroxyurea trial was associated with a decrease in the rate of malaria infection by more than 60%.

    “This was associated with a decrease in the rate of malaria infection by more than 60%.73”

    From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [73]

    The Results (Effects on Survival; page unavailable) report increased fetal hemoglobin during treatment and a lower malaria infection rate, but the reported rates—46.9 versus 22.9 events per 100 patient-years—amount to a reduction of about 51%, not more than 60%. The Discussion (page unavailable) describes the reduction as more than 50% and suggests, rather than establishes, that fetal hemoglobin may explain it. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • Hydroxyurea is also used effectively in low-resource countries.

    “Hydroxyurea is also used effectively in low-resource countries.73,79,80”

    From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [73]

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Authors
Tshilolo, L., Tomlinson, G., Williams, T. N., Santos, B., Olupot-Olupot, P., Lane, A., Aygun, B., Stuber, S. E., Latham, T. S., McGann, P. T., & Ware, R. E.
Affiliations
  • Mount Sinai Hospital (CA)
  • From Centre Hospitalier Monkole, Kinshasa, Democratic Republic of Congo (L.T.); the Department of Medicine, University Health Network and Mt. Sinai Hospital, and the University of Toronto, Toronto (G.T.); the Kenya Medical Research Institute (KEMRI)–Wellcome Trust Research Program, Kilifi, Kenya (T.N.W.); the Department of Medicine, Imperial College London, London (T.N.W.); Hospital Pediátrico David Bernardino, Luanda, Angola (B.S.); Mbale Clinical Research Institute and Mbale Regional Referral and...
  • Cincinnati Children's Hospital Medical Center (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2019-01-10
Volume
380
Issue
2
Pages
121-131
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1813598
PMC
PMC6454575
OpenAlex
W2902147263
Semantic Scholar
c678f2b17bd36f38a14c64ccd2a41b9165ece5b3
Cited by
376
References
38
Citations by year
2026: 47 · 2025: 50 · 2024: 49 · 2023: 77 · 2022: 48 · 2021: 37 · 2020: 37 · 2019: 31
FWCI
14.85
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Spiral (Imperial College London) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (K23 HL128885, U01 HL133883)
  • Cincinnati Children’s Research Foundation (None)
Topics
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Health Sciences › Medicine › Hematology › Blood groups and transfusion
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
Keywords
hydroxyurea, sickle cell disease, pediatric patients, sub-Saharan Africa, resource-limited settings, malaria, vaso-occlusive pain, transfusion requirements, fetal hemoglobin, hemoglobin levels, drug safety, medication adherence, dose escalation, malnutrition, survival, treatment retention, dose-limiting toxicity, malaria prophylaxis, hydroxyurea resistance
MeSH terms
Anemia, Sickle Cell, Antisickling Agents, Child, Child, Preschool, Dose-Response Relationship, Drug, Humans, Hydroxyurea, Infant, Malaria, Pain, Africa South of the Sahara, Neglected Diseases

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