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

Léon Tshilolo, George Tomlinson, Thomas N Williams, Brígida Santos, Peter Olupot-Olupot, Adam Lane, Banu Aygun, Susan E Stuber, Teresa S Latham, Patrick T McGann, Russell E Ware, REACH Investigators, Luis Bernardino, José Luis Reis da Fonseca, Lourenco Nassesa, Darío Adão de Oliveira André, Leydma Cuhna, Afonso Firmino Bengui, Vysolela de Oliveira, Robert Kitenge, Thierry Aberi, Nancy Madingo, Merveille Mbombo, Didier Mbuyi, Patrick Ngoy, Frank Nzengu, Gisèle Kazadi, Joddy Mafema, Guyslain Tshuyi, Yves Mukaba, Landry Kipepe, George Mochamah, Alex Macharia, Gideon Nyutu, Jimmy Shangala, Ruth Mwarabu, Metrine Tendwa, Emmanuel Mabibo, Julius Ngowa, Johnstone Makale, Esther Kivaya, Jacob Golijo, Monica Mwikamba, Kathryn Maitland, Ham Wabwire, Erayu Godfrey Bonface, Akado Clare, Alex Sande, Felix Opio, Florence Masambu, Justin McAdams, Sophie Perier, Jan Englehart, Elizabeth McGann, John Boesing, Thad Howard, Kathryn McElhinney, Léon Tshilolo, George Tomlinson, Thomas N Williams, Brígida Santos, Peter Olupot-Olupot, Adam Lane, Banu Aygun, Susan E Stuber, Teresa S Latham, Patrick T McGann, Russell E Ware, REACH Investigators, Luis Bernardino, José Luis Reis da Fonseca, Lourenco Nassesa, Darío Adão de Oliveira André, Leydma Cuhna, Afonso Firmino Bengui, Vysolela de Oliveira, Robert Kitenge, Thierry Aberi, Nancy Madingo, Merveille Mbombo, Didier Mbuyi, Patrick Ngoy, Frank Nzengu, Gisèle Kazadi, Joddy Mafema, Guyslain Tshuyi, Yves Mukaba, Landry Kipepe, George Mochamah, Alex Macharia, Gideon Nyutu, Jimmy Shangala, Ruth Mwarabu, Metrine Tendwa, Emmanuel Mabibo, Julius Ngowa, Johnstone Makale, Esther Kivaya, Jacob Golijo, Monica Mwikamba, Kathryn Maitland, Ham Wabwire, Erayu Godfrey Bonface, Akado Clare, Alex Sande, Felix Opio, Florence Masambu, Justin McAdams, Sophie Perier, Jan Englehart, Elizabeth McGann, John Boesing, Thad Howard, Kathryn McElhinney

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 .).

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Figure 1.. Screening, Enrollment, and Follow-up of…
Figure 1.. Screening, Enrollment, and Follow-up of the Participants.
The numbers of patients who withdrew from the trial or died are from the group of patients who completed treatment up to the respective time point.
Figure 2.. Retention of Participants in the…
Figure 2.. Retention of Participants in the Trial.
The shaded area represents the 95% confidence interval for death or withdrawal from the trial. The inset shows the same data on an enlarged y axis.
Figure 3.. Adverse Events before and during…
Figure 3.. Adverse Events before and during Hydroxyurea Treatment.
Error bars indicate 68% confidence intervals, which correspond to approximately 1 standard error.

Source: PubMed

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