Hydroxyurea Is Safe, Efficacious in Children With SCA Living in Malaria-Endemic Sub-Saharan Africa

In vitro and animal studies suggest that hydroxyurea – one of two treatments approved by the U.S. Food and Drug Administration for the treatment of sickle cell anemia (SCA) – could increase the incidence and severity of malarial infection. This complicates the recommendation to use hydroxyurea in malaria-endemic sub-Saharan Africa, where the vast majority of children with SCA are born.

In a study published in Blood, Robert O. Opoka, MBChB, MMed, of the Department of Paediatrics and Child Health at Makerere University in Kampala, Uganda, and co-authors shared results from a study of children with SCA living in sub-Saharan Africa in which these children were randomized to receive hydroxyurea or placebo. They found that hydroxyurea treatment did not lead to an increased in severe malarial infections, or adverse events (AEs) in patients, “but optimal dosing and monitoring regimens for Africa remain undefined.”

The prospective, double-blind, randomized NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) study included 207 children (1-3.99 years of age) who were treated at Mulago Hospital Sickle Cell Clinic in Kampala, Uganda, between September 24, 2014, and October 2, 2015, and lived within 31 miles of the clinic. Patients were excluded if they weighed <11 pounds, had severe malnutrition or a known chronic medical condition, were already receiving hydroxyurea at the time of enrollment, or had received a blood transfusion in the previous 30 days.

Children were randomized 1:1 to receive 12 months of treatment with either:

  • hydroxyurea 20±2.5 mg/kg once-daily (n=104; mean age = 2.2 years; standard deviation [SD] = 0.9)
  • placebo (n=103; mean age = 2.3 years; SD=0.9)

Dose adjustments were allowed based on weight gain and hematologic toxicities.

Patients had 10 scheduled visits during the study treatment period to measure complete blood counts with leukocyte differential and absolute reticulocyte count, as well as blood chemistries. Patients with malaria (defined as an axillary temperature ≥99.5 degrees Fahrenheit) were treated with parenteral artesunate, followed by oral artemether-lumefantrine if hospitalized or oral artemether-lumefantrine alone if not hospitalized.

During the 12-month treatment period, malaria testing was performed for 235 episodes of fever, with only 12 confirmed episodes of malaria. The incidence of malaria (primary endpoint) did not differ between the two treatment groups: 0.05 episodes per child, per year in the hydroxyurea group (95% CI 0.02-0.13) versus 0.07 episodes per child, per year in the placebo group (95% CI 0.03-0.16), for a non-significant incidence rate ratio of 0.7 (95% CI 0.2-2.7; p=0.61).

Three children in the hydroxyurea cohort had five malaria episodes and seven children in the placebo cohort had seven malaria episodes.

Six of the total of 12 malaria episodes were severe and required hospitalization related to hemoglobin concentration <5 g/dL (n=2), impaired consciousness (n=1), hemoglobin concentration <5 g/dL and impaired consciousness (n=1), or an inability to take oral medication (n=2). Four malaria episodes had concomitant clinical AEs, including vaso-occlusive crisis (VOC; n=3) and acute chest syndrome/pneumonia (n=1). Two malaria episodes had concomitant serious AEs, including splenic sequestration (n=1) and bacteremia (n=1).

All patients with malaria recovered from the disease; however, three patients died because of presumed sepsis (n=2; one in each treatment group) or sudden death from an unknown cause (n=1; hydroxyurea cohort). Five patients withdrew from the study.

A composite endpoint of SCA-related clinical outcomes (including VOC, dactylitis, acute chest syndrome, splenic sequestration, and blood transfusion) occurred in 45 percent of those treated with hydroxyurea, compared with 69 percent treated with placebo (p=0.001).

Serious AEs (defined as death, acute life-threatening event, or hospitalization for more than 7 days) occurred in six patients in each treatment cohort. (See TABLE for other AE outcomes.)

The results “suggest that hydroxyurea should be strongly considered as an important therapeutic option for young children with SCA living in malaria-endemic areas,” the authors concluded.

Because the overall rate of malaria was low – “perhaps reflecting excellent adherence to malaria prophylaxis,” the authors wrote – the results may not be generalizable to “children with SCA not on malaria prophylaxis and/or not using insecticide-treated bed nets.” The authors also noted that risks of hydroxyurea “may differ in areas of higher malaria transmission, and genetic or environmental factors in other areas could affect risk of hydroxyurea toxicity or malaria-hydroxyurea interactions.”

“Outcomes were excellent … with a safe and relatively easily administered fixed dose (20 mg/kg), so it will be important to investigate how treatment benefits and risks differ with different dosing schemes of hydroxyurea for children with SCA living in malaria-endemic areas,” the authors concluded. The researchers plan to compare the effects of early initiation with longer-term effects of the drug in future studies.

Addmedica donated both hydroxyurea and placebo for the study.

The authors report no conflicts.


Opoka RO, Ndugwa CM, Latham TS, et al. Novel use of hydroxyurea in an African region with malaria (NOHARM): a randomized controlled trial. Blood. 2017. [Epub ahead of print]

TABLE. Adverse Events (AEs) in the NOHARM Population
Hydroxyurea (n=104) Placebo (n=103) P Value
Serious AEs Events Participants Events Participants
Bacteremia/sepsis 2 2 2 2 1.0
Acute chest syndrome/pneumonia 1 1 2 2 0.62
Vaso-occlusive crisis 0 0 1 1 0.5
Acute splenic sequestration 2 2 0 0 0.5
Anemia 0 0 1 1 0.5
Sudden death 1 1 0 0 1.0
SCA-related events (composite) 47 71 0.001
Dose-limiting toxicities
Anemia 6 4 8 8 0.36
Reticulocytopenia 1 1 5 5 0.12
Neutropenia 2 2 0 0 0.5
Thrombocytopenia 12 11 4 4 0.11
SCA = sickle cell anemia