From 2014 to 2024, researchers at the Indiana University School of Medicine and their global health collaborators examined the effects of an oral medication called hydroxyurea on children with sickle cell anemia in sub-Saharan Africa. In a letter recently published in the New England Journal of Medicine, they unpacked strong evidence a decade in the making that further proves the treatment should be considered standard care for children with the inherited blood disorder.
“On the maximum tolerated dose of hydroxyurea, African children with sickle cell anemia survive and thrive,” said Chandy John, MD, the Ryan White Professor of Pediatrics at the IU School of Medicine.
Sickle cell anemia results from abnormally shaped red blood cells that block oxygen from smoothly traveling through the body, leading to symptoms including severe pain, delayed growth, infections and other serious complications. If left untreated, the disease can be life-threatening.
In high-resource regions like the United States and Europe, hydroxyurea is a widely used and successful treatment for sickle cell anemia. However, it has been underutilized in sub-Saharan Africa, where the disease is most prevalent. Through the initial NOHARM (Novel Use of Hydroxyurea in an African Region with Malaria) trial and its subsequent studies, researchers aimed to demonstrate the treatment’s effectiveness for the most vulnerable population of children.
The first two clinical trials followed children in Uganda with sickle cell anemia and compared outcomes of a lower, “fixed” dose of the medicine versus a “maximum tolerated dose.” The long-term final phase further analyzed the effects of the higher dose across all participating children. The findings showed the higher dose resulted in a reduction of severe pain episodes, hospitalizations and the need for blood transfusions.
Most importantly, researchers confirmed a significant reduction in deaths.
“The mortality rate for children in the NOHARM study was 8.7%, compared to a 43.3% mortality rate of children under 10 with sickle cell anemia in a different recent study across five African countries,” said John, the co-principal investigator of the NOHARM studies and co-author on the recent letter. “This reveals an 80% decrease in mortality for children on hydroxyurea as compared to children with sickle cell anemia in Africa not on, or not uniformly on, the treatment.”
The researchers also found that years of hydroxyurea treatment resulted in substantial improvements in both height and weight, signaling improved nutrition outcomes.
As director of the Ryan White Center for Pediatric Infectious Diseases and Global Health and a program leader at the Herman B Wells Center for Pediatric Research, John oversees numerous global health studies in Africa focused on sickle cell anemia and malaria. This includes a recent study that linked severe childhood malaria to cognitive impairment later in life. He credits the collaborative, supportive environment at the IU School of Medicine and Riley Children’s Health for making this long-term research possible.
“As with many of our previous studies, support from partners at IU Dance Marathon, the Riley Children’s Foundation, the Department of Pediatrics and the IU School of Medicine were absolutely critical in allowing us to continue supporting and studying this cohort of Ugandan children,” he said.
The findings in the New England Journal of Medicine were co-authored by IU’s Andrea L. Conroy and collaborators from Cincinnati Children’s Hospital Medical Center, Aga Khan University, Makerere University, Global Health Uganda, Centre Hospitalier Universitaire Sainte-Justine and University of Toronto.
“The project has been a true collaboration from the beginning,” John said. “Bob Opoka of Global Health Uganda and Makerere University had the tremendous knowledge and expertise to make such a project work in the Ugandan context, and Bob and I both agree that the work could not have happened without Russell Ware, a world renowned sickle cell disease researcher from Cincinnati Children’s Hospital and Medical Center, whose knowledge of this kind of clinical trial and how to best conduct it, was key to getting it started and continuing the work over the past decade.”
