Hydroxyurea Proves Safe for Children with Sickle Cell Anaemia in Landmark African Study

One of the longest-running anxieties in global sickle cell medicine has been laid to rest. A major cohort study drawn from the NIH-funded Realizing Effectiveness Across Continents with Hydroxyurea, or REACH, trial has found that children with sickle cell anaemia treated with hydroxyurea show no increase in clinically diagnosed infections, even at the maximum tolerated dose and even in low-income settings where access to intensive medical care is limited. The findings, published in The Lancet Haematology, come from four African sites in Angola, the Democratic Republic of Congo, Kenya and Uganda, and involved 606 children and young adults living with the disease. For clinicians who have long hesitated to prescribe the drug in resource-constrained environments, the results offer what the investigators describe as strong reassurance that hydroxyurea can be used safely as standard of care.

Hydroxyurea is an oral medication taken once daily that works by coaxing the body to produce more fetal haemoglobin, the oxygen-carrying protein normally made by babies in the womb. Fetal haemoglobin has a crucial biochemical property: it prevents red blood cells from adopting the rigid, crescent-shaped sickle form that gives the disease its name. Sickled cells block small blood vessels, causing the excruciating pain crises, organ damage and chronic ill health that characterise sickle cell anaemia. By reactivating fetal haemoglobin production, hydroxyurea reduces these complications at their source. The drug has been recommended treatment in high-income countries for years, but its uptake in much of sub-Saharan Africa, where the vast majority of patients live, has lagged behind for a specific and understandable reason.

That reason concerns the immune system. Hydroxyurea suppresses the bone marrow to some degree, reducing the number of neutrophils, the white blood cells that form the first line of defence against bacterial and viral pathogens. In a hospital with ready access to blood counts, antibiotics and intensive care, this side effect can be monitored and managed. In rural clinics with limited laboratory capacity, doctors have worried that lowering neutrophil counts could tip vulnerable children into severe or fatal infections, including malaria, which is endemic at all four of the trial sites. Malaria is a particular concern because the parasite attacks red blood cells directly, and sickle cell patients already face heightened vulnerability to infection-related complications. Until now, this theoretical risk had not been examined in detail in the settings where it mattered most.

The new analysis addresses that gap with unusual statistical power. Recruitment of children aged one to ten took place between 2014 and 2016, and participants have been followed up every two to three months in the years since, generating more than 5,000 patient years of observation. Children began hydroxyurea at a fixed dose for six months and were then escalated to the maximum dose they could tolerate, the regimen now widely considered optimal. Most infections during the trial were reported retrospectively, usually through clinical history alone rather than real-time laboratory testing, a pragmatic approach that reflects how infections are actually diagnosed in routine care across much of the region.

The results pointed firmly in the opposite direction from the feared harm. Rather than increasing infections, higher hydroxyurea doses were associated with falling infection rates. The risk of malaria dropped by 51 percent with increasing dose, and the risk of non-malarial infections fell by 38 percent. The incidence and severity of infections did not increase over more than a decade of treatment, and in many cases declined. The study authors interpret this pattern as consistent with the drug’s broader benefit: by reducing sickling, vaso-occlusion and the chronic inflammation and organ dysfunction that accompany untreated disease, hydroxyurea appears to leave children better able to withstand the infectious threats around them, not weaker.

Professor Tom Williams of Imperial College London’s Institute of Global Health Innovation, the study lead, emphasised how directly the findings speak to clinical hesitation. He noted that many doctors are cautious of using hydroxyurea because they worry it will increase the risks of severe or fatal infections, particularly in low-income settings with limited medical resources. In the huge study covering more than 5,000 patient years of follow-up, he reported, the team found no increase in illness or death from infections, even when hydroxyurea was used at the maximum tolerated dose. Senior author Professor Russell Ware of Cincinnati Children’s Hospital Medical Center added that the findings provide long-awaited data on the long-term safety of maximum tolerated dose hydroxyurea in low-income settings, with incidence and severity of infections not increasing over ten years of treatment and often decreasing.

The scale of the unmet need behind this research is difficult to overstate. Sickle cell anaemia is the most common and severe inherited blood disease in humans, and approximately 80 percent of cases occur in sub-Saharan Africa. Around 550,000 children are born with the condition every year, facing complications that include chronic pain, vulnerability to life-threatening bacterial and viral infections, and progressive organ damage. Bacterial and viral infections are among the most common and dangerous complications of the disease, yet in many affected countries newborn screening, preventive antibiotics and comprehensive specialist care remain scarce. A cheap, oral, once-daily drug that can be escalated to the right dose with modest monitoring represents one of the few realistic routes to changing that trajectory at scale.

The REACH programme itself has been running for more than a decade and has already demonstrated that hydroxyurea therapy is both safe and highly effective in reducing most sickle-related complications. What this extended analysis adds is the infection-specific evidence that had been missing. Earlier REACH results established the drug’s efficacy against pain crises and other classic complications, but the question of whether immune suppression would translate into real-world infectious harm in malaria-endemic, resource-limited environments remained open. By closing that gap with long-term, dose-escalated follow-up across four countries, the study removes the principal scientific rationale for withholding the drug from the children who need it most.

The study authors’ recommendation is unambiguous: children with sickle cell anaemia living in low-resource settings should receive treatment with hydroxyurea at the maximum tolerated dose. Professor Williams said the results provide strong reassurance that the incidence and severity of infections are not increased with long-term or maximum dose hydroxyurea treatment, and that the findings support the wider use of hydroxyurea as standard of care. For an estimated half a million children born each year into a disease that has historically been undertreated precisely where it is most prevalent, the message from this decade of African-led evidence is clear: the safest option is not to avoid the drug, but to give it, and to give it at the dose the child can tolerate.

Subject of Research: Safety and efficacy of hydroxyurea treatment for children with sickle cell anaemia in low-income African settings

Article Title: Children living with sickle cell can be treated safely using hydroxyurea

Article References: Children living with sickle cell can be treated safely using hydroxyurea. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: sickle cell anaemia, hydroxyurea, REACH trial, fetal haemoglobin, malaria, pediatric haematology, sub-Saharan Africa, infection risk, global health, The Lancet Haematology, neutrophils, maximum tolerated dose