Hydroxyurea for sickle-cell anaemia in Africa: mind the gap
Authors: Stephen K Obaro
Journal: The Lancet Global Health (2015)

An estimated 305 800 newborn babies have sickle cell anemia, and about two-thirds of these babies are born in Africa.1Piel FB Hay SI Gupta S Weatherall DJ Williams TN Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions.Lancet Glob Health. 2014; 2: e80-e89Summary Full Text Full Text PDF Scopus (114) Google Scholar The burden of disease is expected to rise as a result of improved survival in high-prevalence low-income and middle-income countries.1Piel FB Hay SI Gupta S Weatherall DJ Williams TN Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions.Lancet Glob Health. 2014; 2: e80-e89Summary Full Text Full Text PDF Scopus (114) Google Scholar Since the first clinical description of sickle-cell anaemia more than 100 years ago, only one drug, hydroxyurea, has been shown to have proven efficacy for amelioration of symptoms. Human stem-cell transplantation remains the only cure but is not available in many developing countries where the burden of disease is highest. Attention must therefore focus on the use of the relatively more accessible hydroxyurea. However, a few critical questions remain about the applicability of this simple regimen in low-resource, high-burden settings. Evidence suggests that widespread implementation of hydroxyurea for the management of sickle-cell anaemia in these settings might be a leap in the dark. In November, 2014, the US National Heart, Lung, and Blood Institute announced the end of a hydroxyurea efficacy trial2Successful outcome prompts early end to sickle cell anemia clinical trial.http://medicalxpress.com/news/2014-11-successful-outcome-prompts-early-sickle.htmlDate: November 19, 2014Google Scholar because of unequivocal results of efficacy in children. The TWiTCH2Successful outcome prompts early end to sickle cell anemia clinical trial.http://medicalxpress.com/news/2014-11-successful-outcome-prompts-early-sickle.htmlDate: November 19, 2014Google Scholar (Transcranial doppler With Transfusions Changing to Hydroxyurea) study was a clinical phase 3 randomised trial at 25 medical centres in the USA and Canada that compared monthly erythrocyte transfusions (standard therapy) with daily hydroxyurea (the alternative) for 121 children between 4–16 years of age with sickle-cell anaemia and abnormally elevated transcranial doppler velocities, and thus at high risk of stroke. Follow-up was originally scheduled for 24 months, but the study was terminated after only half the children completed the treatment phase owing to overwhelming evidence of benefit in the hydroxyurea-treated group. In a previous multicentre, randomised, double-blind, placebo-controlled trial of hydroxyurea in infants and young children, Wang and colleagues3Wang WC Ware RE Miller ST et al.Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).Lancet. 2011; 377: 1663-1672Summary Full Text Full Text PDF PubMed Scopus (562) Google Scholar assessed the effect of a fixed dose (20 mg/kg) of hydroxyurea in children aged 9–18 months with haemoglobin SS or haemoglobin Sβ(0)thalassaemia. The investigators reported clinical benefits of hydroxyurea, including lower rates of pain and dactylitis, admission to hospital, and transfusion. However, benefits on renal, splenic, and neurological function were inconclusive. Mild-to-moderate neutropenia was found, but there were no associated increase in infections. In a subgroup of children, naive and memory T-cell subsets and antibody responses to pneumococcal, measles, mumps, and rubella vaccines were measured.4Lederman HM Connolly MA Kalpatthi R et al.Immunologic effects of hydroxyurea in sickle cell anemia.Pediatrics. 2014; 134: 686-695Crossref PubMed Scopus (34) Google Scholar The hydroxyurea-treated group had significantly lower total CD4 lymphocyte and memory T-cell count than did the control group. Although antibody concentrations between the two groups were equivalent at study exit, it took longer to reach an antibody peak in the hydroxyurea-treated group. The practical implication of this finding in measles-endemic settings with suboptimum immunisation coverage is unknown. Clearly, this scenario could pose a public health concern in the event of disease outbreaks, such as is often the case with measles in most developing countries. Undoubtedly, hydroxyurea has a huge potential for improving the quality of lives of people affected by sickle-cell anaemia in settings where frequent and probably unsafe blood transfusions are the current standard of care. However, attention needs to be directed towards the potential adverse effects of hydroxyurea in such settings. The studies2Successful outcome prompts early end to sickle cell anemia clinical trial.http://medicalxpress.com/news/2014-11-successful-outcome-prompts-early-sickle.htmlDate: November 19, 2014Google Scholar, 3Wang WC Ware RE Miller ST et al.Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).Lancet. 2011; 377: 1663-1672Summary Full Text Full Text PDF PubMed Scopus (562) Google Scholar from developed countries assessed patients in a controlled setting with optimum preventive care and used the liquid formulation of hydroxyurea in infants and children. The availability and stability of this formulation in low-resource countries could be a challenge. A number of centres in Africa and individual patients have already started to use generic or branded hydroxyurea tablets. Yet the safety of hydroxyurea in Africa, where preventive care is poor and the risk of infection is very high, has not been assessed. The immunosuppressive activity of hydroxyurea suggests that long-term use might predispose people to increased infection risk. One could also argue that an optimum dose to ameliorate the complex manifestation of sickle-cell anaemia might culminate in protection from infection, but there are currently no safety data from Africa. For optimum benefits, the recommendation is to aim for the maximum tolerable dose of hydroxyurea.5Charache S Dover GJ Moore RD et al.Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia.Blood. 1992; 79: 2555-2565PubMed Google Scholar In view of the extreme phenotypic heterogeneity of sickle-cell disease, high infectious-disease burden, and poor immunisation practices, the dose of hydroxyurea needed to achieve optimum clinical benefit should be approached with care. Thus, as a minimum, controlled phase 3 studies of hydroxyurea in Africa are needed to establish its safety in this setting, and prolonged active surveillance should be maintained to ensure that the teratogenic and genotoxic properties of hydroxyurea do not cause delayed complications. I declare no competing interests.