In this issue of Blood Advances, Safeukui et al demonstrate the antimalarial properties of hydroxyurea, a ribonucleotide reductase (RNR) inhibitor, found to be a safe and efficacious therapy used to manage sickle cell disease (SCD) in children and adults.1 The World Health Organization estimates that a child dies of malaria every 2 minutes.2 In addition, SCD, a deadly inherited hemoglobinopathy, characterized by severe anemia and painful vaso-occlusive crises resulting in pain and/or end-organ dysfunction, affects over 300 000 newborns annually,3 predominantly in regions endemic for malaria. Therefore, the promise of a drug that can possibly treat both is urgently needed and undoubtedly welcomed by patients and the providers that care for them in regions where SCD and malaria are most prevalent.
It is widely accepted that both those with SCD and heterozygous carriers (hemoglobin AS [HbAS]) of sickle hemoglobin (HbS), which polymerizes in low oxygen (O2), are partially protected from Plasmodium falciparum malaria4 by O2-dependent parasite growth inhibition.5 As a result, any therapy that results in the inhibition of polymerization may alter the evolutionary benefit provided to those with the sickle β-globin mutation. However, in 2 landmark hydroxyurea clinical trials for the treatment of SCD in malaria-endemic regions, hydroxyurea did not increase the risk of P falciparum malaria.6,7 In a recent subanalysis of the REACH study, it was even found to reduce clinical malaria, unrelated to the induction of fetal hemoglobin,8 a potent antisickling agent, suggesting a potential antimalarial effect.
As a result, the authors set out to demonstrate the stage-specific antimalarial properties of hydroxyurea and 3 other RNR inhibitors. They show that hydroxyurea and other RNR inhibitors expectedly reduce schizont development by ∼40% in both HbAA and HbSS erythrocytes. In addition, the authors also demonstrate the additive effect of hydroxyurea in vitro and in vivo when combined with other known antimalarial drugs. Although hydroxyurea is a weak inhibitor, in comparison with the 3 other RNR inhibitors tested, the authors further explain that this level of inhibition may be of benefit and should be considered a model when it comes to the treatment of genetic disorders that have coevolved with infection. More specifically, the limited potency of hydroxyurea as an antimalarial drug may minimize the development of hydroxyurea-resistant 3D7 parasite strains despite daily use to treat SCD. The authors also show evidence of overexpression of pfr2 and pfr4, 2 genes that encode for the β subunits that make up P falciparum RNR class I, in parasite clones with a shifted 50% effective concentration despite not being able to maintain stably hydroxyurea-resistant parasites.
The extraordinarily complex molecular interactions between the sickle β-globin mutation and malaria remain of great public health importance. For decades, there has been hesitation regarding the use of hydroxyurea for patients with SCD despite its reassuring safety profile. Although it seems unlikely that fetal hemoglobin induction, in the absence of hydroxyurea, or other drugs that inhibit polymerization, would have a similar effect, this study highlights, in part, a potential mechanism behind reduced malaria rates in patients with SCD treated with hydroxyurea and further substantiates the medical communities’ desire to make it widely available in malaria-endemic regions.
Conflict-of-interest disclosure: N.M.A. received clinical trial fees from Global Blood Therapeutics for a clinical trial outside the scope of this submitted work.
