Simultaneous adjunctive treatment of malaria and its co-evolved genetic disorder sickle cell anaemia

Abstract

Effective treatments for genetic disorders that co-evolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anemia (SCA) by reducing clinical complications, transfusions, and death. Despite concerns that HU-treatment for SCA would increase infection risk by the human malaria Plasmodium falciparum, (the genetic driver of the sickle mutation), HU instead reduced clinical malaria. We show that at physiologically relevant exposures, HU (and other ribonucleotide reductase inhibitors) have significant, intrinsic killing activity in vitro against blood stages of P. falciparum, with low risk of eliciting stably resistant parasites or compromising potency of current antimalarial drugs. Additive activity devoid of antagonism by HU was observed with a wide spectrum of commonly used antimalarial treatments. These data endorse broad, safe, long-term use of HU for SCA in malaria endemic countries and provide a novel biological model for simultaneous, adjunct therapy of a life-threatening infection and concomitant management of a co-evolved genetic disorder.

Clinical and laboratory characteristics of children with sickle cell disease on hydroxyurea treated with artemether-lumefantrine for acute uncomplicated malaria

“…The median (range) duration of HU treatment (for those on HU) was 28 (3-60) months and the median (range) HU dose was 25 (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) mg/kg/day.…”

“…HU reduces HbS concentration and increases HbF levels in red cells, and improvements in deformability and cellular hydration, leading to red cells less prone to premature haemolysis. Increased HbF may also be associated with restriction of parasite growth in vitro (27), and HU may act synergistically with antimalarials to prevent parasite growth (28). In vitro studies show that ribonucleotide reductase inhibitors interfere with malaria parasite development at the schizont stage through inhibition of DNA synthesis, while HU may increase expression of endothelial intracellular adhesion molecule 1, facilitating parasite adhesion to the endothelium (29).…”