Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia.

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 anaemia (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 utilized physiologically relevant drug exposures that mimic in vivo pharmacokinetics in humans. Under these conditions, we showed that HU and other ribonucleotide reductase (rnr) inhibitors, have significant, intrinsic killing activity in vitro against schizont stages of P. falciparum in both normal and sickle red blood cells. Long-term in vitro selection with HU increased expression of Pfrnr genes but showed 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 treatment of a genetic disorder with simultaneous, adjunct therapy of a life-threatening infection needed in a global health setting.