Emergence of Mutations Associated with Resistance to Sulfadoxine-Pyrimethamine (SP) After Single Therapeutic Dose: Implications on the Useful Therapeutic Life of SP in Malaria Holoendemic Areas

Background: Drugs with long elimination half-lives such as Sulfadoxine -Pyrimethamine (SP) maintain sub-curative levels in blood for a long time such that in high malaria transmission areas, re-infecting parasites are continuously under selection pressure for resistant genotypes. Objective: To assess SP efficacy and post therapeutic in-vivo selection for Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) mutations associated with SP resistance. Design: SP efficacy trial with prospective follow up for selection of parasites with DHFR and DHPS mutations at re-infection in the resistance selection period (RSP). Subjects: Children aged < 5 years attending the outpatient reproductive and child health clinic of Kibaha district hospital with uncomplicated malaria fulfilling the inclusion criteria for efficacy trials in holoendemic settings. Main outcome measures: Clinical & parasitological efficacy, pre-treatment and post-treatment prevalence of P. falciparum DHFR & DHPS mutations. Results: Very high (98.2%) clinical & parasitological cure rates. DHFR single, double or triple mutations occurred in 46.7% of pre-treatment infections; triple c108/51/59 & double c108/51 mutations being commonest. Few (15.9%) DHPS mutations occurred in pre-treatment infections at c436 and c437. DHFR & DHPS mutations were significantly higher in post- than pre- SP treatment parasites. In a Poisson regression analysis, DHFR mutations at c108, c51 & c59 and the exclusive c108/51/59 triple mutations were strongly associated with exposure to SP at re-infection. Conclusion: DHFR & DHPS mutations associated with SP resistance exist in P. falciparum infections in a background of high SP efficacy. Despite optimal dosage, in holoendemic areas, these mutations will be selected by SP at re-infection; cumulatively shortening the useful therapeutic life of SP due to resistance.