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.
