Randomised trial of chloroquine/sulphadoxine-pyrimethamine in Gambian children with malaria:: Impact against multidrug-resistant P-falciparum

Objectives: In the Gambia, the combination of chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) has replaced CQ monotherapy for treatment of malaria caused by Plasmodium falciparum. We measured the efficacy of the combination CQ/SP, and the prevalence of parasites carrying alleles associated with resistance to CQ or SP. Design: We conducted a single-blind, randomised, controlled trial to compare the efficacy of CQ/SP to that of SP or CQ alone. Setting: The study took place in the town of Farafenni and surrounding villages in the Gambia. Participants: Participants were children aged 12 mo to 10 y presenting as outpatients with uncomplicated P. falciparum malaria. Interventions: 500 children were randomised to receive CQ, SP, or CQ/SP as supervised treatment and actively followed over 28 d. Outcome Measures: Primary outcome was parasitaemia at any time during follow-up. Secondary outcomes were PCR-confirmed recrudescent infections among treatment failures, and clinical failure requiring rescue medication by day 28. Pretreatment parasite isolates from 161 patients were tested for the presence of resistance-associated genetic markers. Results: The prevalence of parasitological failure by day 28 for the CQ group was 60.3%, compared to 17.6% for SP ( odds ratio [ OR], 0.106; 95% confidence interval [CI], 0.057 - 0.194; p < 0.001) and 13.9% for CQ/SP ( OR versus CQ, 0.140; 95% CI, 0.078 - 0.250; p < 0.001). There was no difference between the SP and CQ/SP groups ( OR, 1.324; 95% CI, 0.705 - 2.50). The projected prevalence of PCR-corrected treatment failure was 30.2, 6.06, and 3.94% in the CQ, SP, and CQ/ SP groups, respectively. The pfdhfr-triple mutant and pfdhps-437G mutation were common, with prevalences of 67.4 and 51.2%, respectively. Pretreatment carriage of pfdhps-437G and of multidrug-resistant parasite genotypes was associated with treatment failure in the SP group, but not in the CQ or CQ/ SP groups. Conclusions: The combination of CQ/ SP was an efficacious treatment for uncomplicated malaria in Gambian children in this study, but the frequent occurrence of multidrug-resistant parasites suggests that this observed efficacy is not sustainable.