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

Abstract

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.

Figure 1. CONSORT Flowchart

A total of 1,366 children was screened, and 500 were randomised. Children randomised to receive SP on Thursday or Friday (N = 79), were scheduled for standard follow-up and thus fulfilled the criteria for efficacy evaluation. Follow-up data are shown for these 79, but not for the other SP-treated children. Shaded boxes represent gametocyte screening days [18].

Figure 2. Point Prevalence of Plasmodium falciparum Asexual Parasitaemia 3, 7, 14, and 28 Days after Treatment of Children with CQ, SP, or CQ/SP

Error bars represent the upper 95% confidence limit of the proportion. Denominators for these data are (for CQ, SP, and CQ/SP groups, respectively): day 3, 111, 160, 168; day 7, 107, 52, 152; day 14, 98, 134, 143; and day 28, 94, 124, 130.

Figure 3. Prevalence of Resistance-Associated Loci among 90 Pretreatment Parasite Isolates

Genotypes at seven loci in four P. falciparum genes were determined, as was the prevalence of the pfdhfr triple-mutant IRN, and of the putative multidrug-resistant genotype TYRG.