High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children.

BACKGROUND: Drug resistance contributes to the global malaria burden. Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP). METHODS: The study assessed the frequency of SP resistance-conferring polymorphisms in Plasmodium falciparum-positive samples from two clinical studies in Lambaréné. Their role on treatment responses and transmission potential was studied in an efficacy open-label clinical trial with a 28-day follow-up in 29 children under five with uncomplicated malaria. RESULTS: SP was well tolerated by all subjects in vivo. Three subjects were excluded from per-protocol analysis. PCR-corrected, 12/26 (46%) achieved an adequate clinical and parasitological response, 13/26 (50%) were late parasitological failures, while 1/26 (4%) had an early treatment failure, resulting in early trial discontinuation. Of 106 isolates, 98 (92%) carried the triple mutant dhfr haplotype. Three point mutations were found in dhps in a variety of haplotypic configurations. The 437G + 540E double mutant allele was found for the first time in Gabon. CONCLUSIONS: There is a high prevalence of dhfr triple mutant with some dhps point mutations in Gabon, in line with treatment failures observed, and molecular markers of SP resistance should be closely monitored.

No rebound of morbidity following intermittent preventive sulfadoxine-pyrimethamine treatment of malaria in infants in Gabon.

In the context of a trial studying intermittent preventive sulfadoxine-pyrimethamine treatment of malaria in infants in Lambaréné, Gabon, children aged 18-30 months were followed up after having received their last dose at an age of 15 months. In the intention-to-treat population, the protective efficacy against all malaria episodes was -18.0 (95% confidence interval, -97.4 to 29.5; P = .529). The protective efficacy against first or only anemia episode was -45.3 (95% confidence interval, -234.5 to 36.3; P=.375). The protective efficacies were negative and were not statistically significant. These results do not appear to support the concept of a rebound effect after intermittent preventive sulfadoxine-pyrimethamine treatment of malaria in infants. Clinical trials registration. NCT00167843.

Assessment of fever in African children: implication for malaria trials.

We evaluated methods for assessing body temperature by comparing subjective assessment of fever by parents and doctors with objective axillary, tympanic, and rectal measurements of body temperature in 1000 children < or = 10-years-old who presented at outpatient clinics with recent history of fever. Sensitivity of subjective assessment of fever were higher at thresholds of > or = 38.3 degrees C with specificity as low as 60%. Axillary methods showed better specificity at fever thresholds of > 38.0 degrees C with maximum sensitivity of 63% at thresholds of > or = 37.5 degrees C. Bland-Altman analysis showed wide limits of agreement between objective methods of measurements: -1 degrees C to 3 degrees C for comparison of rectal and axillary, -1 degrees C to 2 degrees C for rectal and tympanic, and -1 degrees C to 2 degrees C for tympanic and axillary measurements. A choice of method to measure body temperature for diagnosis of fever in African children should be informed by a trade-off between its specificity and sensitivity that considers thresholds > 38.0 degrees C.