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<p>Abstract</p> <p>Background</p> <p>A study carried out in 2003–2005 in Southern Benin showed a day-28 sulphadoxine-pyrimethamine (SP) monotherapy failure rate greater than 40%, while for SP combined with artesunate (SP-AS) the failure rate was 5.3%. Such a large difference could be explained by the relatively short 28-day follow-up period, with a substantial number of recurrent infections possibly occurring after day 28. This paper reports the treatment outcome observed in the same study cohort beyond the initial 28-day follow-up.</p> <p>Methods</p> <p>After the 28-day follow-up, children treated with either chloroquine alone (CQ), SP or SP-AS, were visited at home twice a week until day 90 after treatment. A blood sample was collected if the child had fever (axillary temperature ≥37.5°C). Total clinical failure for each treatment group was estimated by combining all the early treatment failures and late clinical failures that occurred over the whole follow-up period, i.e. from day 0 up to day 90. Pre-treatment randomly selected blood samples were genotyped for the <it>dhfr </it>gene (59) and the <it>dhps </it>gene (437 and 540) point mutations related to SP resistance.</p> <p>Results</p> <p>The PCR-corrected clinical failure at day 90 was significantly lower in the SP-AS group (SP-AS: 2.7%, SP alone: 38.2%; CQ: 41.1%) (Log-Rank p < 0,001). The most prevalent haplotype was <it>dhfr </it>Arg-59 with the <it>dhps </it>Gly-437 mutant and the <it>dhps </it>540 wild type (85.5%). The <it>dhps </it>540 mutation could be found in only three (8.3%) samples.</p> <p>Conclusion</p> <p>Combining artesunate to SP dramatically increased the treatment efficacy, even when extending the follow-up to day 90 post-treatment, and despite the high percentage of failures following treatment with SP alone. Such a good performance may be explained by the low prevalence of the <it>dhps </it>540 mutation, by the rapid parasite clearance with artesunate and by the level of acquired immunity.</p>