In India visceral leishmaniasis (VL) caused by Leishmania donovani has been successfully treated with miltefosine with a cure rate of > 90%. To assess the efficacy and safety of oral miltefosine in L. infantum-causing Brazilian VL patients, a phase II, open-label, dose-escalation study of oral miltefosine was conducted in children (ages 2-12) and adolescent-adults (ages 13-60). Definitive cure was assessed at a 6 month follow-up visit. The cure rate was only 42% (6 out of 14 patients) with the recommended 28 days of therapy and 68% (19 out of 28 patients) with an extended treatment of 42 days. The in vitro miltefosine susceptibility profile of intracellular amastigote stages of the pre-treatment isolates, from cured and relapsed patients, showed a positive correlation with clinical outcome. The IC50 mean (SEM) of eventual cures was 5.1 (0.4) µM whereas that of eventual failures was 12.8 (1.9) µM (P = 0.0002). An IC50 below or above 8.0 µM predicts cure or failure, respectively with 82% sensitivity and 100% specificity. The finding of L. infantum amastigotes resistant to miltefosine in isolates from patients who eventually failed treatment, strongly suggests natural resistance to this drug, as miltefosine had never been used in Brazil before this trial was carried out.
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