Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil

Abstract

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 against Brazilian VL, which is caused by Leishmania infantum, a phase II, open-label, dose-escalation study of oral miltefosine was conducted in children (aged 2-12 years) and adolescent-adults (aged 13-60 years). Definitive cure was assessed at a 6-month followup visit. The cure rate was only 42% (6 of 14 patients) with a recommended treatment of 28 days and 68% (19 of 28 patients) with an extended treatment of 42 days. The in vitro miltefosine susceptibility profile of intracellular amastigote stages of the pretreatment isolates, from cured and relapsed patients, showed a positive correlation with the clinical outcome. The IC 50 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 IC 50 above 8.0 μM predicts failure 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.

Trans-Atlantic Spillover: Deconstructing the Ecological Adaptation of Leishmania infantum in the Americas

“…The locus was named 'miltefosine sensitivity locus' (MSL) based on the observation that the patients infected with deletion parasites had a 9.4-fold increased risk of treatment failure after miltefosine administration. This deletion further correlated with reduced parasite miltefosine susceptibility in vitro, suggesting natural resistance to this drug given that it had never been used in Brazil before this trial was carried out [62]. As a result of the identified correlations, the authors proposed this locus as a potential molecular marker to predict miltefosine treatment outcome in VL.…”

Trans-Atlantic Spill Over: Deconstructing the Ecological Adaptation of Leishmania Infantum in the Americas

“…The locus was named 'miltefosine sensitive locus' (MSL) based on the observation that the patients infected with deletion parasites had a 9,4-fold increased risk of treatment failure after miltefosine administration. This deletion further correlated with reduced parasite miltefosine susceptibility in vitro, suggesting natural resistance to this drug given that it had never been used in Brazil before this trial was carried out [61]. As a result of the identified correlations, the authors proposed this locus as a potential molecular marker to predict miltefosine treatment outcome in VL.…”

Treatment of canine visceral leishmaniasis with Milteforan™inducesLeishmania infantumresistance to miltefosine and amphotericin B

“…Over the course of the Milteforan™ therapy, the IC50 values of the isolates reached an average of 0.95 µM, approximately two times more resistant than the reference strain (considered sensitive) and much higher than the limit established for therapeutic success. This factor may further aggravate the limitations of Milteforan™-based monotherapy in dogs, which is already impaired in Brazil, among other factors, by the natural resistance of circulating parasites to this drug (41).…”