A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasisResearch in context

Abstract

Background: Miltefosine has been used successfully to treat visceral leishmaniasis (VL) in India, but it was unsuccessful for VL in a clinical trial in Brazil. Methods: To identify molecular markers that predict VL treatment failure whole genome sequencing of 26 L. infantum isolates, from cured and relapsed patients allowed a GWAS analysis of SNPs, gene and chromosome copy number variations. Findings: A strong association was identified (p = 0·0005) between the presence of a genetically stable L. infantum Miltefosine Sensitivity Locus (MSL), and a positive response to miltefosine treatment. The risk of treatment failure increased 9·4-fold (95% CI 2·11–53·54) when an isolate did not have the MSL. The complete absence of the MSL predicted miltefosine failure with 0·92 (95% CI 0·65–0·996) sensitivity and 0·78 (95% CI 0·52–0·92) specificity. A genotyping survey of L. infantum (n = 157) showed that the frequency of MSL varies in a cline from 95% in North East Brazil to <5% in the South East. The MSL was found in the genomes of all L. infantum and L. donovani sequenced isolates from the Old World (n = 671), where miltefosine can have a cure rate higher than 93%. Interpretation: Knowledge on the presence or absence of the MSL in L. infantum will allow stratification of patients prior to treatment, helping to establish better therapeutic strategies for VL treatment. Fund: CNPq, FAPES, GCRF MRC and Wellcome Trust. Keywords: Visceral leishmaniasis, Miltefosine treatment failure, Whole-genome sequencing, Miltefosine Susceptibility Locus, Prognostic marker