A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis

Carnielli, Juliana B.T., Crouch, Kathryn, Forrester, Sarah, Silva, Vladimir Costa, Carvalho, Sílvio F.G., Damasceno, Jeziel D., Brown, Elaine H., Dickens, Nicholas J., Dorcas L. Costa, Carlos Henrique Nery Costa, R Dietze, Jeffares, Daniel C., Mottram, Jeremy C.

Research output: Contribution to journalArticle

16 Citations (Scopus)

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. infantumMiltefosine 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.
Original languageEnglish
Pages (from-to)83-91
Number of pages8
JournalEBioMedicine
VolumeVol. 36
DOIs
Publication statusPublished - Oct 2018

Keywords

  • Miltefosine Susceptibility Locus
  • Miltefosine treatment failure
  • Prognostic marker
  • Visceral leishmaniasis
  • Whole-genome sequencing

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