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

Trindade, J. B. C. et al. (2018) A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis. EBioMedicine, 36, pp. 83-91. (doi:10.1016/j.ebiom.2018.09.029) (PMID:30268832) (PMCID:PMC6197651)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Damasceno, Dr Jeziel and Mottram, Professor Jeremy and Crouch, Dr Kathryn
Authors: Trindade, J. B. C., Crouch, K., Forrester, S. J., Silva, V. C., Carvalho, S. F.G., Damasceno, J. D., Brown, E., Dickens, N. J., Costa, D. L., Costa, C. H.N., Dietze, R., Jeffares, D. C., and Mottram, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:EBioMedicine
Publisher:Elsevier
ISSN:2352-3964
ISSN (Online):2352-3964
Published Online:27 September 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in EBioMedicine 36: 83-91
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY