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)
|
Text
170014.pdf - Published Version Available under License Creative Commons Attribution. 1MB |
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 > School of Infection & Immunity |
| 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 |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information