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

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.

• Authors: Juliana B T Carnielli, Kathryn Crouch, Sarah Forrester, Vladimir Costa Silva, Sílvio F G Carvalho, Jeziel D Damasceno, Elaine Brown, Nicholas J Dickens, Dorcas L Costa, Carlos H N Costa, Reynaldo Dietze, Daniel C Jeffares, Jeremy C Mottram
• Journal: EBioMedicine (EBioMedicine) Vol. 36 Pg. 83-91 (Oct 2018) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30268832 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antiprotozoal Agents
• Genetic Markers
• Phosphorylcholine
• miltefosine

Topics

• Antiprotozoal Agents (pharmacology, therapeutic use)
• Brazil
• Computational Biology (methods)
• DNA Copy Number Variations
• Genetic Markers
• Genome, Protozoan
• Genomics (methods)
• Geography
• Humans
• Leishmania infantum (drug effects, genetics)
• Leishmaniasis, Visceral (drug therapy, parasitology)
• Phosphorylcholine (analogs & derivatives, pharmacology, therapeutic use)
• Quantitative Trait Loci
• Treatment Failure
• Treatment Outcome