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

2018-10Artigo científico Acesso aberto
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dc.contributor.authorCarnielli, Juliana B.T.
dc.contributor.authorCrouch, Kathryn
dc.contributor.authorForrester, Sarah
dc.contributor.authorSilva, Vladimir Costa
dc.contributor.authorCarvalho, Sílvio F.G.
dc.contributor.authorDamasceno, Jeziel D.
dc.contributor.authorBrown, Elaine
dc.contributor.authorDickens, Nicholas J.
dc.contributor.authorCosta, Dorcas L.
dc.contributor.authorCosta, Carlos H.N.
dc.contributor.authorDietze, Reynaldo
dc.contributor.authorJeffares, Daniel C.
dc.contributor.authorMottram, Jeremy C.
dc.contributor.institutionInstituto de Higiene e Medicina Tropical (IHMT)
dc.contributor.institutionIndividual Health Care (IHC)
dc.contributor.institutionGlobal Health and Tropical Medicine (GHTM)
dc.contributor.pblElsevier
dc.date.accessioned2021-05-02T22:52:02Z
dc.date.available2021-05-02T22:52:02Z
dc.date.issued2018-10
dc.description.abstractBackground: 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent9
dc.format.extent1606809
dc.identifier.doi10.1016/j.ebiom.2018.09.029
dc.identifier.issn2352-3964
dc.identifier.otherPURE: 27541899
dc.identifier.otherPURE UUID: 7fea35c6-a314-45de-bfb5-0f64ec1cead3
dc.identifier.otherScopus: 85053860444
dc.identifier.otherPubMed: 30268832
dc.identifier.otherORCID: /0000-0002-6995-8001/work/86963712
dc.identifier.urihttp://hdl.handle.net/10362/116760
dc.identifier.urlhttps://www.scopus.com/pages/publications/85053860444
dc.language.isoeng
dc.peerreviewedyes
dc.subjectMiltefosine Susceptibility Locus
dc.subjectMiltefosine treatment failure
dc.subjectPrognostic marker
dc.subjectVisceral leishmaniasis
dc.subjectWhole-genome sequencing
dc.subjectInfectious Diseases
dc.subjectGenetics
dc.subjectParasitology
dc.subjectSDG 3 - Good Health and Well-being
dc.titleA Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasisen
dc.typejournal article
degois.publication.firstPage83
degois.publication.lastPage91
degois.publication.titleEBioMedicine
degois.publication.volume36
dspace.entity.typePublication
rcaap.rightsopenAccess

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