TY - JOUR
T1 - A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis
AU - Carnielli, Juliana B.T.
AU - Crouch, Kathryn
AU - Forrester, Sarah
AU - Silva, Vladimir Costa
AU - Carvalho, Sílvio F.G.
AU - Damasceno, Jeziel D.
AU - Brown, Elaine
AU - Dickens, Nicholas J.
AU - Costa, Dorcas L.
AU - Costa, Carlos H.N.
AU - Dietze, Reynaldo
AU - Jeffares, Daniel C.
AU - Mottram, Jeremy C.
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - Miltefosine Susceptibility Locus
KW - Miltefosine treatment failure
KW - Prognostic marker
KW - Visceral leishmaniasis
KW - Whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85053860444&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2018.09.029
DO - 10.1016/j.ebiom.2018.09.029
M3 - Article
C2 - 30268832
AN - SCOPUS:85053860444
SN - 2352-3964
VL - 36
SP - 83
EP - 91
JO - EBioMedicine
JF - EBioMedicine
ER -
