acquired resistance to new tb drugs: insights for ... · acquired resistance to new tb drugs:...
TRANSCRIPT
Acquired Resistance to New TB Drugs:
Insights for Diagnostics and
Treatment
Sébastien Gagneux, PhD
CPTR Workshop
Washington DC, 4th - 7th April 2016
Dept. of Medical Parasitology & Infection BiologyTuberculosis Research Unit
Case Study From Switzerland
• Tibetan refugee (HIV-neg., HBV-pos.)
• Primary resistance to:
1. isoniazid2. rifampicin (+ compensatory mutation in rpoC)3. pyrazinamid4. streptomycin5. ethionomide6. fluoroquinolones7. linezolid (!)
→ Primary preXDR-TB
“Clinical Cure” Relaps
Bloemberg et al. 2015 NEJM 373: 1986-8
Resistance
mutations
to 7 drugs
“Clinical Cure” Relaps
bedaquilineR
clofazimineR
Bloemberg et al. 2015 NEJM 373: 1986-8
“Clinical Cure” Relaps
capreomycinR
bedaquilineR
clofazimineR
Bloemberg et al. 2015 NEJM 373: 1986-8
“Clinical Cure” Relaps
capreomycinR
bedaquilineR
clofazimineR
Bloemberg et al. 2015 NEJM 373: 1986-8
“Clinical Cure” Relaps
delamanidR
capreomycinR
bedaquilineR
clofazimineR
Bloemberg et al. 2015 NEJM 373: 1986-8
“Clinical Cure” Relaps
bedaquilineR
clofazimineR
capreomycinR
delamanidR
Bloemberg et al. 2015 NEJM 373: 1986-8
Treatment History
Bloemberg et al. 2015 NEJM 373: 1986-8
We Need More Research On:
• Within-host dynamics
→ Acquisition of MDR-TB
→ Diagnostics / Treatment
• Between-host dynamics
→ Transmission of MDR-TB
→ Surveillance
A Web of Epistasis Mediates MDR in Mtb
Trauner et al. Drugs 2014 74: 1063-72
Positive Sign Epistasis in DoubleR
Borrell et al. Evolution Med Publ Health 2013 eot003: 65-74
rpoB / gyrA mutations
Mutational Pathway in M. tuberculosis
MDR
(rpoB)
XDR
(gyrA)
G88CG88C
wtwt
H526RH526R
D94GD94G
D94ND94NG88CG88C
H526PH526P
D94GD94G
D94ND94N D94YD94Y
H526YH526Y
D94ND94N
D94GD94G
D94YD94Y
G88CG88C
S531LS531L
D94GD94G
D94ND94N
D94YD94Y
S531WS531W
D94GD94G
D94YD94Y
G88CG88CG88CG88C
wtwt
H526RH526R
D94GD94G
D94ND94NG88CG88C
H526PH526P
D94GD94G
D94ND94N D94YD94Y
H526YH526Y
D94ND94N
D94GD94G
D94YD94Y
G88CG88C
S531LS531L
D94GD94G
D94ND94N
D94YD94Y
S531WS531W
D94GD94G
D94YD94Y
G88CG88C
0.80-0.98
< 0.80
> 0.99
Re
lati
ve
Fit
ne
ss
Borrell et al. Evolution Med Publ Health 2013 eot003: 65-74
0
10
20
30
40
50
60
70
80
D94G D94N D94Y G88C
gyrA mutations
Fre
qu
en
cy
D516V D516S S531L L533P
GyrA Mutations in Clinical XDR-TB (N=89)
Borrell et al. Evolution Med Publ Health 2013 eot003: 65-74
rpoB mutation:
A case for
Personalized
Medicine (?)
Muller et al. 2013 Trends Genet 29: 160-9
Conclusions
• New TB drugs can be “lost” quickly
• Intra- and inter-host bacterial dynamics ???
• Role of epistasis ???
• Host factors need to be considered
→ Need Research in Biology and Epidemiology !!!
Thanks to…
Collaborators:
• Douglas Young - NMIR• Iñaki Comas - UV• Joel Ernst – NYU• Rob Wilkinson – UCT• Rob Warren - SU• Matthias Egger –UBE• Erik Böttger - UZH• Midori Kato-Maeda - UCSF• Simon Harris - WTSI• Moses Joloba – MU• Dorothy Yeboah-Manu - NMIMR
• Bouke de Jong – ITM• Ruedi Aebersold – ETHZ• Uwe Sauer – ETHZ• Tanja Stadler – ETHZ• Jörg Stelling – ETHZ• Christian Beisel - ETHZ• Qian Gao – FU• Stefan Niemann - RCB• Johannes Krause – UT• Abraham Aseffa - AHRI
Thanks to…
• Sonia Borrell• Lukas Fenner• Mireia Coscolla• Daniela Brites• Andrej Trauner• Levan Jugheli• Julia Feldmann• Miriam Reinhard• Sebastian Gygli• Liliana Ruthaiwa• Rhastin Castro• Francis Mhimbira• Chloe Loiseau