genesis of drug resistance in tuberculosis in south...
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Genesis of drug resistance in Tuberculosis in South Africa
Rob Warren
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vv
GCCGACTGTTGGCGCTGG CGGCTGACAACCGCGACC
rpoB gene
109 bacteria
Rifampicin Rifampicin
Spontaneous evolution of drug resistance
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Number of MDR-TB cases in 2013
WHO Global Tuberculosis Report 2014
MDR-TB = resistance to isoniazid and rifampicin
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Number of Patients with confirmed XDR-TB 2013
WHO Global Tuberculosis Report 2014
XDR-TB = MDR-TB plus resistance aminoglycoside and fluoroquinolone
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MDR-TB Treatment outcome in Africa
40%
WHO Global Tuberculosis Report 2014
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Treatment guidelines 2002
Ofloxacin Kanamycin Ethambutol
Pyrazinamide Ethionamide
New Case
Retreatment Case
Isoniazid Rifampicin
Ethambutol Pyrazinamide
Treatment failure
DST
DST
Standardized MDR-TB treatment
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Amplification of Resistance in MDR-TB
Mphahlele et al Unpublished data
48 MDR-TB cases enrolled
Standardized MDR-TB treatment
Different strain during treatment
n=12 (25%)
Same strain during treatment
n=36 (75%)
9 (75%) gained additional resistance
13 (36%) gained additional resistance
46%
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Louw,G.E., Warren,R.M., Donald,P.R., Murray,M.B., Bosman,M., van Helden,P.D., Young,D.B., and Victor,T.C. 2006. Frequency and implications of pyrazinamide resistance in managing previously treated tuberculosis patients. Int.J.Tuberc.Lung Dis. 10:802-807.
Mphahlele M, Syre H, Valvatne H, Stavrum R, Mannsåker T, Muthivhi T, Weyer K, Fourie PB, Grewal HM. Pyrazinamide resistance among South African multi-drug resistant Mycobacterium tuberculosis isolates. J Clin Microbiol. 2008 Aug 27.
52% of MDR-TB isolates showed resistance to PZA
Weakened standardized MDR-TB treatment
Johnson,R., Jordaan,A.M., Pretorius,L., Engelke,E., van der,S.G., Kewley,C., Bosman,M., van Helden,P.D., Warren,R., and Victor,T.C. 2006. Ethambutol resistance testing by mutation detection. Int.J.Tuberc.Lung Dis. 10:68-73.
Pyrazinamide Ethambutol
Hoek KG, Schaaf HS, Gey van Pittius NC, van Helden PD, Warren RM. Resistance to pyrazinamide and ethambutol compromises MDR/XDR-TB treatment. S Afr Med J. 2009 Nov;99(11):785-7.
>50% of MDR-TB isolates showed mutations conferring EMB resistance
Standardized MDR-TB
Treatment
Ofloxacin Kanamycin Ethambutol
Pyrazinamide Ethionamide
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Muller, B., E. M. Streicher, K. G. Hoek, M. Tait, A. Trollip, M. E. Bosman, G. J. Coetzee, E. M. Chabula-Nxiweni, E. Hoosain, N. C. Gey van Pittius, T. C. Victor, P. D. van Helden, and R. M. Warren. 2011. inhA promoter mutations: a gateway to extensively drug-resistant tuberculosis in South Africa? Int.J.Tuberc.Lung Dis. 15:344-351.
Cross-resistance between isoniazid and ethionamide via inhA mutations
48%
Standardized MDR-TB
Treatment
Ofloxacin Kanamycin Ethambutol
Pyrazinamide Ethionamide
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0%
20%
40%
60%
80%
100%
DS DR
MDR s.s.
pre-XDRXDR
0%
20%
40%
60%
80%
100%
DS DR
MDR s.s.
pre-XDRXDR
0%
20%
40%
60%
80%
100%
DS DR
MDR s.s.
pre-XDRXDR
Western Cape
KwaZulu- Natal
Eastern Cape
Programmatic Selection
Muller, B., V. N. Chihota, M. Pillay, M. Klopper, E. M. Streicher, G. Coetzee, A. Trollip, C. Hayes, M. E. Bosman, N. C. Gey van Pittius, T. C. Victor, S. Gagneux, P. D. van Helden, and R. M. Warren. 2013. Programmatically selected multidrug-resistant strains drive the emergence of extensively drug-resistant tuberculosis in South Africa. PLoS.ONE. 8:e70919.
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Immigration
Type 1: katG315 ACC, rrs513 CAC, inhA 17, embB306 ATA, pncA ins172G, rpoB 516GTC, rrs1401G Type 2: katG315 ACC, rrs513 CAC, inhA 15, embB306 ATC, pncA14 GCG, rpoB 531 TTG, rrs1401G
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XDR-TB Treatment outcomes
Pietersen, E., E. Ignatius, E. M. Streicher, B. Mastrapa, X. Padanilam, A. Pooran, M. Badri, M. Lesosky, H. P. van, F. A. Sirgel, R. Warren, and K. Dheda. 2014. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet .
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Discharge into the Community
Pietersen, E., E. Ignatius, E. M. Streicher, B. Mastrapa, X. Padanilam, A. Pooran, M. Badri, M. Lesosky, H. P. van, F. A. Sirgel, R. Warren, and K. Dheda. 2014. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet .
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RR-TB patients must be started on treatment within 5 days
MDR-TB regimen for 18 – 24 months
On confirmation of MDR-TB the laboratory should conduct second-line DST routinely.
New TB diagnosis algorithm
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Impact of New TB diagnosis algorithm
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Time to second-line resistance test result
54 days (IQ range 27-259)
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Drug resistant Patients with second-line results (%), N=451
Kanamycina only 3 (0.7) Ethionamide only 206 (45.7) Fluoroquinoloneb only 13 (2.9) Kanamycin + Ethionamide 25 (5.5) Kanamycin + Fluoroquinolone
4 (0.9)
Ethionamide + Fluoroquinolone
14 (3.1)
Kanamycin + Ethionamide + FQ
28 (6.2)
Any additional resistance 293 (65.0) Pre-XDR 55 (12.2) XDR 32 (7.1)
Second-line resistance profiles associated with rifampicin resistance
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Proportion of patients with resistance to greater than 2 second-line drugs
47%
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TAKE HOME MESSAGE
• Treating blindly leads to amplification of resistance • Surveillance is essential to guide policy • Treatment outcomes for M(X)DR-TB are poor • Nearly half of patients diagnosed with RIF resistant
MTB by Xpert also have resistance to at least two additional MDRTB drugs
• Culture based diagnostic delay treatment decisions by up to 8 weeks possible promoting amplification of resistance
• Rapid molecular based diagnostic methods are desperately needed
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Thank You Karen Jacobson
Borna Muller
Gail Louw
Kim Hoek
Violet Chihota
Matsie Mphahlele
Marinus Barnard
Elize Pietersen
The “Mycobactomics” Group