xdr-tb and management options ninth technical advisory group and national tb programme managers...
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XDR-TB and management options
Ninth Technical Advisory Group and National TB Programme Managers Meeting TB Control in the Western
Pacific Region,Manila, Philippines, 9-12 December 2014
CHIANG Chen-Yuan MD, MPH, DrPhilos
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Global estimates of MDR-TB
• 3.5% (95% CI: 2.2–4.7%) among new cases • 20.5% (95%CI: 13.6–27.5%)of previously treated cases• 480 000 (range: 350 000‒610 000) new MDR-TB cases
worldwide• 300 000 (range: 230 000–380 000) MDR-TB cases
among patients with pulmonary TB notified in 2013.• 9.0% (95% CI: 6.5–11.5%) of MDR-TB cases
have XDR-TB
Global Tuberculosis Report 2014
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Fluoroquinolone-resistant MDR-TB
• Without previous treatment of MDR-TB– use of fluoroquinolone in the treatment of lower
respiratory tract infection– use of fluoroquinolone in the treatment of non-
MDR tuberculosis, such as HREZ + fluoroqunolone (+ injectable) for retreatment TB cases
• With previous treatment of MDR-TB
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Transition from drug-resistant TB to XDR-TB
INH-resistant TB
INH- and Quinolone-resistant TB
XDR-TB
Use of quinolone in the treatment of community acquired pneumonia
Failure to successfully treat MDR-TB using second line drugs
MDR-TB
MDR-TB plus Quinolone resistance
Failure to successfully treat TB using first line drugs
Chiang C-Y, et al. Expert Rev Resp Med 2008;2:47-54
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Resistance to anti-tuberculosis drugs by multidrug-resistant tuberculosis (MDR-TB)
patient group
5
Falzon D, et al Eur Respir J 2013; 42: 156–168
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Treatment outcomes for patients diagnosed with MDR-TB by WHO region, 2007–2011 cohorts
6WHO. Global Tuberculosis Report 2014
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Short Standardized Treatment of Multidrug-resistant Tuberculosis
Intensive phase: GEZC KHP 4 months, extended till sputum conversion
Continuation phase: GEZC5 months
Kanamycin (K)
Prothionamide (P)
Isoniazid (H)*
Gatifloxacin (G)* Gatifloxacin (G)*
Clofazimine, C Clofazimine, C
Ethambutol, E Ethambutol, E
Pyrazinamide, P Pyrazinamide, P
7
*high dose
Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684–692
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GenoType® MTBDRplus test procedure
1) DNAExtractionFrom NALC/NaOHProcessed sputum
2) Amplification by PCR
3) HybridizationReverse hybridization of amplified nucleic acids to specific DNA probes bound on strips
4) Evaluation
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Genetic Mutations Associated with M. tuberculosis Resistance to Amikacin, Kanamycin and Capreomycin: A
Systematic Review
• gene mutations believed to confer resistance to the injectable drugs: the rrs and tlyA genes, and the eis promoter.
Georghiou SB, et al. PLoS ONE 7(3): e33275. doi:10.1371/journal.pone.0033275
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Performance Assessment of the GenoType MTBDRsl Test for Detection of Second-Line and Ethambutol Drug Resistance
among MDR-TB Patients• high levels of specificity: 95.8 to 100%.• the sensitivities of resistance detection using the GenoType
MTBDRsl test were – Fluoroquinolone 85.1%– kanamycin 43.2%, – amikacin 84.2%, – capreomycin 71.4%– Ethambutol 56.2%
• with the inclusion of an extra gene, eis, in sequencing, the sensitivity reached 70.3% for detection of KM resistance.
Huang W-L. et al. 2011
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Forest plots of MTBDRsl sensitivity and specificity when performed indirectly or directly for fluoroquinolone resistance detection and
using phenotypic culture-based DST as a reference standard
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The diagnostic accuracy of the GenoType® MTBDRsl assay
As a test for fluoroquinolone resistance measured against culture-based DST
Pooled sensitivity(95% CI )
Pooled specificity(95% CI )
Direct test 85.1% (71.9% to 92.7%)
98.2% (96.8% to 99.0%)
Indirect test 83.1% (78.7% to 86.7%)
97.7% (94.3% to 99.1%)
Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD010705. DOI: 10.1002/14651858.CD010705.pub2.
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Forest plots of MTBDRsl sensitivity and specificity when performed indirectly for the detection of resistance to amikacin (Ak), kanamycin (Kn) and capreomycin (Cm)
using culture as a reference standard.
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The diagnostic accuracy of the GenoType® MTBDRsl assayAs a test for second-line injectable drugs (amikacin,kanamycin and capreomycin) resistance measured against culture-based DST when performed indirectly
Pooled sensitivity(95% CI )
Pooled specificity(95% CI )
SLIDs 76.9% (61.1% to 87.6%) 99.5% (97.1% to 99.9%)
amikacin 87.9% (82.1% to 92.0%) 99.5% (97.5% to 99.9%)
kanamycin 66.9% (44.1% to 83.8%) 98.6% (96.1% to 99.5%)
capreomycin 79.5% (58.3% to 91.4%) 95.8% (93.4% to 97.3%)
Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD010705. DOI: 10.1002/14651858.CD010705.pub2.
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Clofazimine
18
Study designed and supervised by: Jacques Grosset, MD And conducted by: Sandeep Tyagi, BS, Si-yang Li, BS, Deepak Almeida, PhD, Paul Converse, PhD
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Long-term outcomes of patients with extensivelydrug-resistant tuberculosis in South Africa: a cohort study
• predictors of net culture conversion – no history of multidrug-resistant tuberculosis (p=0·0007) – use of clofazimine (p=0·0069).
• predictors of survival – net culture conversion (p<0·0001) – treatment with clofazimine (p=0·021). – Antiretroviral therapy in patients with HIV (p=0·003).
Pietersen E, et al. Lancet 2014; 383: 1230–39
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Linezolid for Treatment of Chronic XDR-TB
21N Engl J Med 2012;367:1508-18
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Clinical use of the meropenem-clavulanate
combination for XDR-TB
23Int J Tuberc Lung Dis 2012;16:558–560
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Mechanisms of action of new compounds in clinical development for tuberculosis
Ma Z, et al. Lancet 2010; 375: 2100–09
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Diacon AH, et al. N Engl J Med 2014;371:723-32
phase 2b trial, Bedaquiline
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Multidrug-Resistant Tuberculosisand Culture Conversion with Bedaquiline
• In this phase 2b trial, Bedaquiline – reduced the median time to culture conversion from 125
days to 83 days (hazard ratio 2.44 (95% CI 1.57-3.80)– Increased the rate of culture conversion at 24 weeks (79%
vs. 58%, P = 0.008) and at 120 weeks (62% vs. 44%, P = 0.04).
• The overall incidence of adverse events was similar in the two groups.
• There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident.
Diacon AH, et al. N Engl J Med 2014;371:723-32
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Diacon AH, et al. N Engl J Med 2014;371:723-32
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Mean changes from baseline in QTcF* over time among patients treated with bedaquiline plus background regimen† (BR) versus placebo plus BR,
Study C208 (Stage 2)
MMWR / October 25, 2013 / Vol. 62 / No. 9
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WHO Companion Handbook 2014
1. the QT interval needs to be adjusted (corrected) for the heart rate2. the Fredericia method (QTcF): dividing the QT interval by the cubed root of
the interval in seconds between the peak of two successive R waves (RR)
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Flowchart of intent-to-treat patients in delamanid (DLM) Trial 204, Trial 208 and Study 116
Eur Respir J 2013; 41: 1393–1400
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Long-term (24 month) treatment outcomes after treatment with delamanid in combination with an
optimised background treatment regimen: MDR- and XDR-TB patients
Eur Respir J 2013; 41: 1393–1400
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Cascade of regimensRifampicin Quinolone Treatment approach
Susceptible First line anti-TB treatment
Resistant Susceptible Second line anti-TB treatment
(9-month regimen)
Resistant Resistant New drugs and potential group 5 drugs
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In Summary• Globally, 9.0% (95% CI: 6.5–11.5%) of MDR-TB cases have
XDR-TB.• Rapid diagnosis of resistance to rifampicin, fluoroquinolone and
second line injectables will be helpful in the choice of regimens.• Do not add a new drug to a failing MDR-TB regimen.• Evidence is emerging that proper use of clofazimine, linezolid,
meropenem, and new drugs improves the outcome of XDR-TB. However, experience is insufficient in terms of the type of drugs, the number of drugs and the duration required for the treatment of XDR-TB.
• Would countries be interested in using a standardized protocol for the treatment of quinolone-resistant TB and XDR-TB?