Transcript Slide 1

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
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
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 nonMDR tuberculosis, such as HREZ + fluoroqunolone
(+ injectable) for retreatment TB cases
• With previous treatment of MDR-TB
Transition from drug-resistant TB to
XDR-TB
INH-resistant TB
MDR-TB
Use of quinolone in the treatment of
community acquired pneumonia
MDR-TB plus
Quinolone resistance
INH- and
Quinolone-resistant TB
Failure to successfully treat TB using first line drugs
Failure to successfully treat
MDR-TB using second line drugs
XDR-TB
Chiang C-Y, et al. Expert Rev Resp Med 2008;2:47-54
Resistance to anti-tuberculosis drugs by
multidrug-resistant tuberculosis (MDR-TB)
patient group
Falzon D, et al Eur Respir J 2013; 42: 156–168
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Treatment outcomes for patients diagnosed with MDRTB by WHO region, 2007–2011 cohorts
WHO. Global Tuberculosis Report 2014
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Short Standardized Treatment of Multidrugresistant Tuberculosis
Intensive phase: GEZC KHP
Continuation phase: GEZC
4 months, extended till sputum 5 months
conversion
Kanamycin (K)
Prothionamide (P)
Isoniazid (H)*
Gatifloxacin (G)*
Gatifloxacin (G)*
Clofazimine, C
Clofazimine, C
Ethambutol, E
Ethambutol, E
Pyrazinamide, P
Pyrazinamide, P
*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
3) Hybridization
1) DNA
Extraction
From NALC/NaOH
Processed sputum
Reverse hybridization of
amplified nucleic acids
to specific DNA probes
bound on strips
2) Amplification
by PCR
4) Evaluation
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
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
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
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.
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.
The diagnostic accuracy of the GenoType® MTBDRsl assay
As 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.
Clofazimine
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 extensively
drug-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
Linezolid for Treatment of Chronic XDR-TB
N Engl J Med 2012;367:1508-18
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Clinical use of the
meropenemclavulanate
combination for
XDR-TB
Int 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
phase 2b trial, Bedaquiline
Diacon AH, et al. N Engl J Med 2014;371:723-32
Multidrug-Resistant Tuberculosis
and 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
Diacon AH, et al. N Engl J Med
2014;371:723-32
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
1. the QT interval needs to be adjusted (corrected) for the heart rate
2. 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)
WHO Companion Handbook 2014
Flowchart of intent-to-treat patients in delamanid
(DLM) Trial 204, Trial 208 and Study 116
Eur Respir J 2013; 41: 1393–1400
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
Cascade of regimens
Rifampicin
Quinolone
Susceptible
Resistant
Susceptible
Resistant
Resistant
Treatment approach
First line anti-TB
treatment
Second line anti-TB
treatment
(9-month regimen)
New drugs and potential
group 5 drugs
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?