Drug Resistant Tuberculosis
(DR-TB): An Update
Dr. Dick Menzies
Montreal Chest Institute
1
Definitions
– Primary DR: Resistance in person treated <1
month or not at all
– Acquired DR: Resistance in person treated > 1
month
– Mono-drug resistance: Resistance to 1 drug
– Poly-drug resistance: Resistance to >1 drug, but
not MDR.
– MDR: resistant to isoniazid and rifampin
– XDR: MDR & resistance to Quinolones &
Injectable
4
Epidemiology of DR-TB summary
• Global total in new cases: 17%
– 3% MDR and 0.5% XDR
– 14% other forms (INH most common)
• Highest in Former Soviet Union
– And certain Latin American countries
– Increasing in China, India, S Africa
• Low in Canada – mostly seen in immigrants
from these high risk regions
6
Global TB Estimates
All forms of TB
Greatest number of cases in Asia;
greatest rates per capita in Africa
Multidrug-resistant
TB (MDR-TB)
Extensively drugresistant TB (XDR-TB)
Estimated
number of
cases
Estimated
number of
deaths
9.23 million
1.7 million
489,000
120,000
(5.3%)
40,000
(0.5%)
Adapted from a slide provided by Dr. Paul Nunn, WHO Geneva
20,000
Proportion with MDR-TB in new and
previously treated cases, 1994-2007
MDR in
New patients
Previously
treated
patients
Trends in Global Drug Resistance in New
Cases (AZIZ, Lancet 2006)
High Income
Canada
Any Resistance
MDR
USA
Any Resistance
MDR
United Kingdom
Any Resistance
MDR
1994 - 96
2001 – 02
10%
0.8%
9%
0.7%
12%
1.6%
13%
1.1%
7%
1.1%
8%
0.9%
Trends in Global Drug Resistance in
New Cases
(AZIZ, Lancet 2006)
1994 - 96
2001 – 02
Any Resistance
34%
32%
MDR
14%
12%
Any Resistance
29%
37%
MDR
7%
14%
Middle Income
Latvia
Russia (Tomsk)
How does drug resistance
develop?
(aka Pathogenesis)
Treatment with Streptomycin alone, or PAS alone
% Patients with resistance - Days after Tx started
Source: Rieder, Interventions for TB control, IUATLD.
Treating TB with one drug – Improvement then
worsening – the fall and rise phenomenon
Source: Toman Case Finding and Chemotherapy
Rate of spontaneous mutations of
M Tuberculosis to anti-TB drugs
Streptomycin
10-6
Isoniazid
10-6 - 10-7
Rifampin
10-8 - 10-9
Ethambutol
10-7 - 10-8
INH&Rif
10-14
19
Total number of bacilli –
by clinical extent of disease

Lesion
Quantity
AFB

Granuloma
103
Latent

Infiltrates
106- - 107
Negative

Cavity
108 - 109
+ , ++

Many cavities,
1010 - 1012
+++

Death
1013
too late!
Probability of developing resistance
during therapy – by number of drugs
Number of
Drugs
Total number of bacilli
104
106
108
1010
1012
One
1%
63%
100%
100%
100%
Two
0
0
.01%
1%
60%
Three
0
0
0
0
0
22
Transient drug resistance during therapy with two or
more drugs (effect of default)
23
From Toman, Case Finding and Chemotherapy
Association of MDR-TB and regulation
of TB drugs
• Ecologic survey of 100 countries
– Mostly low-middle income countries
• Significant correlation of poor regulations
of TB drug sales and MDR in new cases
– Sales in private pharmacies
– Dispensing/prescription by private MDs rather
than TB programme
25
Ecologic study: MDR and Tx outcomes
• 161 – reported treatment outcomes to WHO in 2003
and 2004
• 121 – Had > 250 cases annually
• 118 - Initial MDR prevalence - (WHO)
• 103 – Used standard Tx schemes (GDF)
– 78 WHO Initial regimen (6 months RIF)
– 27 Union Initial regimen (2 months RIF)
Failure rate with standardized Retreatment in 103
countries – by prevalence of Initial MDR
25
20
15
10
5
0
Failure of Retreatment - Total
<1%
1-2%
Failure Initial, Then
Retreatment
2-3%
>3%
Diagnosis of drug resistance
(very briefly)
Diagnosis of DR-TB
• Old methods – proportional on solid media
– Slow – 4-8 weeks for culture
• Another 4-8 weeks for sub-cultures for DST
– Relatively inexpensive – so used in low-income
• Current methods – Indirect in liquid media
– Faster but more expensive
– Still 2-4 weeks for culture
– Then another 2-4 weeks for DST
30
Microscopically Observed Drug
Susceptibility (MODS)
• Direct inoculation of
specimens – for detection &
DST
• Microscopic colony
detection
• Average time to results: 9 to
11 days
• Excellent sensitivity and
specificity
• Low costs - materials &
equipment
• Labour intensive
www.modsperu.org
Newest and fastest: Molecular tests –
Line probe assays
Detection of MTB & INH & RIF-resistance
 Requires extraction, amplification
 Colorimetric development using
immobilized probes
 Excellent sensitivity and specificity

– Lower for INH (more mutations)
– But limited field studies
– Still potential for contamination
• Expensive ($50-60 per test)
34
Accuracy of Line Probe assays
(from Ling et al, Thorax, 2010)
Sensitivity
Specificity
35
Cepheid GeneXpert MTB/RIF
Boehme et al. 2010 NEJM
• Automated RT-PCR
• Simple 1-step specimen
preparation
• Minimal biohazard risks
• Results in 2 HOURS!!
• Demonstration studies
(6673 patients, 6 sites):
• Sensitivity for diagnosis
99% in smear +
80% in smear - / culture +
• Rifampicin resistance
95% sensitive
98% specific
Treatment of DR-TB
INH Mono-resistance
Other forms of non-MDR resistance
MDR-TB
How good is the published evidence?
One last thing ….
How good is the published evidence?
• Trials of retreatment
– N = 4, all published before 1980
• Trials of INH resistant patients
– N = 5, also older studies
• Trials of current standardized retreatment
– NONE
• Phase 3 Trials of MDR treatment
– NONE
Isoniazid resistance (excluding MDR)
Global weighted mean, 1994-2007*
• 7.4% in new cases
• 12.4% in previously treated
Treatment
• Dogma: “INH-R is of little importance”. Treat
with standard therapy
• Evidence – two systematic reviews
– New cases – some of whom had INH-R
– Studies of INH-R or retreatment
• Risk of failure & acquiring MDR-TB
42
Treatment Failure in New cases
If Initial Drug Resistance
Systematic review of 57 studies with 20,000 patients.
Initial Drug
Resistance
Arms
(N)
Events/
Subjects
Event
rate
(95% CI)
121/15117 0.3%
(0.1, 0.4)
Pan-Sensitive
127
INH resistant
68
26/483
3.0%
(0.7, 5.3)
Streptomycin
Resistant
54
6/316
1.3%
(0, 2.8
Poly-drug
resistance
42
41/287
8.4% (2.1, 14.7)
Initial Drug Resistance and Treatment
outcomes (from Meta-regression)
Systematic review of 57 studies with 20,000 patients.
Initial Drug
resistance
Failure
Relapse
IRR (95% CI)
IRR (95% CI)
Acquired drug
resistance
IRR (95% CI)
Pan-Sensitive 1.0 (reference) 1.0 (reference) 1.0(reference)
INH resistant
9.8 (7.2, 13.7)
2.2 (1.7, 30)
6.3 (4.1, 9.5)
Streptomycin
Resistant
6.4 (3.9, 10.2)
2.0 (1.4, 2.8)
7.0 (4.3, 11.6)
28 (19, 40)
2.2 (1.5, 3.2)
12.9 (8.3, 20)
Poly-drug
resistance
Cohort Studies with Mono-resistance to INH
Standardized WHO Re-treatment
(2HRZES/1HRZE/5HRE)
Total Number
Treated
Number (%) who
Failed
39
7 (18%)
31
6 (19%)
18
8 (44%)
Intermittent therapy and Treatment
outcomes - INH resistance
(from multivariate meta-regression)
Failure
IRR
(95% CI)
Relapse
IRR
(95% CI)
Acquired drug
resistance
IRR (95% CI)
Daily Initially
1.0 (reference)
1.0(reference)
1.0(reference)
3X weekly thru-out
3.0 (2.0, 4.5)
1.5 (0.9, 2.5)
2.4 (1.4, 4.2)
2X weekly thru-out
2.4 (1.6, 3.5)
4.5 (1.9, 10.7)
1.5 (0.9, 2.5)
Number of drugs in initial phase to which
strains sensitive - INH resistance
(from multivariate meta-regression)
Number of
Drugs
Failure
Relapse
IRR (95% CI) IRR (95% CI)
6.8 (1.3, 36)
Acquired drug
resistance
IRR (95% CI)
1
10.0 (3.9, 28)
No obs.
2
5.0 (2.4, 11.0) 4.6 (1.7, 12.2) 60 (4.0, 99)
3
3.1 (1.5, 6.7) 3.8 (1.5, 10.0) 27 (1.7, 99)
4
1.0 (reference)
1.0 (reference) 1.0 (reference)
My take – therapy of INH-R
• Dogma wrong
• Treat with fluoro-quinolone through-out
– Two studies (CDC, and Russia) show that FQ
equal to INH – can replace in regimen
• Avoid intermittent therapy – at least initial 2
months
• Give 4 effective drugs in first 2 months
• Duration?: Longer=safer
49
Other forms of DR-TB - therapy
• If mono-RIF resistance:
– INH/PZA/FQuin/EMB/Injectable – 2-6 mos
• Then INH/EMB & FQuin – total 18 mos
• If PZA resistance:
– INH/RIF/EMB – 2 mos, INH/RIF – 7 mos
• If EMB resistance:
– Can ignore (its rare though)
• If Strep resistance:
– Can ignore (usually not tested)
50
Multi-Drug resistance - therapy
• Long and difficult
• Second line drugs – more toxic, and less
effective
• Optimal therapy controversial
51
Rational selection of MDR-TB regimen
Group 1
Isoniazid
Ethambutol
Rifampin
Pyrazinamide
Group 2
Streptomycin Kanamycin
Amikacin
Capreomycin
Group 3
Ofloxacin
Moxifloxacin
Group 4
Group 5
Levofloxacin
Gatifloxacin
Ethionamide
Prothionamide
Cycloserine
Terizidone
Thioacetazone P-aminosalicylic acid
Clofazimine
Imipenem
Amoxacillin/Clavulanate
52
Macrolides
Linezolid
Individual Patient Data (IPD)
meta-analysis of patients with
Multi-drug Resistant Tuberculosis
Preliminary results
Dick Menzies, on behalf of:
The IPD in MDR Group
The Collaborative Group for Meta-Analysis of
Individual Patient Data in MDR-TB
(members in alphabetic order)
D. Ashkin, S.Ahuja, M. Avendano, M. Bauer, M. Becerra, A.
Benedetti, M. Burgos, R. Centis, E. Chan, C.Y. Chiang, F. Cobelens,
H. Cox, E. Declercq, D. Enarson, D. Falzon, K. Flanagan, J. Flood, J.
Furin, L. Garcia-Garcia, N. Gandhi, P. Hopewell, T. Holtz, S.
Keshavjee, WJ.Koh, V. Leimane, C.C. Leung, J. Li, A.K. Maug, D.
Menzies, G.B. Migliori, C.Mitnick, S.S. Munsiff, M. Narita, E.
Nathanson, P. O’Riordan, M. Pai, D. Palmero, G. Pasvol, J. Pena, C.
Perez, MID Quelapio, H.T. Quy, A. Ponce-de-Leon, V. Riekstina,
J. Robert, S. Royce, M. Salim, H.S. Schaaf, K.J. Seung, L. Shah, K.P.
Shean, T.S. Shim, S.S. Shin, Y. Shiraishi, Jose Sifuentes-Osornio, G.
Sotgiu, M. Strand, P. Tabarsi, T.E. Tupasi, M. Vargas, M. Van der
Walt, T.S. Van der Werf, A. Van Deun, P. Viiklepp, W.W. Yew, J.J.
Yim
Research Objectives
• “Which are the most (and least) effective drugs for
MDR TB treatment?”
• “What is the optimal number of drugs?”
– Intensive phase
– Continuation phase
• “What is the optimal duration of treatment?”
– Initial intensive phase (duration of injectable)
– Total duration
Study Selection
• 3 systematic reviews of MDR treatment:
• Johnston et. al. (2009)
• Orenstein et. al. (2009)
• Akçakir et. al. (2010)
• Inclusion criteria of these 3 reviews:
– Original data, published since 1970
– Bacteriological confirmation of INH- and RIF-resistant TB
– Excluded if strictly XDR-TB patients
• IPD eligibility
– Investigators willing and able to share their data
– At least 25 MDR cases
– Treatment and treatment success known
Meta-analysis Methods
• Random effects logistic regression to obtain the odds ratio
of treatment success for each drug
– Models included a random intercept & random slope
– Estimate OR for each study, then pool estimates
• Multivariate approach controlled for:
– gender
– age
at MDR TB diagnosis
– HIV
– disease severity (AFB smear/CXR cavities)
– past TB treatment (none, previous TB treatment, previous
MDR TB treatment)
3 Systematic reviews identified – Orenstein,
Johnston, Akcakir
Figure 1. Study Selection
93 studies identified from
3 systematic reviews
Excluded: 26 publications representing the
same or overlapping cohorts
67
individual
cohorts
32 data sets
included, with 9898
patients
9153 patients analyzed
Excluded - 35 cohorts
13 – No author response
8 – No longer have access to data
5 – Inadequate outcome data
2 – Refusals
2 – No response following initial
contact
2 – No data on drug sensitivity testing
2 – Data never sent
1 – Cohort with less than 25 patients
Excluded Patients
410 - XDR TB
127 - Extra-pulmonary TB
208 - No treatment info
Treatment Outcomes
N = 9,153 patients
•
•
•
•
Cure/complete (success) - 4932 (54%)
Failure/relapsed - 732 (8%)
Death - 1392 (15%)
Default - 2097 (23%)
Draft WHO Recommendations for new
MDR treatment guidelines(1)
1. Use rapid DST testing for resistance to INH and RIF
or RIF alone at the time of diagnosis of TB over
conventional testing or no testing
2. Use smear and culture over smear alone for
monitoring
3. Use fluoroquinolones
4. Higher generation FQN > lower generation
5. Use ethionamide / prothionamide
Draft WHO Recommendations for new
MDR treatment guidelines(2)
6. Initial phase with 4 SLD TB drugs likely to be
effective (including inj.) and Z
7. Regimen with FQ, Km, Eto/Pto, Cs or PAS, plus Z
8. Initial phase at least 8 months, total treatment of
21-24 months
9. ART in all HIV/MDR-TB patients
10. Use mainly ambulatory care rather than mainly
hospital care
Conclusions
• DR-TB treatment is more complex, usually
longer, and should be daily
• DST essential to guide therapy
• Evidence base for therapy of DR-TB is very
weak – ‘expert’ opinion usually.
– Hence strong differences in opinion
• New drugs and RCT needed
63
Acknowledgements
• Systematic Reviews – Woojin Lew, Olivia
Oxlade, Madhu Pai, Faiz Khan
• Ecologic studies: Anita Paydar, Anton Mak
• IPD meta-analysis: Melissa Bauer, Maria
Holmes-Delgado, Sandra Ramoutar, Lena
Shah,
• Slides (with some edits) from:
– Kitty Lambregts, Fuad Myrzayev, Matteo
Zignol, Sarah Royce, Jessica Minion, Madhu
Pai,
Thank you!
Merci!
Gracias!!
References
• Akçakir Y. Correlates of treatment outcomes of MultidrugResistant Tuberculosis (MDR-TB): a systematic review
and meta-analysis. Montreal: McGill University; 2010.
• Johnston JC, Shahidi NC, Sadatsafavi M, Fitzgerald JM.
Treatment outcomes of multidrug-resistant tuberculosis: a
systematic review and meta-analysis. PLOS One
2009;4(9).
• Orenstein EW, Basu S, Shah NS et al. Treatment outcomes
among patients with multidrug-resistant tuberculosis:
systematic review and meta-analysis. Lancet Infect Dis
2009;9(3).
• 2008 Emergency Update from WHO