Transcript Extreme Drug-Resistance in Tuberculosis (“XDR TB”)

Extensive Second-line Drug Resistance in
Tuberculosis - “XDR TB”:
Global Survey of Supranational TB
Reference Laboratories
Sarita Shah1, Abigail Wright A2, Fadila Boulahbal3, Chris Gilpin3,
Francis Drobniewski3, Gill-Han Bai3, Marta Havelková3, Rosario
Lepe3, Beverly Metchock3, Maria Filomena Rodrigues3, Françoise
Portaels3, Armand Van Deun3, Sabine Rüsch-Gerdes3, Véronique
Vincent3, Lucia Barrera3, Kayla Laserson1, Charles Wells1, Peter
Cegielski1
1CDC
Atlanta, 2WHO Geneva, 3Supranational TB Reference
Laboratory Network
Background
• Green Light Committee (GLC) evaluates and
monitors DOTS-Plus projects world wide, ~60 to
date, 35 approved in 29 countries, ~12,000 patients
• Increasing anecdotal reports of TB resistant to
virtually all 2nd-line drugs (SLDs)
• Informal consultation with several Supranational TB
Reference Laboratory (SRL) directors
– Confirmed similar observations
– Supported a collaborative project to count these cases
Proposal (mid-2005)
• Collaboration with WHO and SRL network to count
cases of TB with extensive resistance to SLDs
– Reputation of SRLs minimize questions of
validity of 2nd-line DST results
– Global geographic distribution
– Many SRLs are (national) reference labs (NRLs)
in their own countries
– In addition to QA for global DRS, many SRLs
assist NRLs world wide
– SRLs history of working together
Objective
• To assess the extent to which extensive
resistance to SLDs has begun to emerge
among MDR Mycobacterium tuberculosis
(Mtb) isolates in the SRL network
Methods
• “XDR TB” defined as MDR TB that also has
resistance to ≥3 of 6 major classes of SLDs
(tested)
• All SRLs invited to contribute data on Mtb
isolates tested for resistance to at least 3
major classes of SLDs, 2000-2004
• 17 of 23 SRLs agreed to participate, 12 sent
data in time for 2005 IUATLD
• SLD resistance patterns analyzed by year,
region, and 1st line drug resistance pattern
Study
Sample
Isolates submitted
by SRLs
(N=18,215)
Tested before 2000
(N=207) or
Tested in 2005
(N=14)
Isolates tested
2000 – 2004
(N=17,994)
Tested for <3 SLD
classes
(N=535)
Isolates tested
for >3 SLD classes
(N=17,459)
Geographic region from which cultures
were received by SRLs (N=17,459)
Sub-saharan Africa
317 (1.8%)
North Africa + Middle East
348 (2.0%)
Asia (except S. Korea)
381 (2.2%)
UK + Western Europe
511 (2.9%)
Eastern Europe
529 (3.0%)
Russia
624 (3.6%)
Latin America
985 (5.6%)
North America
1,767 (10.1%)
Asia (S. Korea)
11,939 (68.4%)
TOTAL
17,459 (100%)
First-line Drug Resistance Patterns
Total number tested
Any resistance
Monoresistance
Multidrug resistance
Polyresist. non-MDR
* Any except RIF
11 SRLs
N (%)
5,520
3,594 (65)
790 (14)
2,163 (39)
1,629 (30)
S. Korea
N (%)
11,939
2,508 (21)
952 (8)
1,298 (11)
329 (3)
Prevalence of Resistance to 2nd-line Drugs
(isolates tested for at least 3 SLDs, %)
any resistance to…
MDR isolates
N=3,461
Other Poly-R
N=3,576
18.1
8.0
19.3
17.4
17.7
7.7
18.3
17.6
Cycloserine (CYS)
14.1
3.9
PAS
12.9
14.0
Amikacin or Kanamycin (AG)
Capreomycin (CM)
Ciprofloxacin or Ofloxacin (FQ)
Ethio/prothionamide (TA)
2nd-line Drug Resistance Patterns
...among isolates tested for MDR isolates
N=3,461
at least 3 SLDs, %
AG+CM
AG+FQ
AG+ >1 Group 4 drug
CM+FQ
CM+ >1 Group 4 drug
FQ+ >1 Group 4 drug
AG+CM+FQ
AG+CM+ >1 Group 4 drug
AG+CM+FQ + >1 Group 4
Any 3 SLD classes
7.2
6.1
7.6
3.1
4.0
11.3
2.5
3.3
1.6
9.9
Other Poly
N=3,576
7.0
6.4
8.2
3.0
3.9
11.1
2.5
3.4
1.6
10.1
Prevalence Second-line Drug Resistance
By Geographic Region (%)
1st line
Any
Mono
Multi
Poly
SLDs
AG
FQ
CAP
TA
CYS
PAS
Latin
America
985
Sub-S.
Africa
317
North
America
1,771
West.
Europe
511
Russia / E.
Euro 1,153
N. Afr.
Mid.E
348
Asia
12,316
72
9.4
55
41
34
10
19
11
63
26
18
13
99
2.4
88
59
61
13
35
32
36
5.7
27
25
23
7.9
13
4.2
19.6
8.0
3.9
13.5
1.1
5.6
1.3
0.6
0.9
5.4
0.9
0.6
2.1
3.2
1.4
4.9
0.3
2.3
6.8
10.8
4.7
24.3
5.3
7.8
16.6
4.2
8.5
9.9
1.3
8.5
2.9
0.6
0.9
5.2
0.6
0
1.9
4.6
1.0
2.5
0.7
3.4
Patterns of Second-line Drug Resistance in MDR
Isolates by Geographic Region (N=3,461)
AG+CM
AG+FQ
AG+ >1 Group 4
CM+FQ
CM+ >1 Group 4
FQ+ >1 Group 4 drug
AG+CM+FQ
AG+CM+ >1 Group 4
AG+CM+FQ+1 Grp 4
Any 3 SLD classes
Latin
America
543 (%)
N Amer
320 (%)
UK /
W Euro
451 (%)
Russia /
E Euro
406 (%)
N Afr
Mid E
95 (%)
Asia
1,563 (%)
6.6
6.1
6.6
1.8
2.2
5.0
1.8
2.2
0.9
5.9
6.2
3.1
5.3
2.2
4.1
4.7
2.2
4.1
2.2
4.7
4.0
4.0
5.8
2.4
3.5
9.3
1.5
2.7
1.3
7.8
20.9
5.7
17.7
1.2
7.6
6.6
1.2
7.6
0.5
13.5
0
0
9.5
0
0
2.1
0
0
0
0
5.6
8.1
6.4
4.7
4.0
17.7
3.8
3.0
2.4
13.0
Patterns of 2nd-line Drug Resistance in MDR
Isolates By Year Of Test (%)
2000
2001
2002
2003
2004
Number tested, Total=3,461
294
319
512
520
1,816
AG+CM
AG+FQ
AG+ >1 Group 4 drug
CM+FQ
CM+ >1 Group 4 drug
FQ+ >1 Group 4 drug
AG+CM+FQ
AG+CM+ >1 Group 4 drug
AG+CM+FQ + >1 Group 4
Any 3 SLD classes
5.4
4.8
5.8
0.3
1.4
4.4
0.3
1.4
0.3
4.4
3.4
4.4
7.2
1.6
0.9
7.5
1.6
0.9
0.3
6.0
11.9
2.3
9.8
1.0
5.3
4.1
1.0
5.3
0.6
7.6
8.3
5.4
7.5
2.3
3.8
7.7
1.9
3.3
1.3
7.7
6.5
7.9
7.4
4.6
4.6
16.2
3.7
3.6
2.5
12.8
Limitations
• Variation in methods and results for SLD testing
– No standards for QA for SLD susceptibility testing
– Limited reproducibility of DST for certain drugs
• Sampling bias
– Convenience sample does not represent a specific
geographic region or patient population
– No true denominator; not possible to determine case
rates, only case counts
– Differing indications for SLD testing (all patients,
failures/retreatment cases, only MDR isolates)
• Different and minimal patient data available to each SRL
limited comparisons
Conclusions and Recommendations
• Extremely drug-resistant “XDR” TB has emerged in all
continents
• XDR strains may be
– More prevalent in regions with high rates of MDR TB
– Increasing over time
• Imperative to prevent, treat TB & MDR TB more
effectively
• Population-based data needed to estimate current
magnitude of XDR TB and monitor trends
• QC/QA standards for 2nd-line DST needed to help
ensure global reproducibility
Next Steps
• SRLs that agreed to participate but have not
yet sent data or only part of data (< 5 years)
please send data a.s.a.p.
• Finalize analysis, draft manuscript, rapid
submission
• Prepare advocacy, publicity strategy
• Plan population-based survey and/or
prospective study