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Overview of progress in
drug resistance surveillance,
current challenges and future strategy
Matteo Zignol
TME/STB
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Outline of the presentation
Progress in drug resistance surveillance to date
Challenges and opportunities
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AMR surveillance
DR-TB surveillance project: the largest
and oldest AMR surveillance project globally
Other AMR surveillance projects:
Malaria: selected sites
HIV: sentinel system in selected countries
STI (N. gonorrheae): hospital based, selected sites
Gram+/- bacteria (MRSA, E. coli and K. pneumoniae):
hospital based, limited to Europe and America
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The Global Project on
anti-TB drug resistance surveillance
Hosted by WHO
Key technical partners:
SRLs, US CDC, The Union, KNCV, ECDC, RIT-Japan
Key donor Agencies:
USAID, The Global Fund, PEPFAR, Lilly MDR-TB
Partnership
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History of the Global Project on
anti-TB drug resistance surveillance
2009
1st ed. DRS
guidelines
Global Project
launched
SRLN launched
2nd ed. DRS
guidelines
1st global
DRS report
2nd global
DRS report
3rd ed. DRS
guidelines
3rd global
DRS report
4th global
DRS report
4th ed. DRS
guidelines
M/XDR-TB
report
2003 2008 1994 1997 2000 2004 2010
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The Global Project on
anti-TB drug resistance surveillance
Objectives:
To estimate the magnitude of drug resistance
To determine trends
Principles: Sample accurately represents population under study
Differentiation between new and previously treated cases
Quality assured laboratory results
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Country-year data points on drug resistance
surveillance, 1994-2010
Data available from 127 out of 193 countries (66%)
• 64 countries rely on surveillance systems
• 63 countries rely on periodic surveys
Trends data from 71 countries (751 country-year data points)
1
2
3 or more
No data available
Subnational data only
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Proportion of MDR among new TB cases,
1994-2010
• High levels of MDR in EEU (1/3 of new cases in some settings)
• Lack of data from Russia, India, Western and Central Africa
• Overall MDR in new cases: 3.4% (95%CI: 1.9-5.0)
0-<3
3-<6
6-<12
12-<18
>18
No data available
Subnational data only
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Proportion of MDR among previously
treated TB cases, 1994-2010
• High levels of MDR in EEU (3/4 of retr. cases in some settings)
• Lack of data from Russia, India, Western and Central Africa
• Overall MDR in previously treated cases: 19.8% (95%CI: 14.4-25.1)
0-<6
6-<12
12-<30
30-<50
>50
No data available
Subnational data only
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77 countries reported at least one
XDR-TB case by Feb 2012
Argentina Burkina Faso Estonia Japan Namibia Republic of Korea The Former Yugoslav Republic of Macedonia
Armenia Bhutan France Kazakhstan Nepal Republic of Moldova Togo
Australia Cambodia Georgia Kenya Netherlands Romania Tunisia
Austria Canada Germany Kyrgyzstan Niger Russian Federation Turkey
Azerbaijan Chile Greece Latvia Norway Slovenia Ukraine
Bangladesh China India Lesotho Pakistan South Africa United Arab Emirates
Belarus Colombia Indonesia Lithuania Peru Spain United Kingdom
Belgium Czech Republic Iran (Islamic Rep. of) Mexico Philippines Swaziland United Republic of Tanzania
Benin Dominican Republic Ireland Mongolia Poland Sweden United States of America
Botswana Ecuador Israel Mozambique Portugal Tajikistan Uzbekistan
Brazil Egypt Italy Myanmar Qatar Thailand Viet Nam
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XDR
Surveillance
57 countries &
3 territories
% XDR in MDR
9.4%
(95%CI: 7.4-11.6)
number of
cases%
Albania surveillance 2010 2 2 0 0.0
Australia surveillance 2010 32 32 1 3.1
Austria surveillance 2010 15 15 1 6.7
Bangladesh (14 districts covering 30 million population)a surveillance 2008 168 168 1 0.6
Belgium surveillance 2009 10 10 3 30.0
Botsw ana survey 2008 32 24 0 0.0
Bulgaria surveillance 2008 32 28 0 0.0
Canada surveillance 2010 15 14 1 7.1
China survey 2008 401 401 29 7.2
China, Hong Kong SAR surveillance 2009 3 3 0 0.0
China, Macao SAR surveillance 2010 6 6 0 0.0
Cyprus surveillance 2008 1 1 0 0.0
Czech Republic surveillance 2008 11 10 1 10.0
Denmark surveillance 2007 2 2 0 0.0
Estonia surveillance 2010 63 61 12 19.7
Georgia surveillance 2010 359 313 30 9.6
Greece surveillance 2009 14 9 3 33.3
Guam surveillance 2010 2 2 0 0.0
Iceland surveillance 2008 1 1 0 0.0
India, Gujarat State survey 2006 216 216 7 3.2
Israel surveillance 2010 12 12 1 8.3
Italy surveillance 2009 82 32 1 3.1
Latvia surveillance 2010 87 86 13 15.1
Marshall Islands surveillance 2010 1 1 0 0.0
Montenegro surveillance 2009 1 1 0 0.0
Namibia survey 2008 100 100 0 0.0
Norw ay surveillance 2008 4 4 0 0.0
Oman surveillance 2010 1 1 0 0.0
Paraguay survey 2008 8 8 0 0.0
Poland surveillance 2008 52 52 5 9.6
Qatar surveillance 2010 4 4 0 0.0
Singapore surveillance 2010 3 3 0 0.0
Slovakia surveillance 2010 1 1 0 0.0
South Africa surveillance 2008 8,026 5,451 572 10.5
Sw aziland survey 2009 122 122 1 0.8
Sw eden surveillance 2009 13 9 0 0.0
Sw itzerland surveillance 2010 8 8 0 0.0
Tajikistan, Dushanbe city and Rudaki district survey 2009 100 100 21 21.0
The Former Yugoslav Republic of Macedonia surveillance 2010 7 5 1 20.0
United Kingdom of Great Britain and Northern Ireland surveillance 2009 58 40 2 5.0
United States of America surveillance 2010 92 59 1 1.7a Only previously treated cases; DST = drug susceptibility testing.
XDR-TBMDR-TB
cases w ith
DST results
for 2nd-line
drugs
Country or settingType of
surveillanceYear
MDR-TB
cases
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Ongoing & planned surveys, 2011-2012
31 ongoing surveys
• 24 nationwide surveys
• 7 subnational surveys
21 planned surveys
1
2
3 or more
Ongoing survey
Planned survey
No data available
Subnational data only
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Enrolment completed
Enrolment completed
Enrolment completed
Enrolment completed
Enrolment completed
Underway
Enrolment completed
?
2 underway
Enrolment completed
Planned
Planned
Underway
Another planned
Another planned
Underway
Underway
Underway
Class B
Class B
Another planned
Class A
21 oblasts
Class A
Class A
Class A
1999
Several
2004
2007
2006
2005
2007
2007
2007
2006
2005
2004
2006
2001
2001
2007
4 oblasts
Class A
Class A
Class A
Bangladesh
Belarus
Bulgaria
Kyrgyzstan
Nigeria
Pakistan
Tajikistan
DR Congo
India
Indonesia
Azerbaijan
Ukraine
Uzbekistan
Armenia
China
Myanmar
Vietnam
Ethiopia
Philippines
Moldova
Kazakhstan
South Africa
Georgia
Russia
Estonia
Lithuania
Latvia
2008
None
Subnational
surveys
Nationwide
surveys
Routine
surveillance
Progress on obtaining representative data on drug
resistance in the 27 high MDR-TB burden countries
2012
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Time trends in MDR-TB
in selected settings, 1996-2010
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
7.4% per year
10.9% per year
Rep. of Korea
cases p
er
100,0
00 p
opula
tio
n
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
0.3% per year
19.4% per year
Botswana
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
-3.3% per year
4.3% per year
Peru
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
0% per year
3.7% per year
Russian Federation, Arkhangelsk Oblast
cases p
er
100,0
00 p
opula
tio
n
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
- 2.4% per year
2.4% per year
Russian Federation, Tomsk Oblast
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
-4.0% per year
6.6% per year
Russian Federation, Orel Oblast
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
-5.5% per year
-4.9% per year
Latvia
cases p
er
100,0
00 p
opula
tio
n
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
-7.4% per year
-5.5% per year
Estonia
0.01
0.1
1
10
100
1000
1996 1998 2000 2002 2004 2006 2008 2010
-5.4% per year
-5.1% per year
United States
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Global and regional trends in MDR-TB,
1994-2011
• Trends data available from 71 countries only
• Regional and global trends difficult to predict
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Challenges
1. Lab capacity still a major issue in many countries
2. Coordination between lab and epi communities not
always easy (sometimes lack of epi support in surveys)
3. Transportation of live bacilli within and between
countries becoming more difficult
As a consequence:
Baseline data still not available for 1/3 of countries
gaps in India, Russia and Western/ Central Africa
Trends data available only in 1/3 of all countries (mainly
countries with surveillance systems)
Repeat surveys difficult to implement
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611 GXP machines and 863,790 Xpert MTB/RIF
cartridges procured in 61 countries
Dec 2010 Mar 2012
Opportunities
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Cumulative number of Xpert modules and
cartridges procured under concessional pricing
Data provided by FIND
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Possible solutions to improve baseline
coverage and availability of trends data (I)
1. LQAS:
• Pros: smaller sample
• Cons: not useful for trends, possibly difficult to explain
in some countries
2. Sentinel system:
• Pros: possibly useful for trends, easier to implement
• Cons: not representative
3. Continuous surveillance of retreatment cases:
• Pros: possibly easier to implement
• Cons: not useful for trends (retr. very heterogeneous)
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Possible solutions to improve baseline
coverage and availability of trends data (II)
4. Xpert/MTB-RIF:
• Pros: virtually no need of labs, works on dead bacilli,
rapid response (no need for patients to come back), no
need to modify survey design
• Cons: focus on R resistance H (& SLD) results
possibly available only for patients with R-res
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How well can rapid diagnostics of R-
resistance diagnose MDR?
New cases Previously treated cases
R-resistance not a good proxy of MDR
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Consequence of implementation of Xpert
on design of treatment regimens
Provisional recommendation of WHO Expert meeting
March 2012 to be presented at STAG:
"All patients at high risk of MDR detected with a rapid
rifampicin test should be treated with an MDR
regimen containing isoniazid until DST results to
isoniazid are available and appropriate adjustments
to the regimen made."
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Conclusions
Progress:
Baseline data available for 2/3 of all countries globally
Trends data available for only 1/3 of all countries
globally
Challenges and opportunities:
Lab capacity still a major issue in many countries
Molecular technologies represent a unique opportunity
to accelerate surveillance of drug resistance
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Questions for the Task Force
1. What are your general comments on progress in
DRS to date?
2. To improve our ability to monitor time trends in
drug resistance:
a. Should we explore new methods for the design
and analysis of repeat DR surveys and if so what
methods would you recommend?
b. Should we focus on production and collection of
data on RIF resistance only as opposed to both
RIF and INH resistance?
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Acknowledgments
Babis Sismanidis
Dennis Falzon
Hazim Timimi
Karin Weyer
Katherine Floyd
Philippe Glaziou
Wayne van Gemert