Overview of progress in

drug resistance surveillance,

current challenges and future strategy

Matteo Zignol

TME/STB

Outline of the presentation

Progress in drug resistance surveillance to date

Challenges and opportunities

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

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

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

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

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

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

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

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

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

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

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

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

Global and regional trends in MDR-TB,

1994-2011

• Trends data available from 71 countries only

• Regional and global trends difficult to predict

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

611 GXP machines and 863,790 Xpert MTB/RIF

cartridges procured in 61 countries

Dec 2010 Mar 2012

Opportunities

Cumulative number of Xpert modules and

cartridges procured under concessional pricing

Data provided by FIND

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)

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

How well can rapid diagnostics of R-

resistance diagnose MDR?

New cases Previously treated cases

R-resistance not a good proxy of MDR

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."

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

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?

Acknowledgments

Babis Sismanidis

Dennis Falzon

Hazim Timimi

Karin Weyer

Katherine Floyd

Philippe Glaziou

Wayne van Gemert