Download MDR-TB

Epidemiology
G.B. Migliori, Stefan Niemann
WHO Collaborating Centre for Control of TB and Lung Diseases,
Fondazione S. Maugeri, IRCCS, Tradate, Italy
Research Center Borstel, Borsel, Germany
Outline:
•
•
•
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Epidemiology of TB
Epidemiology of MDR-TB
Outcomes of MDR-TB
Fingerprinting for TB and MDR-TB
•Prevalence of infectious cases
•Duration of illness
•Intensity, frequency and duration of contact
Largely exogenous
•Particles/volume x exposure time
•Production of infectious droplets
•Clearance of air
•Extent of exposure
Largely endogenous
Innate resistance
Performance of cell-mediated
immunity
Re-infection
Strain virulence
RF
RF
RF
RF
Exposure
Subclinical
Infection
TB epidemiological model
Form and site of TB
Age
Patient’s susceptibility
Delay in diagnosis
Infectious
TB/MDR-TB
Death
Non-infectious
TB/MDR-TB
•Prevalence of infectious cases
•Duration of illness
•Intensity, frequency and duration of contact
Largely endogenous
Largely exogenous
•Particles/volume x exposure time
•Production of infectious droplets
•Clearance of air
•Extent of exposure
Innate resistance
Performance of cell-mediated
immunity
Re-infection
Strain virulence
RF
RF
RF
RF
Exposure
?
Subclinical
Infection
?
Form and site of TB
Age
Patient’s susceptibility
Delay in diagnosis
Infectious
TB/MDR-TB
Death
Non-infectious
TB/MDR-TB
?
?
% PPD (+) reactors in 0-14 y.o. contacts
Rotterdam (1967-1969): SS+ cases are infectious
50
45
40
35
30
25
SS+
C+
C-
20
15
10
5
0
Household
contacts
other contacts
% of PPD+
children 0-14
yrs
RR of TB by Risk Group compared to Gen. Popul.
Risk Group
Relative Risk
AIDS
HIV (+), PPD (+)
HIV (+), PPD (-), ANERGIC
HIV (+), PPD (-), NOT ANERGIC
170
40-50
30
3-25
SILICOSIS
FIBROTIC LESION
IMMUNOSUPPRESSIVE TREATMENT
HEMODIALYSIS
JEJUNOILEAL BYPASS
CA OF HEAD OR NECK
PPD CONVERSION <1 YEAR
PPD CONVERSION > 7 YEARS
30
4-26
12
10-15
27-63
16
10
2
Risk of TB infection in European countries
Age-specific prevalence of TB Infection,
Switzerland 1920-1990
TB reported in Switzerland by age, 1990
TB reported incidence in African
Countries, 1990-2002
1000
RATE PER 100 000
BOTSWANA
MALAWI
MOZAMBIQUE
SOUTH AFRICA
UGANDA
TANZANIA
ZIMBABWE
100
1990
91
92
93
94
95
96
97
98
99
2000
1
2
TB Case notifications, SS+ and all forms
of TB, Kenya, 1990-2002
300
263
PTB+
250
242
All types
TB
218
202
n/100,000 pop.
200
171
144
150
130
108
100
50
89
84
32
62
54
53
31
33
42
95
44
98
104
110
83
53
63
68
0
'90
'91
'92
'93
'94
'95
'96
Year
'97
'98
'99
'00
'01
'02
Latest global TB estimates
Estimated
number of
cases
All forms of TB
Greatest number of cases in Asia; greatest
rates per capita in Africa
Estimated
number of
deaths
9.27 million
1.77 million
(139 per 100,000)
(27 per 100,000)
Multidrug-resistant
TB (MDR-TB)
511,000
~150,000
Extensively drug-resistant
TB (XDR-TB)
~50,000
~30,000
HIV-associated TB
1.4 million (15%)
456,000
(2009)
Estimated number of new TB cases, 2007
9.2 million new cases (~434,000 in Europe)
1.7 million death (~63,000 in Europe)
Notified TB Incidence Rate 2007
Estimated TB Incidence Rate 2007
1.5-3 times higher than cases notified…
Estimated TB burden, 2007
TB incidence rates stable or falling slowly
450
400
350
300
AFR
AMR
EMR
EUR
SEAR
WPR
10
9
8
7
6
5
4
3
2
1
0
World
250
200
1990
9.27
Cases in million
1995
2000
150
100
50
0
1990
1995
2000
2005
2005
WHO European Region (EUR)
53 countries
18 high priority countries for TB
25 EU countries
1.
2.
3.
4.
5.
6.
7.
8.
9.
Armenia
Azerbaijan
Belarus
Bulgaria
Estonia
Georgia
Kazakhstan
Kyrgyzstan
Latvia
10.
11.
12.
13.
14.
15.
16.
17.
18.
Lithuania
Moldova
Romania
Russian Fed.
Tajikistan
Turkey
Turkmenistan
Ukraine
Uzbekistan
19
TB case notification rate in EUR
Annual TB cases per 100,000 pop.
90
80
295,240
70
East+ EUR
(18 countries)
60
50
354,954
40
All EUR
(53 countries)
30
373,497
20
54,231
10
European Union
(25 countries)
Year
0
80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04
Incidence of TB among TB-infected persons
HIV (+) vs HIV (-)
TB Infection
HIV (-)
5%
first 2 years
<10%
lifetime
World Health Organization
Incidence of TB among TB-infected persons
HIV (+) vs HIV (-)
TB Infection
HIV (-)
HIV (+)
3-13%
every year
>30%
lifetime
5%
first 2 years
<10%
lifetime
World Health Organization
Nairobi
600
0.15
500
400
6 yr
0.10
300
200
0.05
100
0
Williams B. 3rd Global TB/HIV
Working Group Meeting; Montreux,
1980
4-6 June 2003
0.00
1990
2000
HIV prevalence
TB notification/100k
700
(per 100K adults, 1999)
Estimated annual TB incidence
Estimated TB incidence vs. HIV prevalence
in high burden countries
1600
1200
800
400
HIV prevalence increases by 1%
TB incidence increases by 26/100k/yr
0
0.0
Williams B. 3rd Global TB/HIV
Working Group Meeting; Montreux,
4-6 June 2003
0.1
0.2
0.3
HIV prevalence, adults 15-49 years
0.4
Pattern of the anti-TB resistance
100%
80%
60%
40%
20%
0%
Estonia
Patients resistant to HR only
Latvia
Orel
Patients resistant to HRES
Peru
Philippines
Tomsk
Patients resistant to HRES and second-line drugs
XDR-TB – extensively and 'extreme'
drug resistant TB
XDR = MDR-TB plus resistance to any
fluoroquinolone, and to at least 1 of 3 injectable
second-line anti-TB drugs
(capreomycin, kanamicin, amikacin)
Of 17,690 isolates during 2000-2004
20% were MDR and 2% were XDR
XDR found in:
USA: 4% of MDR
Latvia: 19% of MDR
S Korea: 15% of MDR
XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)
1st-line agents
•INH
Injectable agents
•RIF
•SM
Fluoroquinolones
•KM
•Cipro
2nd-line Oral agents
•AMK
•Oflox
•ETA/PTA
•CM
•Levo
•PASA
•Moxi
•CYS
•PZA
•EMB
•Gati
"3rd-line" agents
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
Estimated MDR-TB incidence
More than 50 000 cases
From 10 000 to 50 000 cases
From 1 000 to 9 999 cases
From 100 to 999 cases
Less than 100 cases
Top 19 settings with MDR among new cases > 6%
(1994-2007)
Baku City, Azerbaijan
Republic of Moldova
Donetsk, Ukraine
Tom sk Oblast, Russian Federation
Tashkent, Uzbekistan
Kazakhstan*
Estonia
Mary El Oblast, Russian Federation
Ivanovo Oblast, Russian Federation*
Latvia
Liaoning Province, China
Lithuania
Arm enia
Orel Oblast, Russian Federation
Henan Province, China
Inner Mongolia Autonom ous Region, China
Indicates survey data reported
in an earlier phase of the project
Heilongjiang Province, China
Georgia
Dom inican Republic*
0.0
5.0
10.0
15.0
20.0
25.0
Countries with XDR-TB confirmed cases as of Dec 2008
Study 2: Italy, Germany, Estonia, Russia
(Archangels Obl)
4,346 C+
361 MDR
64 XDR
Italy: MDR 4.2%; XDR 0.4%
Germany: MDR 6.1%; XDR 0.4%
Estonia:
MDR 27.4%; XDR 5.9%
Russia:
MDR 7.3%; XDR 0%
3 Groups compared:
• XDR: 64 (48 with definite outcome)
• MDR “complicated” (res. to all 1st line drugs): 267 (187 with outcome)
• “Other” MDR (suscept. to at least 1 first-line drug): 94 (53 with outcome)
XDR: a death
sentence?
N° of
previous
TX
periods >
30 days
Hospital
Admission
(days)
Smear
conversion
(days)
Culture
conversion
(days)
SRHEZ;
FQ,AK,Cyc
220
Not
achieved
Not
achieved
Regular
TX°,
improved
73
SRHEZ;
FQ,Eth,Ak,PAS,Cyc
SRHEZ;
FQ,AK,Cyc
83
Not
achieved
Not
achieved
Died
16
3
SRHEZ;
FQ,Eth,AK,PAS,K,
Cyc,Clof
SRHZ;
FQ,Eth,K
406
300
300
Regular
TX°,
improved
10
Bilateral
cavities
4
SRHEZ;
FQ,PAS,Cyc
SRHZ;
FQ,Eth,AK,PAS
69
49
35
Regular
TX°,
improved
6
Italy
Bilateral
cavities
3
SRHEZ;
FQ,Eth,AK,PAS,C,
K,Cyc,Rb,Clof,Dap,
Cl,Th
SRHEZ;
FQ,Eth,AK,PAS,C,
K,Cyc,Rb,Clof
422
Not
achieved
Not
achieved
Died
94
38/F
Italy
Bilateral
cavities
3
SRHEZ;
FQ,Eth,PAS,C,Cyc
SRHEZ;
FQ,AK,PAS,Cyc
80
Not
achieved
Not
achieved
Died
12
7) It
49/F
Italy
Bilateral
cavities
3
SRHEZ;
FQ,Eth,AK,PAS,C,
K,Cyc,Rb,Clof,
Dap,Cl,Th
SRHEZ;
FQ,Eth,AK,PAS,C,
K,Cyc,Rb,Clof,
Dap,Cl,Th
625
Not
achieved
Not
achieved
Died
60
8) G
33/M
Uzbekistan
Monolateral
cavity
2
SRHEZ;
SRHEZ;
FQ,Eth,AK,C,Rb
120
Not
achieved
Not
achieved
Regular
TX°,
improved
4
9) G
29/M
Uzbekistan
Bilateral
cavities
2
SRHEZ;
Rb
SRHEZ;
FQ,C
240
180
160
Regular
TX°,
improved
12
10)G
52/M
Azerbaijan
Monolateral
cavity
Not available
SRHEZ;
FQ,AK,PAS,C,Cyc,
Rb
140
7
35
Regular
TX°,
improved
6
11) It
36/F
Romania
Bilateral
cavities
SRHEZ;
FQ,Eth,PAS,Cyc,Rb
RHZ;
FQ,AK,Rb
248
110
Not
achieved
Regular
TX°
28
Country of
birth
Radiology at XDR
diagnosis
Drug received during
previous TX periods
Country
Age/sex
1) It
40/M
Italy
Bilateral
cavities
3
SRHEZ;
Rb
2) It
61/F
Peru
Monolateral
cavity
1
3) It
27/F
Moldova
Monolateral
cavity
4) It
46/M
Senegal
5) It
43/F
6) It
>1
4
Drug resistance at XDR
diagnosis
Outcome
TX
duration
(months)
MDR-TB, susceptible at least one 1st drug
MDR-TB, resistant to all 1st line drugs
XDR-TB
Eur Respir J 2007
Prisons…
Migration
Poverty, malnutrition….
Congregate settings: homeless
shelter
The goals of TB control:
To reduce mortality, morbidity and
transmission of the disease, while prevention
drug resistance, until it no longer poses a
threat to public health
An Expanded DOTS Framework for Effective TB control. WHO/CDS/TB/2002.297
World Health Organization
Regional Office for Europe
TB control & elimination strategies
Control: to reduce the incidence of new TB infection
through rapid identification and effective treatment of
infectious cases (sources of infection)
Elimination: additional strategy aimed at reducing
the prevalence of latent TB infection by provision of
preventive therapy to persons at increased risk of
progression from latent infection to TB disease
World Health Organization
Regional Office for Europe
Principles of TB control:
1. Contagious persons must be detected and their
TB diagnosed, treated, and rendered noncontagious
2. Non-contagious persons must be prevented
from becoming contagious
3. Persons not infected must be prevented from
becoming infected
World Health Organization
Regional Office for Europe
R
TB elimination
Less than 1 smear positive case per
1 million population emerges
annually and /or the prevalence of TB
infection is below 1% and continues to
decrease
(K. Styblo, 1990)
World Health Organization
Regional Office for Europe
Full implementation of Global Plan: 2015 MDG
target reached but TB not eliminated by 2050
Propects for TB elimination by 2050
Incidence/100,000/yr
10000
1000
Projected incidence
100x bigger than
elimination target in
2050
100
10
Elimination 16%/yr
Elimination
target: 1 /
million / year
by 2050
Global Plan 6%/yr
Current trajectory 1%/yr
1
2000
2010
2020
2030
Year
2040
2050
Interventions over time: old weapons might be
useful again to manage XDR
First sanatorium
Germany, 1857
First Dispensary,
Scotland, 1897
BCG vaccination
Pneumotorax, Italy, 1907
Drugs, 1945-1962
Koch, Mtb,
1882
MMR,1950-1980
Fox:Ambulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
Outbreak Management,
sanatoria
Risk Group Management
screening
drug therapy
Socio-economic improvement
Carlo Forlanini,
first notes on
Pneumotorax
January 7th, 1907
The STOP TB Strategy – 2009
1.
Pursue high-quality DOTS expansion and enhancement
2.
Address TB-HIV, MDR-TB, and the needs of poor and vulnerable populations
3.
Contribute to health system strengthening based on primary health care
a.
b.
c.
d.
e.
a.
b.
c.
a.
b.
c.
d.
4.
Help improve health policies, human resource development, financing, supplies, service delivery and information
Strengthen infection control in health services, other congregate settings and households
Upgrade laboratory networks, and implement the Practical Approach to Lung Health (PAL)
Adapt successful approaches from other fields and sectors, and foster action on the social determinants of health
Involve all public, voluntary, corporate and private providers through Public-Private Mix (PPM) approaches
Promote use of the International Standards for TB Care (ISTC)
Empower people with TB, and communities through partnership
a.
b.
c.
6.
Scale-up collaborative TB/HIV activities
Scale-up prevention and management of multidrug-resistant TB (MDR-TB)
Address the needs of TB contacts, and of poor and vulnerable populations, including
women, children, prisoners, refugees, migrants and ethnic minorities
Engage all care providers
a.
b.
5.
Secure political commitment, with adequate and sustained financing
Ensure early case detection, and diagnosis through quality-assured bacteriology
Provide standardized treatment with supervision, and patient support
Ensure effective drug supply and management
Monitor and evaluate performance and impact
Pursue advocacy, communication and social mobilization
Foster community participation in TB care
Promote use of the Patients' Charter for TB Care
Enable and promote research
a.
b.
Conduct programme-based operational research, and introduce new tools into practice
Advocate for and participate in research to develop new diagnostics, drugs and vaccines
2006/rev. 2009
“Nobody wants me around..”
TB Control
Extensively drug resistant (XDR) - TB
MDR = Multi Drug Resistance
Resistance against at least INH and RMP
XDR = Extensively Drug Resistance
Resistance against at least INH and RMP (MDR-TB)
+ Fluoroquinolone (e.g. ofloxcin)
+ injectible drugs (e.g. capreomycin, amikacin)
Epidemiology
Complex Interactions: Treatment failure, Transmission
Relative Fitness of MDR strains,...
Efficient methods for strain typing
MDR TB in Germany
Beijing Genotype
MDR TB in Germany
Hospital transmission of MDR tuberculosis
patient
A
A
B
IS6110 fingerprint pattern
resistanc
e
susceptible
MDR
MDR
Patient A was reinfected with the MDR strain of
patient B during their stay at hospital
Niemann et al., JCM 1997
MDR TB in Germany
o
Transmission of drug-resistant strains could be shown and seem to
contribute to the problem of drug-resistant TB Germany
o
In most cases, drug-resistant M. tuberculosis strains seem to be as
infectious as drug-susceptible strains
o
Regular tuberculosis therapy is not sufficient to protect patients
against infection with a multidrug-resistant M. tuberculosis strain
o
Drug-resistant M. tuberculosis strains are presumably carried over
from the former SU to Germany
o
M. tuberculosis strains of the "Beijing Family" could be found in
Germany too, representing a rising proportion of all drug-resistant
TB cases in Germany
TSRU Meeting 1998, ESM Meeting 1998
MDR TB in Germany
1995-2005: 806 strains
1995
Beijing genotype 12 %
2005
Beijing genotype 68 %
Origin of Patients with Beijing strains
>70% of the patients with
Beijing strains had an
indication of foreign birth
These patients
were mainly
coming from
the former SU (Kazakhstan,
Georgia, Ukraine, etc.)
Resistant TB in Abkhazia
• “Chronic Conflict”
– War 1991-94
– Independent since 1994
– Blockade since 1994
• 150,000 citizens
• Prospective study
2003 – 2006
326 patients
Pardini et al. Tuberculosis 2009
Resistant TB in Abkhazia
Total tested
Fully sensitive
Any resistance
- Any H resistance
- Any R resistance
- Any E resistance
- Any S resistance
H and R resistance
- MDR
- H+R only
- H+R+S only
- H+R+E+S only
Number of resistant drugs
- 1 drug
- 2 drugs
- 3 drugs
- 4 drugs
New cases
No.
%
196
90
45.9
106
54.1
59
30.1
17
8.7
36
18.4
75
38.3
Previously treated cases
No.
%
127
40
31.5
87
68.5
74
58.3
51
40.2
50
39.4
67
52.8
Total
No.
%
326*
131
40.6
195
60.4
135
41.8
69
21.4
88
27.2
144
44.6
17
1
5
11
8.7
0.5
2.6
5.6
49
2
12
35
38.6
1.6
9.5
27.6
68
3
17
48
21.0
0.9
5.3
14.9
55
32
8
11
28.1
16.3
4.1
5.6
21
12
19
35
16.5
9.5
15.0
27.6
76
44
27
48
23.3
13.5
8.3
14.7
Resistant TB in Abkhazia
Second line resistance among MDR strains
No resistance to 2nd line drugs
Any resistance to 2nd line drugs
- Ethionamide
- Kanamycin
- Capreomycine
- Ofloxacin
> three 2nd line drugs
XDR strains**
New cases
N=17*
No.
%
11
64.7
6
35.3
5
7.1
3
4.3
0
0
0
0
0
0
0
0
Previously treated cases
N=49*
No.
%
16
32.6
33
67.3
20
60.6
18
54.5
3
9.1
3
9.1
2
6.1
3
9.1
Total
N=68
No.
29
39
25
21
3
3
2
3
%
42.6
57.3
36.8
30.9
4.4
4.4
2.9
4.4
Resistant TB in Abkhazia
Beijing genotype and
MDR-TB:
OR 20.9
(95% CI 10.5-41.7 ), p<0.001
Resistant TB in Abkhazia
MDR - strains
Cluster 5 variants
23 % of all MDR cases
Caused by one clone
(Cluster 5)
Highly resistant –
Super virulent phenotype
Resistant TB in the Aral Sea region
TB – incidence of more
than 100/100.000
High resistance rate
supposed
416 patients recruited
between July 2001
and March 2002
76% of eligible patients
in Dashoguz and 68%
in Karakalpakstan
2005
Resistant TB in the Aral Sea region
Karakalpakstan
50%
Dashoguz
40%
MDR-TB
40%
27%
30%
20%
10%
19%
13%
11%
4%
0%
New
Re-treatment
Total
Cox et al., EID, 2004
Resistant TB in the Aral Sea region
40% of all isolates in
clusters
50% of all isolates belong
to the Beijing genotype
55% of Beijing genotype
isolates in clusters
Cox et al. & Niemann, Resp Res, 2005
Resistant TB in the Aral Sea region
New (n=198)
Previously treated (n=184)
80
73
76
% of Beijing type strains
70
58
60
50
40
46
39
59
55
46
45
38
30
20
10
0
fully
susceptible
resistant to 1
drug
poly resistance
(not MDR-TB)
MDR-TB
Total
Cox et al. & Niemann, Resp Res, 2005
Treatment failure
Patient 1
Isolat
e1
Resistance
H, R
2
H, R, E, Z, P
Patient 2
Isolat
e1
Resistance
susc.
2
H, S
3
H, R, E, S
Cox H, et al. CID, 2007
Treatment failure
382 patients analyzed with DNA fingerprint
72 patients with follow up culture
10 had a different strain
62 had the same strain
Cox H, et al. CID, 2007
Treatment failure
11 (39%) of 28 polyresistant Beijing genotype strains amplified resistance
compared with none of the 27 non-Beijing polyresistant strains
Cox H, et al. CID, 2007
Resistant TB in the Aral Sea region
Cox et al. & Niemann NEJM 2008
Resistant TB in the Aral Sea region
Cox et al. & Niemann NEJM 2008
Summary
TB is back
MDR- and XDR-TB are a new challenge
Major driving force for the spread of MDR is
transmission
Exogenous reinfection even with XDR-TB
Beijing genotype strongly associated with
drug resistance/transmission
Clonal expansion of particular MDR strains
with super transmissible phenotype
Molecular mechanisms mainly unclear