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Global Epidemiology of TB. 1/3 of global population infected (246/ 100,000 p) 8.8 million new cases a year (141/ 100,000 pop) 2 million deaths a year – PowerPoint PPT presentation

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1
  • Thank you for viewing this presentation.
  • We would like to remind you that this material is
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    submitted by the author.
  • 2008 by the author

2
Resistance Pattern for Tuberculosis in
Europediagnostic aspects
Postgraduate course Update in tuberculosis
advances in the management of drug resistant and
MDR-TB cases ERS, Vienna 12/9/2009
  • Daniela M. Cirillo
  • San Raffaele Scientific Institute
  • Milan Italy

3
Global Epidemiology of TB
  • 1/3 of global population infected (246/ 100,000
    p)
  • gt 8.8 million new cases a year (141/ 100,000 pop)
  • gt 2 million deaths a year
  • gt 95 of cases and deaths occur in the developing
    world
  • 75 of cases in 15-54 age group
  • Devastating economic costs
  • gt 1/ million deaths due to TB/HIV
  • MDR ubiquitous

4
TBC good news, bad newsRio de Janeiro March
24th 09
  • Good news slow decrease of incidence from 2004.
  • Bad news
  • 1. TB incidence is decreasing too slowly. New
    strategies are needed
  • 2. 1/3rd of cases is not diagnosed by Countries
    implementing the Stop TB Strategy
  • 3. MDR-TB 500.000 cases over 9.3 millions for
    2007, 150.000 deaths over 1.7 millions. 50.000
    cases of XDR per year. (55 Countries have
    reported cases)
  • 4. TB/HIV 1.4 millios of cases of TB are
    associated to HIV causing half million of deaths
    (1.7 total for 2007).
  • 5. Need for speeding up the implementation of
    collaborative activities

5
Changing epidemiology of TB in Europe
  • the white plague starting with the industrial
    revolution
  • true epidemic in the 19th century
  • Controlled by improving living and nutritional
    condition of the population and availability of
    drugs after the 1950
  • Between1974 and 1990 notification rate declined
    of 5.4 per year inwestern Europe

6
Changing epidemiology of TB in Europe (2)
  • Factors reversing the trend
  • HIV pandemic
  • Increasing immigration from high burden Countries
  • Break down of health system in Some Eastern
    European Countries
  • new poverty related factors for marginalized
    population

7
TB burden, EUR, 2007
8
Rural/ Residential versus metropolitan areas
  • In Western Europe the incidence of tuberculosis
    is highly increased in Metropolitan settings

9
Global TB targets
  • Outcome targets (World Health Assembly, Stop TB
    Partnership)
  • Case detection gt70
  • Treatment success gt85
  • 2015 Impact targets (MDGs, StopTB Partnership)
  • Halt and reverse incidence of TB
  • Halve prevalence and mortality levels of 1990

10
The European Region wont meet the MDG targets
  • In 2007 reported case detection was 53
  • Treatment success rate among new TB cases
    reported as 73
  • Mortality rate of 1.1 (excluding HIV positive
    cases)

11
Outcomes for those patients not successfully
treated, by WHO region, 2005 cohort
DOTS
Non - DOTS
82
12
  • Point 5 comma II

13
  • Increase the infectious cases detection
  • Increase the number of culture confirmed cases
  • Detect MDR/XDRTB cases from samples
  • Perform a quality assured DST for all second and
    third line Tb drugs for the appropriate
    management of MDR/XDR TB cases

14
A unique, proprietary illumination system with
high power solid-state light sources (LEDs)
replacing Mercury and Xenon arc-lamps found in
traditional epifluorescence microscopy available
as add-on kit for existing microscopes.
15
  • Increase the infectious cases detection
  • Increase the number of culture confirmed cases
  • Detect MDR/XDRTB cases from samples
  • Perform a quality assured DST for all second and
    third line Tb drugs for the appropriate
    management of MDR/XDR TB cases

16
Culture services
  • Global effort to
  • Offer to each TB patient the access to culture
  • Rationalize the number of Culture services
  • Improve their quality trough standard SOPs QA
    programs
  • Upgrade the laboratories to liquid manual and
    liquid automated cultures systems
  • European standards on biosafety in place in all
    TB laboratories

International Standards of TB care empathize the
key role of MTB detection for diagnosis and
management
17
MDR-TB and XDR-TB Definitions
  • Polyresistance
  • strains of TB resistant to more than one anti-TB
    drug
  • MDR-TB is defined as resistance to isoniazid and
    rifampin
  • XDR-TB is defined as resistance to at least
    isoniazid and rifampin in addition to any
    fluoroquinolone and any of the three injectable
    anti-TB drugs
  • Amikacin
  • Capreomycin
  • Kanamycin

18
  • Increase the infectious cases detection
  • Increase the number of culture confirmed cases
  • Detect MDR/XDRTB cases from samples
  • Perform a quality assured DST for all second and
    third line Tb drugs for the appropriate
    management of MDR/XDR TB cases

19
Background on drug resistance in the MTB complex
  • Natural resistance to antibiotics
  • hydrophobic cell envelope (permeability barrier)
  • drug efflux systems and drug-modifying enzymes
  • Resistance is due to chromosomal point mutations
    leading to amino acid substitution
  • Mutations occur spontaneously with different
    frequency for different drugs
  • Resistance emergence is linked to a large
    bacterial population

19
19
20
Selection of drug-resistant mutants
  • Spontaneous mutations occur in the DNA of all
    cells
  • Mutations can change the structure of a protein
    that is a drug target.
  • Protein still functions, but is no longer
    inactivated by the drug.
  • TB can therefore grow in the presence of the
    drug.
  • Resistance is linked to large bacterial
    populations
  • Mutants resistant to any drug occur on average
    once in every 100 million (108) cells .
  • In TB in the lung, cavities often contain 107
    109 organisms.
  • By using two antibiotics, the chance of both
    targets mutating is extremely small (108 x 108
    1016).
  • Monotherapy led to selection of drug-resistant
    populations in cavitary disease more often than
    in cases with non-cavitary lesions (about 103104
    organisms).
  • This is the rationale for treatment regimens with
    more than one drug.

20
20
21
MDR-TB is spreading worldwide
  • The spread of drug-resistant M. tuberculosis
    strains compromises the positive clinical outcome
    and the efficiency of TB control programmes
  • MDR-TB outbreaks are associated with fatal
    outcome (90 in HIV pos.)
  • The treatment and the isolation of infected
    patients increase public health expenses
  • MDR-TB incidence is increasing in Eastern Europe
    (10 )
  • Developed by selective pressure caused by
  • Inadequate treatment
  • Low compliance
  • Intermittent therapy
  • OR
  • Primary infection by MDR strains

22
MDR-TB prevalence, EUR, 2007
Estimated, among new 10.35 (43
600) Estimated, among re-treatment
43,41 Notified, among new 9,59 (7
351) Notified, among re-treatment 38,55
Detection rate, new - 17
23
13 settings with gt30 resistance to any TB drug
among new cases 2002-2007
24
14 settings with 6 MDR-TB among new cases
2002-2007
25
16 settings with 25 MDR-TB among previously
treated cases 2002-2007
26
Countries with XDR-TB confirmed cases as of May
2008
Argentina
Italy
Armenia
Japan
Latvia
Azerbaijan
Australia
Lesotho
Bangladesh
Lithuania
Mexico
Botswana
The boundaries and names shown and the
designations used on this map do not imply the
expression of any opinion whatsoever on the part
of the WHO concerning the legal status of any
country, territory, city or area or of its
authorities, or concerning the delimitation of
its frontiers or boundaries. Dotted lines on
maps represent approximate border lines for which
there may not yet be full agreement. ? WHO 2005.
All rights reserved
Brazil
Moldova
Canada
Mozambique
Chile
Namibia
Russian Fed.
China, Hong Kong SAR
Czech Rep.
Netherlands
Ecuador
Slovenia
Nepal
South Africa
Norway
Estonia
Peru
Spain
France
Georgia
Philippines
Swaziland
Germany
Sweden
Poland
Portugal
Thailand
Ireland
Rep of Korea
UK
India
USA
Ukraine
Islamic Rep. of Iran
Romania
Israel
Vietnam
Based on information provided to WHO Stop TB
Department - May 2008
27
XDR-TB among MDR-TB cases 2002-2007
Sub-national averages applied to Russia
lt 3 or less than 3 cases in one
year of surveillance
3 - 10
gt 10
Report of at least one case
No data
The boundaries and names shown and the
designations used on this map do not imply the
expression of any opinion whatsoever on the part
of the World Health Organization concerning the
legal status of any country, territory, city or
area or of its authorities, or concerning the
delimitation of its frontiers or boundaries.
Dotted lines on maps represent approximate border
lines for which there may not yet be full
agreement. ? WHO 2006. All rights reserved
28
Extensively Drug-Resistant Tuberculosis Is Worse
than Multidrug-Resistant Tuberculosis Different
Methodology and Settings, Same ResultsGiovanni
Battista Migliori,Christoph Lange,Enrico
Girardi,Rosella Centis,Giorgio Besozzi,Kai
Kliiman,Johannes Ortmann,Alberto
Matteelli,Antonio Spanevello, and Daniela M.
Cirillo Clinical Infectious Diseases
200846958959
  • With the multiple regression analysis, the
    presence of XDR was an independent risk factor
    for both death (OR, 2.07 95 CI 1.054.05P V
    .034) and treatment failure (OR, 2.3795 CI,
    1.144.89 P V .02).
  • XDR TB has a negative clinical and prognostic
    significance, even in patients with different
    susceptibility profiles and from different
    setting (e.g., Korea and Eastern and Western
    Europe)

29
Priority Countries for MDR/XDR TB response
  • 18 Countries in the European Region mostly from
    the former Soviet Union
  • From some countries data are based on modeling
    programs
  • Big differences in the need to respond to MDR-XDR
    TB
  • Common the need to
  • Improve case detection
  • Address a quality assured prompt diagnosis of the
    resistance pattern of the strain

30
Molecular line probe assays for rapid screening
of patients at risk of MDR-TB
  • Policy statement by WHO and Partners
  • June 27, 2008

Endorsement of the two commercial line probe
assays for rifampicin resistance
detection Tests are CE marked and meet
predefined performance targets in controlled
evaluation studies Both tests are highly
sensitive and specific for rifampicin resistance
detection from TB strains
30
31
Commercial Line Probe Assays
Hain Lifescience
Innogenetics INNO-LiPA-Rif.TB
31
32
Comparison GenoType MTBDR and INNO-LiPA Rif.TB
GenoType MTBDR INNO-LiPA Rif.TB
Company Hain Lifescience Innogenetics
M. tuberculosis detection Yes Yes
Detection of RMP Resistance in M. tb Complex Yes Yes
Detection INH Resistance in M. tb Complex Yes No
Strip Assay Yes Yes
DNA-Basis PCR Yes Yes
Culture requested Yes Yes
Direct assay No Yes (modified version)
TB-complex Detection 23S-rRNA/16S-rRNA Yes Yes
RMP-Resistance rpoB gene Yes Yes
INH-Resistance katG gene/inhA gene Yes No
Universalcontrol Yes No
rpoB unicontrol Yes No
kat G unicontrol Yes No
33
GenoType MTBDRsl (Hain Lifescience)
33
34
The GenoType MTBDR platform
  • Targets the most common mutations conferring
    resistance to 1st and 2nd line drugs
  • Allows to meet MDR and XDR definition
  • Test is simple to be performed
  • Detects mixed infections
  • But ( areas for improvement)
  • DNA extraction needs to be improved
  • Not automated
  • Some possibility of misinterpretation (double
    patterns or faint bands)
  • Limited in the number of probes (absence on
    probes for NTMs)
  • P2 biosafety required
  • Possibility of cross contamination

35
Available from April 14th GeneXpert MTB
36
Sensitivity and Specificity
  • Sensitivity in smear negative, culture positive
    (S-C) was 90.9 (70/77)
  • Sensivity in smear positive, culture positive
    (SC). was 100 (275/275)
  • Specificity of the assay was 98.3
  • Sensitivity observed for Rifampicin resistance
    was 96.7
  • Specificity observed for Rifampicin resistance
    was 98.6

37
Xpert MTB/RIF kit
PAGE 37
38
Lab-On-Chip microfluidic technology
  • PCR
  • Ultra-Fast PCR ? 40C\s ? 10C\s 0.1C
  • PCR strategy Asymmetric Cy5-dCTP multiple
    incorporation
  • Microarray
  • Orientation probes Pre-labeled oligo capture
    probes to correctly align the grids onto the
    array during data analysis using MAT software
  • PCR Control probes un-labeled oligo capture
    probes that assure the correct functionality of
    the PCR module
  • Hybridization Control probes un-labeled oligo
    capture probes that assure the correct
    functionality of the microarray module (3
    different sequences at equal concentration the
    hybridization buffer carry out the complementary
    labeled targets at different concentrations)
  • Hybridization Negative Controls probes
    un-labeled oligo capture probes containing
    randomized sequence probes used to estimate the
    level of non-specific binding on the array

39
Wrong DSTs have huge impact at
  • Patient level
  • Community level
  • Health care costs
  • Leading to mismanagement of TB cases and
    increasing MDR

40
Global WHO/IUATLD/CDC Survey
  • Convenience sample (17,690 isolates) submitted to
    participating international SRL network,
    2000-2004
  • 3520 (20) of isolates MDR TB
  • 347 ( 2) of isolates XDR TB
  • XDRTB in all regions, more common FSU and Asia
    (Republic of Korea)
  • Denominator information unavailable

41
Patterns of Second-line Drug Resistance in MDR
Isolates by Geographic Region (N3,461)
Latin America 543 () N Amer 320 () UK / W Euro 451 () Russia / E Euro 406 () N Afr Mid E 95 () Asia 1,563 ()
AGCM AGFQ AG gt1 Group 4 CMFQ CM gt1 Group 4 FQ gt1 Group 4 drug AGCMFQ AGCM gt1 Group 4 AGCMFQ1 Grp 4 Any 3 SLD classes 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
42
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43
MOLECULAR TYPING and MDR-TB
  • Methods should be standardized and QA
  • MIRU 24 may replace IS6110 RLFP
  • Role in patient management ( failure/
    reinfection/ changing in sensitivity
    pattern/laboratory cross contamination)
  • Epidemiological studies
  • Monitoring recent transmission (contact tracing
    and contact management)

44
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47
Risk Factors for Clustering
  • 521 cases
  • 250 (48) belonged to European clusters
  • 271 (52) unique fingerprinting
  • Multivariate analysis
  • Association between origin from Baltic states or
    FSU countries and clustering
  • Clustering and Beijing genotype strongly
    associated
  • High proportion of MDR among clustered strains

Devaux et al. EID 2009
48
MDR/TB and HIV
  • Data are controversial
  • Data from 5 different countries on DR stratified
    by HIV status showed no association
  • Data from Latvia and Ukraine supported the
    association
  • Not clear if association is related to
    acquisition or transmission

49
MDR/TB and HIV
  • Existing evidences
  • Institutional outbreaks of MDR-TB have primarily
    affected HIV-infected persons.
  • Highly fatal MDR-TB appears not to cause
    infection or disease more readily than
    drug-susceptible TB in HIV-infected persons.
  • HIV infection may lead to malabsorption of
    anti-TB drugs and acquired rifamycin resistance.

50
Problems related to TB diagnosis in Europe
  • Inconsistent DOTS coverage
  • Concentration of TB cases among marginalized
    population
  • Western Europe decreased interest in TB among
    health professionals
  • Eastern Europe quality assurance of laboratory
    structure

51
Improving capacity to diagnose MDRTB and collect
quality data
  • Prompt access to diagnostic facilities
  • Quality assured laboratories
  • Implementation of liquid cultures
  • Implementation of molecular methods for MDR/XDR
    TB detection

52
Ongoing programs supporting the MDR-TB control in
Europe
  • WHO Euro support and technical assistance to Tb
    programs
  • ECDC
  • Molecular surveillance of MDR-TB and database
  • ERLN-TB network
  • Analysis of TB case management in the EU and
    EEA/EFTA countries with special focus on MDR/XDR
    TB
  • EU DG research (TBPANNET)

53
Conclusion
  • National and regional variation in DR TB
    (possible undereporting)
  • Absence of data on DR or questionable quality
  • FSU Countries are facing an MDRTB epidemic
  • Half of TB cases in FSU are resistant to at least
    one TB drug with the Baltic countries
    representing the best scenario for the region
  • XDR is emerging where 2nd line drugs are used
  • Data on XDR are mined by shortage in laboratory
    capacity
  • New methods for gathering resistance data are
    neded
  • Better understanding on the association between
    TB and HIV is needed
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