xdr tuberculosis in europe epidemiological … meeting 24 may 2007/xdr-tb... · xdr tuberculosis in...
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Pag. 1
XDR TUBERCULOSIS IN EUROPE
EPIDEMIOLOGICAL ASPECTS
Enrico Girardi
Unità di Epidemiologia Clinica
INMI Spallanzani, Roma
Pag. 2
TB estimated incidence in EUR,
2004
TB cases (all) per 100,000 pop.
< 10
10-24
25-74
75-124
125-177
Source: WHO. WHO report 2006: global tuberculosis control; surveillance, planning, financing. Geneva: WHO
(WHO/HTM/TB/2006.362)
Russian Fed. 12th among the 22
TB high-burden countries
Pag. 3
3
WHO European Region (EUR)
25 EU countries
53 countries
18 high priority countries for TB 10. Lithuania
11. Moldova
12. Romania
13. Russian Fed.
14. Tajikistan
15. Turkey
16. Turkmenistan
17. Ukraine
18. Uzbekistan
1. Armenia
2. Azerbaijan
3. Belarus
4. Bulgaria
5. Estonia
6. Georgia
7. Kazakhstan
8. Kyrgyzstan
9. Latvia
Pag. 4
TB case notification rate in EUR, 1980-04
295,240East+ EUR
(18 countries)
354,954All EUR
(53 countries)
54,231European Union
(25 countries)
Annual TB cases per 100,000 pop.
Year0
10
20
30
40
50
60
70
80
90
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
373,497
Pag. 5
MDR-TB prevalence (%) in new cases, 1994-2003
Estonia
Russia (Ivanovo)
Latvia
China (Henan)
China (Liaoning)
Dominican Rep
Russia (Tomsk)
Israel
Ivory Coast
Ecuador
Kazakhstan
Uzbekistan
Lithuania
Iran
4.9
7.8
10.4
12.2
5.0
14.2
5.3
14.2
9.3
9.4
9.0
13.7
13.2
6.6
Pag. 6
0%
20%
40%
60%
80%
100%
Estonia Latvia Orel Peru Philippines Tomsk
Patients resistant to HR only Patients resistant to HRES Patients resistant to HRES and second-line drugs
Pattern of the anti-TB resistance
Pag. 7
Pag. 8
1st-line agents
•INH
•RIF
•PZA
•EMB
Injectable agents
•SM
•KM
•AMK
•CM
Fluoroquinolones
•Cipro
•Oflox
•Levo
•Moxi
•Gati
2nd-line Oral agents
"3rd-line" agents•ETA/PTA
•PASA
•CYS
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
Classification of drugs into 5 groups based on Classification of drugs into 5 groups based on
hierarchy of efficacy and safety including 2ndhierarchy of efficacy and safety including 2nd--
line drugs (guidelines)line drugs (guidelines)
Pag. 9
1st-line agents
•INH
•RIF
•PZA
•EMB
Injectable agents
•SM
•KM
•AMK
•CM
Fluoroquinolones
•Cipro
•Oflox
•Levo
•Moxi
•Gati
2nd-line Oral agents
"3rd-line" agents•ETA/PTA
•PASA
•CYS
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)
Pag. 10
XDR = MDR-TB plus resistance to any
fluoroquinolone, and to at least 1 of 3
injectable second-line anti-TB drugs
(capreomycin, kanamicin, amikacin)
Pag. 11
What is known
• Operational definition, proposed without solid
evidence
• SRLs’ survey on XDR-TB isolates (“ a
posteriori”, no outcomes)
• Anecdotal description of virtually untreatable TB
patients
Pag. 12
What is not known on XDR?
• Is the risk of death/ probability of success differentfrom that of MDR?
• Are their clinical characteristics different? in HIV-negative patients?
• Is their infectiousness different?
• Has the XDR definition a clinical relevance? Which is the role of susceptibility to first-line drugs differentfrom HR?
Pag. 13
Italy-Germany studyMigliori GB, Ortmann J, Girardi E et al Emerg Inf Dis 2007
• Clinical records were reviewed in TB clinical reference
centers (Italy: Sondalo, Milan, Rome; Germany: Borstel,
Grosshansdorf, Bad-Lippspringe).
• Drug susceptibility testing (DST) for first- and second-line
anti-TB drugs was performed according to WHO
recommendations by quality assured laboratories and
retested at WHO’s Supranational Reference Laboratories
(Rome/Milan; Borstel).
• XDR-TB was defined as resistance to at least rifampin and
isoniazid (MDR-TB definition), in addition to any
fluoroquinolone, and at least one of the three injectable anti-
TB drugs (capreomycin, kanamycin, amikacin).
Pag. 14
Italy-Germany study
Findings -1
• 2,888 C+ TB
• 126 (4.4%) MDR
• 11 (0.4%) XDR
Pag. 15
Italy-Germany study
Findings-2: XDR vs MDR
• Death rate: 36.4 % vs 6.3%
• RR death 5.45 (95% CI 2.04-16.04;
P<0.01)
• > resistance to all first-line drugs (72.7%
vs. 28.6%, P<0.005)
• > previous anti-TB treatment (100% vs.
58.7%, P<0.01)
• > older than 45 yrs (63.6% vs 23%,
P<0.01).
Pag. 16
Italy-Germany study
Findings-3: XDR vs MDR
• Longer hospitalization (241.2±177.0 vs. 99.1±85.9 days; P<0.001)
• Longer treatment duration (30.3±29.4 vs. 15.0±23.8 months; P<0.05)
• Bacteriological conversion in 4/11 XDR- vs. 102/126 MDR-TB cases (median: smear: 110 vs. 41 days; culture: 97.5 vs. 58 days; P <0.01)
Pag. 17
4 – Countries study
Italy, Germany, Estonia, Russia
• Data from all culture confirmed TB cases diagnosed
consecutively by the TB clinical reference centers in
Italy (Sondalo, Milan, Rome), Germany (Borstel,
Grosshansdorf, Bad-Lippspringe), Estonia (Tallin,
Tartu) and Russia (Archangels Oblast) were analyzed.
• 3 groups compared:
• XDR:
• “complicated” MDR (resistant to all 1st-line drugs
• “Other” MDR (susceptble to at least one 1st-line drug)
Pag. 18
4 - Countries study
Findings 1
4,583 C+ Italy: MDR 4.2%; XDR 0.4%
361 MDR Germany: MDR 6.1%; XDR 0.4%
64 XDR Estonia: MDR 27.4%; XDR 5.9%
Russia: MDR 5.2%; XDR 0%
Groups compared:
• XDR: 64 (48 with final outcome)
• “complicated” MDR: 267 (187 final outcome)
• “Other” MDR: 94 (53 final out)
Pag. 19
4-Countries study
Findings 2
XDR: none resistant to H,R, FQ, Injectable only,
vast majority resistant to all first-line drugs
• 90.6% resistant to HRES (± Z), 9.4%
susceptible to at least one 1st-line drug
MDR: majority resistant to all first-line drugs
• 74% HRES (± Z)
• 14.1% HRS
• 5.3% HRE
• 6.6% HR
Pag. 20
4-Countries study
Findings 3: XDR vs MDR
XDR:
• > retreatment (75 vs 49.3%, P<0.001)
• > resistance to all first-line drugs (P<0.005)
• RR 1.58 of worse outcome than “complicated”
MDR (P<0.05) and 2.61 than “other” MDR
(P<0.01)
“Complicated” MDR worse than “other” MDR
Pag. 21
4-Countries study
Findings - 5: XDR vs ‘complicated’ MDR vs MDR
Outcomes
0,912,616,416,453,7348TOTAL
0,04,815,912,766,763“Other”
MDR-TB
1,312,717,015,353,7229“Complicated”
MDR-TB
0,021,414,325,039,356XDR-TB
Transferred
%
Failure
%
Default
%
Died
%
Success
%
n
Pag. 22
4-Countries study
Findings 6: XDR vs ‘complicated’ MDR vs MDR
Time to treatment success
XDR
cMDR
MDR
Pag. 23
Summary of findings
Study 1 (Italy- Germany)
• XDR: higher risk of death than MDR (5.5)
• longer Tx, hospital admission and infectiousness
Study 2 (4-countries)
• XDR: worse outcomes than “complicated” and
“other” MDR (“continuum” of severity)
• “simple” XDR cases: do not exist
• XDR definition: has clinical and operational value
Pag. 24
What needs to be done to face the XDRWhat needs to be done to face the XDR--TB TB
ThreatThreat
World Health OrganizationWorld Health Organization
• Accelerate access to rapid tests for rifampicin resistance
• Ensure adherence to WHO drug resistance guidelines, improve .. access to MDR-TB drugs under proper conditions…
• Ensure all patients with HIV are adequately treated for TB and started on antiretroviral therapy
• Accelerate implementation of infection control measures toreduce transmission especially among those HIV positive
• Initiate information-sharing strategies that promote prevention, treatment and control of XDR-TB
• Strengthen laboratory capacity to diagnose, manage and surveydrug resistance.
• Commence rapid survey so that the size of the XDR-TB epidemiccan be determined
Pag. 25
A hot question…
Pag. 26
Carlo Forlanini,
first notes on
Pneumotorax
January 7th, 1907
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