1. XDR TUBERCULOSIS IN EUROPE EPIDEMIOLOGICAL ASPECTS
Enrico Girardi
Unità di Epidemiologia Clinica
INMI Spallanzani, Roma

2. TB estimated incidence in EUR, 2004
TB cases (all) per 100,000 pop.
< 10
10-24
25-74
75-124
TB estimated incidence in Europe, 2004
Russian Fed. 12th among the 22 TB high-burden countries
Source: WHO. WHO report 2006: global tuberculosis control; surveillance, planning, financing. Geneva: WHO (WHO/HTM/TB/ )

3. WHO European Region (EUR)
53 countries
18 high priority countries for TB
1. Armenia
2. Azerbaijan
3. Belarus
4. Bulgaria
5. Estonia
6. Georgia
7. Kazakhstan
8. Kyrgyzstan
9. Latvia
10. Lithuania
11. Moldova
12. Romania
13. Russian Fed.
14. Tajikistan
15. Turkey
16. Turkmenistan
17. Ukraine
18. Uzbekistan
25 EU countries

4. TB case notification rate in EUR, 1980-04
Annual TB cases per 100,000 pop.
295,240
East+ EUR
(18 countries)
354,954
All EUR
(53 countries)
373,497
54,231
European Union
(25 countries)
Year

5. MDR-TB prevalence (%) in new cases, 1994-2003
14.2
Kazakhstan
14.2
Israel
13.7
Russia (Tomsk)
13.2
Uzbekistan
12.2
Estonia
10.4
China (Liaoning)
9.4
Lithuania
9.3
Latvia
9.0
Russia (Ivanovo)
7.8
China (Henan)
6.6
Dominican Rep
5.3
Ivory Coast
5.0
Iran
4.9
Ecuador

6. Pattern of the anti-TB resistance

7. The recent MMWR report on emergence of Extensively drug resistant tuberculosis further emphasizes and alerts us to the need for working collboratively to investigate and controlling TB outbreaks

8. Classification of drugs into 5 groups based on hierarchy of efficacy and safety including 2nd-line drugs (guidelines)
1st-line agents
Injectable agents
INH
RIF
PZA
EMB
Fluoroquinolones SM KM
AMK CM
2nd-line Oral agents
Cipro
Oflox
Levo
Moxi
Gati
"3rd-line" agents
ETA/PTA
PASA
CYS
Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine,

9. XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)
1st-line agents
Injectable agents
INH
RIF
PZA
EMB
Fluoroquinolones SM KM
AMK CM
2nd-line Oral agents
Cipro
Oflox
Levo
Moxi
Gati
"3rd-line" agents
ETA/PTA
PASA
CYS
Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine,

10. (capreomycin, kanamicin, amikacin)
XDR = MDR-TB plus resistance to any fluoroquinolone, and to at least 1 of 3 injectable second-line anti-TB drugs
(capreomycin, kanamicin, amikacin)

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

12. What is not known on XDR?
Is the risk of death/ probability of success different from 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 different from HR?

13. Italy-Germany study Migliori 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).

14. Italy-Germany study Findings -1
2,888 C+ TB
126 (4.4%) MDR
11 (0.4%) XDR

15. Italy-Germany study Findings-2: XDR vs MDR
Death rate: 36.4 % vs 6.3%
RR death 5.45 (95% CI ; 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).

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)

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)

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)

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

20. 4-Countries study Findings 3: XDR vs MDR
> 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

21. 4-Countries study Findings - 5: XDR vs ‘complicated’ MDR vs MDR Outcomes
Success %
Died %
Default %
Failure
Transferred %
XDR-TB 56
39,3
25,0
14,3
21,4
0,0
“Complicated” MDR-TB
229
53,7
15,3
17,0
12,7
1,3
“Other”
MDR-TB 63
66,7
15,9
4,8
TOTAL
348
16,4
12,6
0,9

22. 4-Countries study Findings 6: XDR vs ‘complicated’ MDR vs MDR Time to treatment success
cMDR
MDR

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

24. What needs to be done to face the XDR-TB Threat
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 to reduce 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 survey drug resistance.
Commence rapid survey so that the size of the XDR-TB epidemic can be determined
World Health Organization

25. A hot question…

26. Carlo Forlanini,
first notes on Pneumotorax
January 7th, 1907