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

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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)

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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

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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

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A hot question…

Pag. 26

Carlo Forlanini,

first notes on

Pneumotorax

January 7th, 1907