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

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

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

3 WHO European Region (EUR) 53 countries 25 EU 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 3 Pag. 3

4 TB case notification rate in EUR, Annual TB cases per 100,000 pop ,497 0 Year ,240 East+ EUR (18 countries) 354,954 All EUR (53 countries) 54,231 European Union (25 countries) Pag. 4

5 MDR-TB prevalence (%) in new cases, Kazakhstan Israel Russia (Tomsk) Uzbekistan Estonia China (Liaoning) Lithuania Latvia Russia (Ivanovo) China (Henan) Dominican Rep Ivory Coast Iran Ecuador Pag. 5

6 Pattern of the anti-tb resistance 100% 80% 60% 40% 20% 0% Estonia Latvia Orel Peru Philippines Tomsk Patients resistant to HR only Patients resistant to HRES Patients resistant to HRES and second-line drugs Pag. 6

7 Pag. 7

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

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

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. 10

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. 11

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 HIVnegative 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? Pag. 12

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). Pag. 13

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

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). Pag. 15

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. 16

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. 17

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. 18

19 4-Countries study Findings 2 XDR: none resistant to H,R, FQ, Injectableonly, 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. 19

20 XDR: 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 Pag. 20

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

22 4-Countries study Findings 6: XDR vs complicated MDR vs MDR Time to treatment success XDR cmdr MDR Pag. 22

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. 23

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 Pag. 24

25 Pag. 25 A hot question

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