1. Will Personalized Medicine be the clue to eradicate TB?. Pere-Joan Cardona CONFER È NCIA DE L ’ EUROPAN PARLIAMENTARY TECHNOLOGY

2. Mycobacterium tuberculosis is still the major killer of the humankind PER YEAR! 2 million deaths 10 million new TB cases 100 million new LTBI cases Prevalence of LTBI Currey et al 2007 7,7 142.3 million -7,7%- (18%) 7 130.2 million -7%- (12%) 85 1583.4 million -85%- (38%)

3. Incidence of TB is still very high: about 10 milion/year

4. Very much related to HIV prevalence

5. Being resistance a growing issue.

6. Proportion MDR among new TB (2010) WHO REPORT 2011

7. Being resistance a growing issue.

8. … and not that far from Europe…

9. 13 27 27 33 55 89 89

10. The evolution of TB in Barcelona 1986-2010 cases/100,000 inhab. TB Program founded High incidence HIV-IDU association Prison inmates Lower incidence Less IDU among prison inmates. HIV-infection treated with HAART Increase in immigration 7,1/100000 Annual decline 10%

11. …Very much related to poverty…

15. WHY D O T S ??? BASES of TB Treatment Rifampicin Isoniazid Pyrazinamide Ethambutol Spontaneous mutation rate Bactericidal activity 10 8 10 5 10 3 10 6 100 5-10 3-4

16. 1 st Rule: the need to avoid resistance

17. 2 nd Rule: to treat all the different bacilli populations

18. The “SHORT-TERM” CHEMOTHERAPY Sputum culture negative 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 Log Bacillary load (in logs) Time (in months) HRZM HR Replicating bacilli Non-replicating bacilli H= isoniazid; R= rifampicin; Z=pyrazinamide; M=ethambutol

19. The “SHORT-TERM” CHEMOTHERAPY can be even worse… 1 2 3 4 5 6 7 8 9 0 1 3 5 7 9 11 13 15 17 19 21 AEMO EMO Replicating bacilli Non-replicating bacilli A= aminoglycoside; E= ethionamide; M=ethambutol; O=ofloxacine Log Bacillary load (in logs) Time (in months)

20. Nobody is perfect but Rifampicin and isoniazid…

21. Is “D O T S” enough?

25. Natural history of TB “Only” a 10% with LTBI will develop an active TB Primary TB Post primary TB Time (years) Log (bacilli/lung) Active TB LTBI

26. The M. tuberculosis cycle Cardona et al. 2011

27. PRESENCE OF NEW LESIONS ARE CONTROLLED THROUGH TIME TOWARDS A LOW RATE CT New lesions Old lesions weeks No of lesions Gil et al. 2010

28. Risk of having active TB is higher soon after the infection… B Acute Phase Chronic Phase Chance to develop TB

29. pO 2 ! % ?% ?% ?% ? Active disease in adults tends to focus in the upper lobes. This is because a high oxygen pressure and a lower capillary net that favors a delayed immune response.

30. 0,5 mm 20 mm Marzo et al. Submitted Towards Active TB

31. 0,5 mm Ø, d21 Marzo et al. Submitted Progression Towards Active TB

32. 1 mm Ø, d28 Marzo et al. Submitted

33. 2 mm Ø, d30 Marzo et al. Submitted

34. 8 mm Ø, d33 Marzo et al. Submitted

35. The M. tuberculosis cycle: last sketch? Cardona PJ. 2012 … requiring a host’s hyper-reactivity from the beginning…

36. The M. tuberculosis cycle: last sketch? Cardona PJ. 2012 The discovery of the host’s hyperreactivity will be the clue to identify the 5% of susceptible population…

37. Tobin et al 2010

38. The discovery of the host’s hyperreactivity will be the clue to identify the 5% of susceptible population… Tobin et al 2010

39. Berry et al 2010

40. THANK YOU !!!