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

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 , million -7,7%- (18%) million -7%- (12%) million -85%- (38%)

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

Very much related to HIV prevalence

Being resistance a growing issue.

Proportion MDR among new TB (2010) WHO REPORT 2011

Being resistance a growing issue.

… and not that far from Europe…

The evolution of TB in Barcelona 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/ Annual decline 10%

…Very much related to poverty…

WHY D O T S ??? BASES of TB Treatment Rifampicin Isoniazid Pyrazinamide Ethambutol Spontaneous mutation rate Bactericidal activity

1 st Rule: the need to avoid resistance

2 nd Rule: to treat all the different bacilli populations

The “SHORT-TERM” CHEMOTHERAPY Sputum culture negative Log Bacillary load (in logs) Time (in months) HRZM HR Replicating bacilli Non-replicating bacilli H= isoniazid; R= rifampicin; Z=pyrazinamide; M=ethambutol

The “SHORT-TERM” CHEMOTHERAPY can be even worse… AEMO EMO Replicating bacilli Non-replicating bacilli A= aminoglycoside; E= ethionamide; M=ethambutol; O=ofloxacine Log Bacillary load (in logs) Time (in months)

Nobody is perfect but Rifampicin and isoniazid…

Is “D O T S” enough?

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

The M. tuberculosis cycle Cardona et al. 2011

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

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

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.

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

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

1 mm Ø, d28 Marzo et al. Submitted

2 mm Ø, d30 Marzo et al. Submitted

8 mm Ø, d33 Marzo et al. Submitted

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

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

Tobin et al 2010

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

Berry et al 2010

THANK YOU !!!