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

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

Mycobacterium tuberculosis is still the major killer of the humankind

PER YEAR! 2 million deaths10 million new TB cases

100 million new LTBI cases

Prevalence of LTBI Currey et al

2007

142.3 million -7,77,7%-(18%)

130.2 million -77%-(12%) 1583.4 million -

8585%-(38%)

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

Very much related to HIV prevalence

Being resistance a growing issue.

Being resistance a growing issue.

0-<3

3-<6

6-<12

12-<18

>18

No data available

Subnational data only

Proportion MDR among new TB (2010)Proportion MDR among new TB (2010)

WHO REPORT 2011WHO REPORT 2011

Being resistance a growing issue.

… and not that far from Europe…

… and not that far from Europe…

1313

27273333

5555 89 89

4339

3735

3230

2630

2831

2624

27

6768

6058

46

36

27

48

55566061

0

10

20

30

40

50

60

70

80

observed objective

The evolution of TB in Barcelona The evolution of TB in Barcelona 1986-20101986-2010

cases/100,000 inhab.cases/100,000 inhab.

TBTBProgram Program

foundedfounded

High incidenceHigh incidenceHIV-IDU associationHIV-IDU association

Prison inmatesPrison inmates

Lower incidence Lower incidence Less IDU among prison inmates.Less IDU among prison inmates.

HIV-infection treated with HAART HIV-infection treated with HAART

Increase in immigrationIncrease in immigration

7,1/1000007,1/100000

Annual decline 10%Annual decline 10%

…Very much related to poverty…

…Very much related to poverty…

…Very much related to poverty…

WHY D O T S ???BASES of TB Treatment

Rifampicin

Isoniazid

PyrazinamideEthambutol

Spontaneous mutation rate

Bactericidal activity

108

105

103

106

1001005-103-4

1st Rule: the need to avoid resistance

2nd Rule: to treat all the different bacilli populations

The “SHORT-TERM” CHEMOTHERAPY

Sputum culture negative

1

2

3

4

5

6

7

8

9

01 2 3 4 5 6

Log

Bacilla

ry load

(in

log

s)

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…

11

22

33

44

55

66

77

88

99

0011 33 55 77 99 1111 1313 1515 1717 1919 2121

AEMO

EMO

Replicating bacilli

Non-replicating bacilli

A= aminoglycoside; E= ethionamide; M=ethambutol; O=ofloxacine

Log

Bacilla

ry load

(in

log

s)

Time (in months)

Nobody is perfect but Rifampicin and isoniazid…

Is “D O T S” enough?

Is “D O T S” enough?

Is “D O T S” enough?

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)

Lo

g (

bac

illi/l

un

g)

Active TB

LTBI

The M. tuberculosis cycle

Cardona et al. 2011

IVb

I II

IV

V

VIVb III

PRESENCE OF NEW LESIONS ARE CONTROLLED THROUGH TIME TOWARDS A LOW RATE

CT

New lesions

Old lesions

weeks

No

of

les

ion

s

Gil et al. 2010

Risk of having active TB is higher soon after the infection…

BB

Acute Phase Chronic Phase

Chance to develop TB Chance to develop TB

pOpO2 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 mmMarzo et al. Submitted

Towards Active TB

0,5 mm Ø, d21Marzo et al. Submitted

Progression Towards Active

TB

1 mm Ø, d28Marzo et al. Submitted

2 mm Ø, d30Marzo et al. Submitted

8 mm Ø, d338 mm Ø, d33

Marzo et al. Submitted

The M. tuberculosis cycle: last sketch?Cardona PJ. 2012

… requiring a host’s hyper-reactivity from the beginning…

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…

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 !!!THANK YOU !!!