Tuberculosis: the many faces of an old
witch
G. B. Migliori
WHO Collaborating Centre for TB and Lung Disease,
Fondazione S. Maugeri, Care and Research Institute
Tradate, Italy
Introduction
AIMS: to describe
• The present of TB epidemiology
• TB control and Elimination
• Diagnosis of TB and LTBI
• Treatment
• ERS and TB Elimination
TB Elimination: from Wolfheze to Rome
Wolfheze, May 1990
THANK
Rome 4-5 July 2014
prev
TX >
30
days
Drug received
during previous
TX periods
Age/
sex
Country
of birth
43/F
IT
3
SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof,Dap,Cl,Th
49/F
IT
3
SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof, Dap,Cl,Th
Hospit
Admis
(days)
SS
conv
(days)
C conv
(days)
SRHEZ;
FQ,Eth,AK,PAS,C,K,
Cyc,Rb,Clof
422
No
No
Died
94
SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof,Dap,Cl,Th
625
No
No
Died
60
Drug resistance at
XDR diagnosis
TX
dur
(mo
Out
come
First tuberculosis cases in Italy resistant to all tested drugs
Eurosurveillance 2007
6
The case of
Mumbai and the
“TDR-TB
outbreak”
Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant
tuberculosis in India. Clin Infect Dis. 2012 Feb 15;54(4):579–81.
Resistance to fluoroquinolones and second-line injectable drugs: impact on MDR-TB outcomes. Eur Respir J. 2012 Oct 25; doi:
10.1183/09031936.00134712
Treatment success among different MDR-TB patient groups
XDR alone
XDR+2sli
XDR+sliG4†
XDR+sliG4EZ
n = 301
n = 68
n = 48
n =42
Cured
43 (27, 58)
30 (17, 43)
34 (-, -)
19 (0, 48)*
Failed
20 (15, 25)
29 (8, 50)
33 (-, -)
26 (14, 38)
Died
13 (6, 20)
18 (7, 29)
30 (18, 41)*
35 (21, 50)*
Failed or died
35 (26, 45)
54 (40, 69)*
48 (-, -)
49 (37, 61)
Defaulted
15 (5, 24)
15 (3, 27)
18 (-, -)
19 (6, 32)
XDR-alone
XDR+2sli
XDR+sliG4
XDR+sliG4EZ
n = 301
n = 68
n = 48
n =42
Cured
1.0 (reference)
0.4 (0.2, 0.8)
0.6 (0.2, 1.6)
0.5 (0.2, 1.7)
Failed
1.0 (reference)
2.1 (1.0, 4.5)
1.8 (0.7, 4.7)
1.9 (0.7, 5.3)
Died
1.0 (reference)
1.6 (0.6, 4.4)
1.7 (0.6, 4.9)
1.8 (0.6, 5.3)
Failed or Died
1.0 (reference)
2.6 (1.2, 4.4)
2.6 (1.1, 6.7)
2.8 (1.0, 7.9)
Defaulted
1.0 (reference)
1.0 (0.3, 2.6)
0.5 (0.2, 1.8)
0.5 (0.1, 2.0)
Treatment outcome
Treatment outcome
10
Epidemiological characteristics
High incidence






Generalised (with social gradient)
Important community transmission
Many incident cases from recent transmission
Relatively high burden among young people
Dominant public health problem
Poorly resourced health systems
Low incidence







Highly concentrated to risk groups
Close to elimination in large parts of the population
Low transmission
Outbreaks in special groups
LTBI relatively more important
Migration impact
Stronger health system but less TB visibility
Sotgiu et al, NEJM 2013
Interventions to prevent and manage TB
First sanatorium
Germany, 1857 First Dispensary,
Scotland, 1897
BCG vaccination
Pneumotorax, Italy, 1907
Drugs, 19451945-1962
Koch, Mtb,
1882
MMR,1950MMR,1950-1980
Fox:Ambulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
Outbreak Management,
sanatoria
Risk Group Management
screening
drug therapy
TB Elimination
SocioSocio-economic improvement
13
Stop TB Strategy
DOTS Strategy
1.
Pursue high-quality DOTS expansion and
enhancement
•
Government commitment
•
•
Case detection by SS microscopy
among self-reporting symptomatic
patients
•
•
Standardised short-course
chemotherapy for at least all confirmed
smear positive cases, DOT during the
intensive phase for all new SS+ cases,
continuation phase of RMP-containing
regimens and the whole re-treatment
regimen.
•
A regular, uninterrupted supply of all
essential anti-TB drugs
•
A standardised R&R system allowing
assessment of case-finding and
treatment results and of NTP
performances
Int J Tuberc Lung Dis 2001;
•
•
•
Political commitment with increased
and sustained financing
Case detection through quality-assured
bacteriology
Standardised treatment, with
supervision and patient support
An effective drug supply and
management system
Monitoring & evaluation system, and
impact measurement
2
Address TB/HIV, MDR-TB and other
challenges
3.
Contribute to health system strengthening
4.
Engage all care providers
5.
Empower people with TB and communities
6.
Enable and promote research
Lancet 2007
14
World Health Assembly approves Post-2015 Global TB Strategy
and Targets – WHA TB Resolution
Vision
A WORLD FREE OF TB
ZERO
TB DEATHS
GLOBAL TB
PROGRAMME
ZERO
TB CASES
ZERO
TB SUFFERING
Goal and Targets
GOAL: End the Global TB Epidemic
2035
Target 1
95% reduction in
TB deaths (compared
with 2015)
GLOBAL TB
PROGRAMME
Target 2
<10/100 000
TB incidence rate
Incidence decline: technological breakthrough by 2025
addressing the pool of latent infection
-2%/year
Business as usual
Average -10%/year
Optimize current tools,
ensure Universal Health
Coverage and Social
Protection
New tools: vaccine, prophylaxis
-5%/year
Average -17%/year
GLOBAL TB
PROGRAMME
Post-2015 Global TB Strategy: Pillars
Targets
<1 case per million
<10 cases per million
<100 cases per million
Pre-elimination: 2035
Current TB burden-2012
in low-incidence countries
in low-incidence countries
Elimination: 2050
Projected incidence rates in low-incidence countries in 2035
considering a decline of 90% between 2015 and 2035.
Pre-elimination
Elimination
TB Elimination is possible: the case of Cyprus (ERJ 2014)
1 Case
per million
7 Core areas:
1.
2.
3.
4.
5.
6.
7.
TB control commitment, TB
awareness, and capacity of
health systems
Surveillance
Laboratory services
Prompt, quality TB care for all
M/XDR-TB and TB/HIV coinfection
New tools
Partnership and collaboration
Europe how far to reach elimination?
10 (33%)
7 (23%)
15 (50%)
10 (33%)
16 (53%)
11 (37%)
25 (87%)
5 (17%)
4 (13%)
20 (67%)
10 (33%)
10 (33%)
13 (43%)
21 (70%)
21 (70%)
10 (33%)
EU LOW / MIDDLE TB INCIDENCE COUNTRIES
No TB Elimination plan
No TB elimination guideline
No HRD plan
No TB Reference centres
No TB budget
No supervision
No modelling
No NRL performing all F/SLD DST
No free access for all TB cases
No all F/SLD
Drugs stock-outs
No TB/HIV collab. activities
Hospital-based MDR-TB care
No strategy to introduce new tools
No international collaboration for TB
control/elimination
No TB Consilium
ITALY
NO
NO
NO
YES
NO
NO
NO
YES
YES
NO
NO
NO
YES
NO
NO
NO
What is in the pipelines for new diagnostics,
drugs and vaccines in 2013?
Diagnostics:
₋7 new diagnostics or diagnostic methods
endorsed by WHO since 2007;
₋6 in development;
₋yet no PoC test envisaged
Drugs:
-2 new drugs approved in 2012 & 2013 for
MDR-TB : little impact on epidemiology;
-a regimen and other 2-3 drugs likely to be
introduced in the next 4-7 years
Vaccines:
₋11 vaccines in advanced phases of
₋development;
₋1 reported in 2012 with no detectable
efficacy
Genes involved in drug-resistance for major
anti-tubercular drugs
Drug
Gene
Streptom yci n
rpsL
M utati ons
12 S ribo somal pro t ein
Codin g regio n (6 0 %)
16 S rRNA
Reg. 5 3 0 an d reg. 9 1 5 (8%)
katG
Cat alase-p ero x idase
co din g regio n (co d. 3 1 5 - 6 0 -8 0 %)
inhA
NADH-dep en o y l-A CP red
p ro mo t er reg. (Ribo some bin ding sit e - 1 5 %); codin g regio n
ndh
NADH deh y dro gen ase
co din g regio n
rrs
I soni az i d
Gene product
ahpC-OxyR
regulo n (co n t rols
katG an d sev eral ot h er gen es)
p ro mo t er region (mut at ion s relat iv ely rare)
Ri fam pi n
rpoB
RNA p ol (_ subun it )
h ot sp ot regio n (co d. fro m 5 0 8 t o 5 35 - 9 8 %); N-t erm region
Etham butol
embB
Arabino syl t ransferase
ERD R (cod. 30 6 - 7 0 %)
embC
Arabino syl t ransferase
co din g regio n
inhA
NADH-dep en o y l-A CP red
p ro mo t er reg. (Ribo some bin ding sit e); co din g regio n
ethA
M o n oo x y gen ase
co din g regio n
ethR
M o n oo x y gen ase rep ressor
co din g regio n
ndh
NADH deh y dro gen ase
co din g regio n
Pyraz i nam i de
pncA
Py razin amidase
co din g regio n (7 0 %)
Fl uoroqui nol ones
gyrA
DNA gyrase (sub. A)
QRDR (7 0 %)
gyrB
DNA gyrase (sub. B)
QRDR
rpoB
RNA p ol (_ subun it )
co din g regio n
16 S rRNA
co din g regio n
rRNA met h y lt ran sferase
co din g regio n
Ethi onam i de
Ri fabuti n
Capreom yci n
rrs
tlyA
V i om yci n
rrs
16 S rRNA
co din g regio n
Kanam yci n
rrs
16 S rRNA
co din g regio n
Am i kaci n
rrs
16 S rRNA
co din g regio n
D-Cycl oseri ne
alr
D-Ala racemase
p ro mo t er region
T hy midy lat e syn t h ase
co din g regio n
Para-sal i cyl i c aci d
thyA
27
Commercial Line Probe Assays
Hain Lifescience
Innogenetics
INNO-LiPA-Rif.TB
28
Genes involved in drug-resistance for major
anti-tubercular drugs
Drug
Gene
Streptom yci n
rpsL
M utati ons
12 S ribo somal pro t ein
Codin g regio n (6 0 %)
16 S rRNA
Reg. 5 3 0 an d reg. 9 1 5 (8%)
katG
Cat alase-p ero x idase
co din g regio n (co d. 3 1 5 - 6 0 -8 0 %)
inhA
NADH-dep en o y l-A CP red
p ro mo t er reg. (Ribo some bin ding sit e - 1 5 %); codin g regio n
ndh
NADH deh y dro gen ase
co din g regio n
rrs
I soni az i d
Gene product
ahpC-OxyR
regulo n (co n t rols
katG an d sev eral ot h er gen es)
p ro mo t er region (mut at ion s relat iv ely rare)
Ri fam pi n
rpoB
RNA p ol (_ subun it )
h ot sp ot regio n (co d. fro m 5 0 8 t o 5 35 - 9 8 %); N-t erm region
Etham butol
embB
Arabino syl t ransferase
ERD R (cod. 30 6 - 7 0 %)
embC
Arabino syl t ransferase
co din g regio n
inhA
NADH-dep en o y l-A CP red
p ro mo t er reg. (Ribo some bin ding sit e); co din g regio n
ethA
M o n oo x y gen ase
co din g regio n
ethR
M o n oo x y gen ase rep ressor
co din g regio n
ndh
NADH deh y dro gen ase
co din g regio n
Pyraz i nam i de
pncA
Py razin amidase
co din g regio n (7 0 %)
Fl uoroqui nol ones
gyrA
DNA gyrase (sub. A)
QRDR (7 0 %)
gyrB
DNA gyrase (sub. B)
QRDR
rpoB
RNA p ol (_ subun it )
co din g regio n
16 S rRNA
co din g regio n
rRNA met h y lt ran sferase
co din g regio n
Ethi onam i de
Ri fabuti n
Capreom yci n
rrs
tlyA
V i om yci n
rrs
16 S rRNA
co din g regio n
Kanam yci n
rrs
16 S rRNA
co din g regio n
Am i kaci n
rrs
16 S rRNA
co din g regio n
D-Cycl oseri ne
alr
D-Ala racemase
p ro mo t er region
T hy midy lat e syn t h ase
co din g regio n
Para-sal i cyl i c aci d
thyA
29
40-80%
Procedure for the Xpert MTB/RIF test
Boehme CC et al. N Engl J Med 2010;363:1005-1015.
Reference Lab
Surveillance
Regional Lab
Faster than solid
culture
LJ- 40 days
MGIT
15 days
LPA
1 day
< 2 hours
In-house DST
(MODS, NRA, CRI)
Peripheral Lab
More sensitive than
microscopy
Smear
LED +10%
sensitivity
Xpert +40%
sensitivity
Clinic / Health Post
Simpler than
microscopy
Xpert MTB/RIF
can be placed at
all levels of the
network if basic
conditions for
electricity,
placement and
biosafety
measures
similar to smear
microscopy can
be assured, and
machine
throughput
utilized
effectively
Symptoms
Placement of Xpert MTB/RIF in a laboratory network
IGRAs
antigens/
peptides
APC
IGRA
IFN- release assay
T cell
cytokine
induction
Skin test
PPD (= tuberculin)
cytokine
induction
ELISA
cytokine
induction
ELISPOT assay
QuantiFERON TB gold
T.SPOT.TB
ESAT-6, CFP-10, Tb7.7
ESAT-6, CFP-10
Evolution of LTBI testing.
New IGRA as an opportunity to advance TB Prevention
IGRA represented a key advancement compared with TST but still lacking predictivity,
ability to distinguish various phases of TB infection and disease, impaired sensitivity in
CD4 depleted individuals.
New IGRA on the market (QuantiFERON-PLUS), built on innovative combined CD4 and CD8
response technology
Achieving:
Higher sensitivity at >95%
Highest specificity of any test for TB infection
Potential research into distinguishing TB infection spectrum
Title, Location, Date
34
1966, the last anti-TB drug was discovered
After 40 yrs, 2 new drugs approved by
the American Food and Drug
Administration (FDA) and/or the
European Medicine Agency (EMA)
35
Bedaquiline
Pretomanid
Delamanid
36
Delamanid
•
Delamanid added to a
background MDR-TB regimen
improves significantly SS-C
conversion at month 2 (45.4 vs
29.6%)
•
•
Favourable outcomes in 143/192 pts (74.5%)
receiving delamanid ≥6 months, compared to
126/229 patients (55.0%) receiving delamanid ≤2
months.
Mortality reduced to 1.0% among those receiving
long-term delamanid, VS short-term/no delamanid
(8.3%), p<0.001.
Treatment benefit also among XDR-TB pts
37 Skripconoka V, ERJ 2013
Bedaquiline (Bq) and Pretomanid (PA-824)
• EBA at 2 w: PA-824+moxi+Z better
than: bq, bq+Z, bq+PA-824 Comparable
to WHO Cat 1
•
•
• IIb trial, BQ + background regimen VS placebo,
reduced median time to C conversion,(125 to 83
days) and increased C conversion at 24 weeks
(79% VS. 58%) and at 120 weeks (62% vs. 44%).
Cure rates at 120 weeks were 58% VS 32%
Similar incidence AE (10 deaths BQ gr)
•
New phase IIb trial comparing bactericidal
activity of 8-week regimens: moxifloxacin
+ pretomanid (100 mg or 200 mg,
according to the arm), + Z vs standard
anti-TB regimen to treat sputum SS + pts
with DS and DR-TB.
Bactericidal activity higher vs current
WHO-recommended regimen in both DS
and DR-TB after 2 months of TX.
Experimental treatment well tolerated (no
episode of QT interval exceeding 500
msec identified )
Lancet 2014, in press
38
WHO recommendations on Bq and Delamanid
• 400 mg daily 2/12 200
mg 3/w 22 w added to
OBR in adults
• Pharmacovigilance
• Informed consent
• QT monitoring
1.
2.
3.
4.
5.
6.
Country prepardness & planning
National plan new tools
M&E (DRS & pharmacovigilance)
Private sector engaged
Uniterrupded supply
Operational research
•
•
•
•
100 mg BD added
to OBR in adults
Pharmacovigilance
Informed consent
Not added to BQ
39
Meropenem
Variables
SS conv at 90 d, n (%)
C conv at 30 d, n (%)
C conv at 60 d, n (%)
C conv at 90 d, n (%)
Total
37/48
(77.1)
24/66
(36.4)
37/62
(59.7)
46/61
(75.4)
37 Cases
28/32 (87.5)
61 Controls p-value
9/16 (56.3)
0.02
12/37 (32.4) 12/29 (41.4)
0.45
24/37 (64.9) 13/25 (52.0)
0.31
31/37 (83.8) 15/24 (62.5)
0.06
40
Proportion of adverse events (95% CI)
Alffenaar JWC et al. [46]
Anger HA/Condos R et al. [34]
De Lorenzo S et al. [35]
FortunJ et al. [22]
Koh WJ et al. [45]
Migliori GB et al. [8]
Park IN et al. [44]
Schecter GF et al. [30]
Singla R et al. [31]
Udwadia ZF et al. [32]
Villar M et al. [33]
Von der Lippe B et al. [43]
0
0.2
0.4
0.6
Adverse events
0.8
0.00
1.00
0.67
1.00
0.82
1.00
0.71
0.22
0.71
1.00
0.22
0.80
(0.00 - 0.37)
(0.78 - 1.00)
(0.09 - 0.99)
(0.29 - 1.00)
(0.48 - 0.98)
(0.03 - 1.00)
(0.29 - 0.96)
(0.07 - 0.44)
(0.42 - 0.92)
(0.29 - 1.00)
(0.03 - 0.60)
(0.44 - 0.97)
Pooled Proportion = 0.59 (0.49 to 0.68)
Chi-square = 61.94; df = 11 (p = 0.0000)
1 Inconsistency (I 2 ) = 82.2 %
Proportion of linezolid interruption due to adverse events (95% CI)
Alffenaar JWC et al. [46]
Anger HA/Condos R et al. [34]
FortunJ et al. [22]
Koh WJ et al. [45]
Migliori GB et al. [8]
Park IN et al. [44]
Schecter GF et al. [30]
Singla R et al. [31]
Udwadia ZF et al. [32]
Villar M et al. [33]
Von der Lippe B et al. [43]
0
0.2
0.4
0.6
0.8
Linezolid interruption due to adverse events
AE in Linezolid- containing regimens. Sotgiu et al, ERJ 2012
0.00
0.87
1.00
0.82
1.00
0.40
1.00
1.00
0.54
1.00
0.70
(0.00 - 0.37)
(0.60 - 0.98)
(0.29 - 1.00)
(0.48 - 0.98)
(0.03 - 1.00)
(0.05 - 0.85)
(0.03 - 1.00)
(0.69 - 1.00)
(0.25 - 0.81)
(0.03 - 1.00)
(0.35 - 0.93)
Pooled Proportion = 0.69 (0.58 to 0.79)
Chi-square = 37.19; df = 10 (p = 0.0001)
1 Inconsistency (I2) = 73.1 %
41
Introduction
AIMS: to describe
• The present of TB epidemiology
• 20 years of control leading to the concept of
TB Elimination
• 20 years of diagnosis of TB and LTBI
• 20 years of treatment
• ERS and TB Elimination
F. Blasi
Presidential
plan
ESTC
(EU Standards for
TB Care)
Treating M/XDR-TB is difficult
www.tbconsilium.org
ERS/WHO Consilium for M/XDR-TB
 Objectives:
 To allow a European clinician, free cost,
to load patient’s data and receive in 1
working day suggestions by 2 experts on
how to manage a difficult-to treat TB
case
 To support follow-up of TB patients
travelling within Europe
 Web-based regional platform
 Specialized team able to cover several
perspectives:(clinical for both adults and
children, surgical, radiological, public
health, psychological, nursing, etc.
 Managed by ERS, in collaboration with
WHO Europe (formal agreement) and ECDC
The web platform:
www.tbconsilium.org
• Now in ENG. RUS, SPA, PORT (FREN)
• Hosted in Switzerland (-> Swiss regulation)
• 4 processes supported + 2 in preparation:
o “Consilium” (get experts advice on cases in24-36 hrs)
o Trans border cases (send a case to a National TB Project
Representative)
o M&E of guidelines implementation
o Expert opinion for compassionate use
o Patient’s track
o LTBI management
• Next steps: « Drug-O-Gram » plug in
www.tbconsilium.org
ERS RA
ERS Conference, Munich,
September 2014: the launch
Conclusions
• Many changes over the last 20 yrs
• Potentially brillant diagnostics, we need to use
properly
• Still waiting for the vaccine
• 2 new drugs: the challenge is not to loose them and to
understand which regimens they can boost
• Ambitious strategy, whose results will rely on
consistent international funding and commitment
THANK
YOU !