Treatment of Multidrug-resistant and Extensively Drug-Resistant Tuberculosis - Prof. G.B. Migliori

TREATMENT OF MDR- AND XDR-TB
G. B. Migliori
WHO Collaborating Centre for TB and Lung Disease,
Fondazione S. Maugeri, Care and Research Institute
Tradate, Italy

5
1st-line
oral
•INH
•RIF
•PZA
•EMB
•(Rfb)
Injectables
•SM
•KM
•AMK
•CM
Fluoroquinolones
•Cipro
•Oflox
•Levo
•Moxi
•(Gati)
Oral bacteriostatic 2nd line
Unclear efficacy•ETA/PTA
•PASA
•CYS
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
linezolid, inmipenem/cilastatin,
high dose isonizid
XDR= HR + 1 FQ + 1 Injectable (AMK, CM or
KM)
XDR= extensively drug-resistant TB
GR 1
GR 2
GR 3
GR 4
GR 5

6
Expensive and
toxic drugs are
necessary

TREATMENT OUTCOMES BY MDR-TB PATIENT
GROUP
XDR TB
(n=405)
MDR-TB +FQr
(n = 426)
MDR-TB
+INJr
(n=1130)
MDR-TB,
susceptible to
FQ & Inj
(n=4763)
Total
Pooled Outcomes
(From study level meta-analysis)
Success 40% (27, 53) 48% (36, 60) 56% (45, 66) 64% (57, 72) 62% (54,69)
Failed/Relapse 22% (15, 28) 18% (14, 21) 12% (9, 15) 4% (2, 6) 7% (4, 9)
Died 15% (8, 23) 11% (3, 19) 8% (3, 14) 8% (5, 11) 9% (5, 12)
Defaulted 16% (8, 24) 12% (1,23) 16% (7, 24) 18% (12,24) 17% (11, 22)

Number
of drugs XDR MDR–TB+FQr MDR–TB+INJr MDR-TB, susceptible to FQ & Inj
N aOR (95%CI) N aOR (95%CI) N aOR (95%CI) N aOR (95%CI)
0 - 2
24
1.0 (reference)
10
1.0 (reference)
29 1.0 (reference) 45 1.0 (reference)
3 47 32 27 1.7 (0.5, 5.2) 62 1.1 (0.5, 2.3)
4 46 1.9 (0.8, 4.3) 49 1.6 (0.7, 3.8) 83 1.3 (0.5, 3.1) 165 1.9 (1.0, 3.7)
5 36 1.8 (0.5, 6.6) 35 1.4 (0.3, 6.4) 137 1.2 (0.4, 3.4) 296 1.7 (0.8, 3.8)
6+
20 4.9 (1.4, 16.6) 27 1.1 (0.4, 2.9) 120 1.3 (0.5, 3.3) 380 1.0 (0.5, 1.8)
Number
of drugs
XDR MDR–TB+FQr MDR–TB+INJr MDR, susceptible to FQ & Inj
0 - 2 27 1.0 (reference) 35 1.0 (reference) 46 1.0 (reference) 77 1.0 (reference)
3 32 3.3 (1.3, 8.5) 27 2.5 (0.8, 7.4) 33 12.2 (3.4, 44) 133 5.9 (3.1, 11.0)
4 28 6.1 (1.4, 26.3) 27 3.1 (0.5, 21.1) 101 3.7 (1.7, 8.2) 239 6.0 (2.8, 13.1)
5+ 17 2.3 (0.7, 7.6) 20 2.3 (0.7, 7.2) 100 3.1 (1.7, 6.0) 233 4.7 (2.7, 8.1)
Number of drugs likely to be effective used during the continuation phase
Odds of success (vs fail/relapse/death) by the number of effective drugs used
in treatment in the MDR-TB patient sub-groups
Number of drugs likely to be effective used during the intensive phase

ODDS OF SUCCESS (VS FAIL/RELAPSE) BY DURATION OF
TREATMENT IN THE MDR-TB PATIENT SUB-GROUPS
Duration of
intensive
phase
(months)
XDR MDR–TB+FQr MDR–TB+INJr
MDR-TB, susceptible to FQ
& Inj
1 - 4.0 55 1.0 (reference) 33 1.0 (reference) 99 1.0 (reference) 1924 1.0 (reference)
4.1 - 6.5 41 6.1 (0.6, 62) 41 0.9 (0.2, 4.5) 82 3.2 (0.8, 13.6) 274 2.8 (0.8, 9.7)
6.6 - 9.0 37 71.0 (5.2, 200) 36 0.6 (0.1, 4.1) 79 9.8 (1.9, 49) 244 3.1 (1.1, 8.3)
9.1 - 20.0 77 5.1 (1.2, 21) 55 0.4 (0.1, 2.0) 155 4.1 (1.5, 11.2) 347 2.1 (0.9, 5.1)
Total
duration of
treatment
(months)
XDR MDR–TB+FQr MDR–TB+INJr
MDR-TB, susceptible to FQ
& Inj
6.0 - 15.0 87 1.0 (reference) 54 1.0 (reference) 279 1.0 (reference) 443 1.0 (reference)
15.1 - 20.0 79 2.0 (0.3,11.7) 47 2.4 (0.4, 14.3) 260 3.1 (1.0, 9.1) 2171 3.6 (1.7, 7.9)
20.1 - 25.0 61 5.5 (1.7, 17.6) 60 2.1 (0.7, 6.5) 202 7.7 (3.8,15.7) 484 5.9 (3.0, 11.5)
25.1 - 30.0 21 5.8 (1.3, 25.1) 24 4.1 (0.9, 19.4) 65 6.0 (2.3,15.6) 147 2.8 (1.2, 6.9)
30.1 - 36.0 10 1.3 (0.2, 7.8) 13 1.1 (0.2, 5.2) 17 2.9 (0.7,12.2) 61 1.8 (0.6, 5.6)

12
Age/
sex
Country
of birth
prev
TX >
30
days
Drug received
during previous
TX periods
Drug resistance at
XDR diagnosis
Hospit
Admis
(days)
SS
conv
(days)
C conv
(days)
Out
come
TX
dur
(mo
43/F IT 3 SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof,Dap,Cl,Th
SRHEZ;
FQ,Eth,AK,PAS,C,K,
Cyc,Rb,Clof
422 No No Died
94
49/F IT 3 SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof, Dap,Cl,Th
SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof,Dap,Cl,Th
625 No No Died
60
First tuberculosis cases in Italy resistant to all tested drugs
GB Migliori (gbmigliori@fsm.it), G De Iaco, G Besozzi, R Centis, DM Cirillo
WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri,
Care and Research Institute, Tradate
Eurosurveillance 2007

13
Treatment outcome
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
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)

14
Changes to the recommendations on regimen composition between the
2008 and 2011 updates of WHO MDR-TB guidelines
2008 emergency update 2011 update
Include at least four anti-TB drugs with either
certain, or almost certain, effectiveness during the
intensive phase of Tx
Include at least 4 2nd -line anti-TB drugs likely to be
effective as well as Z during the intensive phase of Tx
Consider adding more drugs in patients with
extensive disease or uncertain effectiveness
No evidence found to support the use of > 4 2nd-line
anti-TB drugs in patients with extensive disease.
Increasing the number of 2nd -line drugs in a regimen
is permissible if the effectiveness of some of the drugs
is uncertain.
The regimen should include Z and/or E one FQ, one
parenteral agent and 2nd -line oral bacteriostatic anti-
TB drugs (no preference of oral bacteriostatic 2nd -
line anti-TB drug was made).
The regimen should include Z a FQ, a parenteral
agent, ethionamide (or prothionamide), and
cycloserine, or else PAS if cycloserine cannot be used.
E may be considered effective and included in the
regimen if DST shows susceptibility
E may be used but is not included among the drugs
making up the standard regimen.
Tx with Group 5 drugs is recommended only if
additional drugs are needed to bring the total to 4
Group 5 drugs may be used but are not included
among the drugs making up the standard regimen
Intensive phase min 6 months (min 4 months after C
conversion) for a total duration of min 18 months
after C conversion
Intensive phase min 8 months for a total duration>=20
months

15
LATVIA, SIDE EFFECTS - COHORT 2000
 86% pts with AE
 Median: 4 AE per person
 Most common AE
• Nausea 3.0%
• Vomiting 38.7%
• Abdominal pain 38.2%
• Dizziness 35.8%
• Hearing problems 28.4%
 61% changed or discontinued drugs
during treatment owing to AE
 2 pts stopped treatment due to AE
0
10
20
30
40
50
60
1-2
3-4
5-6
7-8
9-10
11-12
13-14
15-16
17-18
19-20
21-22
23-24
25-26
Months after treatment initiation
Numberofpatientsconverted
0
10
20
30
40
50
60
70
80
90
100
Cumulativepercent
Patients Cumulative percent

19
Building a regimen for XDR-TB

22
1966, the last anti-TB drug was discovered

23
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)

24
Bedaquiline
Delamanid
Pretomanid

DELAMANID
• 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
Skripconoka V, ERJ 201325
Delamanid added to a
background MDR-TB regimen
improves significantly SS-C
conversion at month 2 (45.4
vs 29.6%)

BEDAQUILINE (BQ) AND PRETOMANID (PA-824)
• 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
26
• 2b 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)
• EBA at 2 w: PA-824+moxi+Z better
than: bq, bq+Z, bq+PA-824
Comparable to WHO Cat 1

WHO RECOMMENDATIONS ON BQ AND DELAMANID
• 100 mg BD added
to OBR in adults
• Pharmacovigilance
• Informed consent
• Not aded to BQ
27
• 400 mg daily 2/12 200
mg 3/w 22 w added to
OBR in adults
• Pharmacovigilance
• Informed consent
• QT monitoring
1. Country prepardness & planning
2. National plan new tools
3. M&E (DRS & pharmacovigilance)
4. Private sector engaged
5. Uniterrupded supply
6. Operational research

MEROPENEM
29
Variables Total 37 Cases 61 Controls p-value
SS conv at 90 d, n (%)
37/48
(77.1)
28/32 (87.5) 9/16 (56.3) 0.02
C conv at 30 d, n (%)
24/66
(36.4)
12/37 (32.4) 12/29 (41.4) 0.45
37/62
(59.7)
24/37 (64.9) 13/25 (52.0) 0.31
46/61
(75.4)
31/37 (83.8) 15/24 (62.5) 0.06

30
Adverse events
0 0.2 0.4 0.6 0.8 1
Alffenaar JWC et al. [46] 0.00 (0.00 - 0.37)
AngerHA/CondosR et al. [34] 1.00 (0.78 - 1.00)
De Lorenzo S et al. [35] 0.67 (0.09 - 0.99)
FortunJ et al. [22] 1.00 (0.29 - 1.00)
Koh WJ et al. [45] 0.82 (0.48 - 0.98)
Migliori GB et al. [8] 1.00 (0.03 - 1.00)
Park IN et al. [44] 0.71 (0.29 - 0.96)
SchecterGF et al. [30] 0.22 (0.07 - 0.44)
Singla R et al. [31] 0.71 (0.42 - 0.92)
Udwadia ZF et al. [32] 1.00 (0.29 - 1.00)
VillarM et al. [33] 0.22 (0.03 - 0.60)
Von der Lippe B et al. [43] 0.80 (0.44 - 0.97)
Proportionof adverse events (95% CI)
Pooled Proportion = 0.59 (0.49 to 0.68)
Chi-square = 61.94; df = 11 (p = 0.0000)
Inconsistency (I2)= 82.2 %
Linezolid interruption due to adverse events
0 0.2 0.4 0.6 0.8 1
Alffenaar JWC et al. [46] 0.00 (0.00 - 0.37)
Anger HA/Condos R et al. [34] 0.87 (0.60 - 0.98)
FortunJ et al. [22] 1.00 (0.29 - 1.00)
Koh WJ et al. [45] 0.82 (0.48 - 0.98)
Migliori GB et al. [8] 1.00 (0.03 - 1.00)
ParkIN et al. [44] 0.40 (0.05 - 0.85)
Schecter GF et al. [30] 1.00 (0.03 - 1.00)
Singla R et al. [31] 1.00 (0.69 - 1.00)
Udwadia ZF et al. [32] 0.54 (0.25 - 0.81)
Villar M et al. [33] 1.00 (0.03 - 1.00)
Von der Lippe B et al. [43] 0.70 (0.35 - 0.93)
Proportion of linezolid interruption due to adverse events (95% CI)
Pooled Proportion = 0.69 (0.58 to 0.79)
Chi-square = 37.19; df = 10 (p = 0.0001)
Inconsistency (I2) = 73.1 %
AE in Linezolid- containing regimens. Sotgiu et al, ERJ 2012

Index case
FAMILY
Male, 12 years
Laryngeal + PTB
Long diagnostic delay
Direct Sputun examination +++
Resistant to SHREZ+FQ+Inj+Eto
Haarlem strain Mother, TST+, QF+
PTB, immigrant,
histopathology+,
CXR improved Cat 1
21 classmates tested:
1 monolateral pleurisy (immigrant)
10 TST+, QF+ (7 native, 3 immigrant)
2 dental hygienists tested:
2TST+, QF+
56 playmates tested:
3 TST+, QF-
(BCG vaccinated)
24 students tested in parallel class
performing common activities:
1 TST+, QF+
1TST+, QF-
57 students tested in other classes:
1TST+, QF+
13 TST+, QF-
TB disease TST+, QF+ TST+, QF -
18 school staff tested:
4TST+, QF+
5TST+, QF-
Sister 6 yrs, PTB
Brother 10 yrs, PTB
Father, TST-, QF-
19 school canteen staff
tested:
3 TST+, QF -
37 educators tested:
1 TST+, QF-
Summer camp circle
27 tested:
All TST-, QF-
Sport related circle
Catechism related circle
50 tested:
1 TST+, QF+
4 TST+, QF-
Other contacts

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

Conclusions
• EBA studies: do not allow to attribute
specific AE to a specific drug
• The regimen PA-824+moxi+Z ideally ok for
new & MDR-TB cases,well tolerated & does
not interfere with ARVs
• Delamanid, well tolerated, and promising
• New regimens to be built on new drugs’
potentialities
• New rules to use new drugs
• WHO recommendations to be followed in
developing regimens

40
“Nobody wants me
around..”

41
XDR and TB control burden: lower in the future ?

Treatment of Multidrug-resistant and Extensively Drug-Resistant Tuberculosis - Prof. G.B. Migliori

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