TREATMENT OF MDR- AND XDR-TB

G. B. MiglioriWHO Collaborating Centre for TB and Lung Disease,Fondazione S. Maugeri, Care and Research InstituteTradate, Italy

Faculty disclosure

NO COI !!!

4

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

7

The challenge of MDR

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 - 224

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

N aOR (95%CI) N aOR (95%CI) N aOR (95%CI) N aOR (95%CI)

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+INJrMDR-TB, susceptible to FQ

& Inj

N aOR (95%CI) N aOR (95%CI) N aOR (95%CI) N aOR (95%CI)

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+INJrMDR-TB, susceptible to FQ

& Inj

N aOR (95%CI) N aOR (95%CI) N aOR (95%CI) N aOR (95%CI)

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

1-23-4

5-67-8

9-1011-12

13-14

15-16

17-18

19-20

21-22

23-24

25-26

Months after treatment initiation

Nu

mb

er

of

pa

tie

nts

co

nv

ert

ed

0

10

20

30

40

50

60

70

80

90

100

Cu

mu

lati

ve p

erc

en

t

Patients Cumulative percent

16

Designing an MDR-TB regimen

19

Building a regimen for XDR-TB

20

21

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

28

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

C conv at 60 d, n (%)37/62

(59.7)24/37 (64.9) 13/25 (52.0) 0.31

C conv at 90 d, n (%)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)Anger HA/Condos R 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)Schecter GF 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)Villar M et al. [33] 0.22 (0.03 - 0.60)Von der Lippe B et al. [43] 0.80 (0.44 - 0.97)

Proportion of 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)

Park IN 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

31

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 implementationo Expert opinion for compassionate useo Patient’s tracko LTBI management

• Next steps: « Drug-O-Gram » plug in

www.tbconsilium.org

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 ?