New perspectives in the treatment of MDR-

TB

G. B. Migliori, ERS Secretary General

WHO Collaborating Centre for TB and Lung Disease, Fondazione S. Maugeri, Care and Research Institute

Tradate, Italy

Introduction

AIMS: to discuss

The global MDR/XDR-TB threat

The (poor) outcomes of M/XDR-TB treatment

New drugs & new regimens with new insights

The ERS/WHO TB Consilium

WHO Global Report 2015

sont réduits sont réduits sont réduits sont réduits sont réduits

Proportion of MDR-TB among new cases

Number of MDR-TB cases estimated to occur among

notified P TB cases, 2014

10 areas with top % of MDR-TB among new and previously

treated cases

7

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

Eurosurveillance 2007

WHO Global Report 2015

1/3 MDR-TB cases diagnosed and 1/4 treated

Esposito S. et al, ERJ 2015

The face of TB in low incidence countries: micro-epidemics

Treatment

OC

T

NO

V

DE

C

JA

N

FE

B

MA

R

AP

R

MA

Y

JU

NE

JU

LY

AU

G

SE

PT

OC

T

NO

V

DE

C

JA

N

FE

B

MA

R

AP

R

MA

Y

JU

NE

JU

LY

AU

G

SE

PT

OC

T

NO

V

DELAMANID

ETHIONAMIDE

CLOFAZIMINE

AMIKACIN

MEROPENEM

PAS

LINEZOLID

CLARITHROMYCIN

TERIZIDON

AMOXI/CLAV

MOXIFLOXACIN

ISONIAZIDE

PYRAZINAMID

ETHAMBUTOL

2013 2014 2015

History of the large cohort

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

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)

Increased severity

14

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)

After > 40 yrs…

Bedaquiline and Delamanid

Approved in 2012 by FDA Approved in 2013 by EMA

Drug group Drug name Acronym

A. Fluoroquinolones Levofloxacin

Moxifloxacin

Gatifloxacin

Lfx

Mfx

Gfx

B. Second-line injectable agents Amikacin

Capreomycin

Kanamycin

(Streptomycin)¶

Am

Cm

Km

(S)

C. Other core second-line agents Ethionamide / Prothionamide

Cycloserine / Terizidone

Linezolid

Clofazimine

Eto / Pto

Cs / Trd

Lzd

Cfz

D. Add-on agents

(not part of the core MDR-TB

regimen)

D1 Pyrazinamide

Ethambutol

High-dose isoniazid

Z

E

Hh

D2 Bedaquiline

Delamanid

Bdq

Dlm

D3 p-aminosalicylic acid

Imipenem-cilastatin#

Meropenem#

Amoxicillin-clavulanate#

(Thioacetazone)**

PAS

Ipm

Mpm

Amx-Clv

(T)

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 2013

17

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

18

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)

• 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 added to BQ

19

• 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

20

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

TDM: is it the future of MDR-TB treatment?

Meropenem

22

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

New evidence on Carbapenems

International Carbapenems Study Group (ICSG)

Meropenem 96 cases (49.0% XDR) Imipenem 84 cases (67.9% XDR)

Setting 5 centres /15 countries, 4 continents

10 centros /15 countriess, 4 continents

Age/sex M 34±10.3 yr/56.3% (76.0% migr) 36±11.2 yr/60.7% (32.1% migr)

HIV+/ART 8 HIV+ (9%)/ 6 ART 2 HIV+ (2.4%) on ART

Previous Diagnosis Failure 79.0%; success 11.3% Failure 87.2%; success 1.3% P<0.05

Previous Tx Median 2 (IQR 1-4) Median 2 (IQR 1-3)

Resistant to Median 8 drugs (IQR 6-9) Median 8 drugs (IQR 7-8) P<0.05

Duration 85 d (IQR 49-156) 187 d (IQR 60-428)

SS neg 45 d (IQR 28-68) 30 d (IQR 30-60)

C neg 44 d (IQR 28-75) 60 d (IQR 30-90) P<0.05

Outcomes Success 57.3%; continue Tx 25.0%; died 11.4%; default 5.2%

Success 40.5%; continue Tx 27.3%; died 23.9%; adefault 7.1% P <0.0001

Interruptions AE Linezolid 17.1%; Meropenem 8.5%

Linezolid 22.5%;Imipenem 7.3%

New drugs 1 Delamanid, 9 BQ 0 Delamanid, 7 BQ

Ertapenem to treat M/XDR-TB

Tiberi S, et al. ERJ 2016 in press

Alsaad N et al, ERJ 2014

Co-trimoxazole to treat MDR-TB

Alsaad N et al, ERJ 2013

Median dose: 6.5 mg/kg BW OD for 381 days (IQR 129-465) 8/10 cured, 2 still on treatment 100% bacteriological conversion 2 G/I adverse events

30

Bangladesh regimen

Gati+clofa+EMB+Z for all 9 months

+

prothio+kana+HDH for the initial 4 months

IF DRUG RESISTANCE PREVALENCE IS LOW,

MAJORITY OF DRUGS LIKELY TO BE ACTIVE

IF DRUG RESISTANCE PREVALENCE IS HIGH,

MAJORITY OF DRUGS LIKELY TO BE INACTIVE

Bangladesh regimen

Gati+clofa+EMB+Z for all 9 months

+ prothio+kana+HDH for initial 4 months

Probability of DR in Former Soviet Union:

Fq: 30%; Clofa: ??; EMB: 65%; Z: 70%

Prothio: 45%; Kana: 45%; HDH: ??

Günter G et al, EID 2015 and IJTLD 2015

HDH works when we have inhA withut katG: 12,3% global average Seifert M y Catanzaro A, PLoS One 2015

Prevalence of resistance to the drugs composing the Bangladesh regimen (ERJ 2016)

Cohort FQ

(95% CI)

Clofa

(95% CI)

E

(95% CI)

Z

(95% CI)

Prothio

(95% CI)

Kana

(95% CI)

International

Carbapenems

Study Group

(ICSG)

137/336,

40.8%

(35.6-46.1)

-

232/339,

68.4%

(63.5-73.4)

195/300,

65.0%

(59.6-70.4)

174/314,

55.4%

(49.9-60.9)

100/225,

44.4%

(37.9-50.9)

ICSG Europe

91/283,

32.2%

(26.8-37.6)

-

195/284,

68.7%

(63.3-74.1)

165/255,

64.7%

(58.8-70.6)

150/279,

53.8%

(48.0-59.7)

64/172,

37.2%

(30.0-44.4)

ICSG S.

America

46/53,

86.8%

(77.7-95.9)

-

37/55,

67.3%

(54.9-79.7)

30/45, 66.7%

(52.9-80.5)

24/35,

68.6%

(53.2-84.0)

36/53,

67.9%

(55.3-80.5)

The cost (€) to treat TB and M/XDR is enormous: prevention is cost-effective

Cost per case Susceptible MDR-TB XDR-TB

Estonia* 2,615 15,344 15,344

France 5,691

Germany 7,7,51 55,003 188.466

UK 6,234 62,343

Netherlands 8,340 46,990 148,136

Italy 9,294

Finland 8,243

Spain 9,384

AVERAGE 7,848 54,779 168,310

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 (20’) and receive in suggestions (36 hrs) 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 platform managed by ERS in collaboration with WHO (MoU) and ECDC

Specialized team able to cover several perspectives: clinical (adults and children, surgical, radiological), public health, psychological, etc.

> 200 cases manged in 4 languages (ENG, SPA, PORT, RU)

www.tbconsilium.org

2014; Cited 29 times

[

First case of extensively drug-resistant

tuberculosis treated with both delamanid and

bedaquiline

Researchers have described the first case of

severe extensively drug-resistant tuberculosis

(XDR-TB) treated with both delamanid and

bedaquiline. The findings, published as a letter in

the European Respiratory Journal, reports the

rationale for prescribing both delamanid and

bedaquiline in an XDR-TB case and describes the

difficulties encountered in the early phase of

treatment.

Read the full study

Access the ERS/WHO TB Consilum

First case treated with DLM+BQ

Variable Details

Details India, 39 years, Female, 65 kg (at diagnosis: 31/08/2015)

Case category Retreatment case; 4 previous treatment rounds

Drugs administered in

previous anti-TB

treatments

Kanamycin 750 mg im (12 months)

Levofloxacin 1g, PAS 10 g, Cycloserine 750 mg, Ethionamide 750 mg,

Capreomycin 1g im (14months) High dose Isoniazid 900mg; Rifabutin 300mg;

Clofazimine 200mg; Clarythromycin 1g; Amoxicillin-clavulanate 625mg;

Terizidone 1g TDS; Imipenem 500mg iv TDS (12 months); Linezolid 600 mg

then 300mg

Previous outcome Cured (twice)

Bacteriology at baseline Sputum smear +; Culture +; Xpert + At Day 18: SS -; C: ongoing

Radiology Bilateral upper zones fibrocavitary lesions

Drug resistances Resistant to 12 drugs: H,R, Km,Amk,Cm,Mfx,Ofx,Eto, PAS,Lzd, HdH, High

dose Mfx

Susceptible to: Cfz

Last treatment regimen delamanid, bedaquiline, clofazimine (200 mg) and terizidone (1 g), all started on

25/2/2016; and meropenem 1g TDS plus amoxi/clav 1g/200mg TDS iv (started

28/2/2016) BQ stopped on 07/03/2016 restarted 12/03/2016

[

UPDATE ON THE CASE

Tadolini M et al. ERJ 2016, in press

New and Repurposed Drugs and Novel Regimens for Children and Adolescents

with Multidrug-Resistant Tuberculosis: Practice-Based Recommendations

Authors

Elizabeth P. Harausz1, Anthony Garcia-Prats2, James A. Seddon3, H. Simon Schaaf2, Anneke

Hesseling2, Jay Achar4, Jonathan Bernheimer5 , Andrea Cruz6, Lia D’Ambrosio7,8, Anne

Detjen9, Stephen Graham10, Jennifer Hughes5, Sylvie Jonckheree11 , Ben Marais12, Giovanni

Battista Migliori7, Lindsay McKenna13, Alena Skrahina14, Marina Tadolini15 Peyton

Wilson16, and Jennifer Furin17 on behalf of the Sentinel Project on Pediatric Drug-Resistant

Tuberculosis

Delamanid

Recommended dose:

>35kg: 100mg twice daily

20-34kg: 50 mg twice daily

<20kg: consult with exper

Duration: 24 weeks; longer duration could be considered on a case-by-case basis (no alternative drug option).

Indications for use: children > 6 years old and > 20kg

• Confirmed MDR-TB when a four drug-regimen plus pyrazinamide cannot be constructed due to resistance or significant

intolerance;

• Probable MDR-TB with a source case with known or suspected additional resistance to second-line agents;

• Confirmed or probable MDR-TB with a high risk of treatment failure.

Indications for use: children < 6 years old and < 20kg It is recommended that consultation with expert clinicians be sought prior to administering delamanid to children in this age range via

consultation with the European Respiratory Society0hosted TB Consilium (https://www.tbconsilium.org) or the Sentinel Project on Pediatric

Drug-Resistant TB (tbsentinelproject@gmail.com)

MINIMUM REQUIREMENTS COMBINED USED DLM+BQ – LANCET ID 2015

Requisite Comment

1 Clinical centre

qualified

The clinical centre is highly qualified in terms of clinical expertise,

number of cases managed and laboratory services. The eligibility

criteria for these centres should comply with national regulation, and,

ideally, to international ones to be developed

2 Informed consent The patient should sign it, as recommended by the World Health

Organization separately for delamanid5 and bedaquiline

3 Pharmaco-

vigilance

Pharmacivigilance to be seen as both a guarantee for the patient and

an additional source of information complementing existing trials

4 Expert opinion on

rational use of

drugs

The use of the drugs is considered rationale by an independent and

qualified body such as the ERS TB Consilium (available at:

www.tbconsilium.org in different languages and free of charge ). This

step is also an essential component of the Otsuka’s delamanid

compassionate use programme

Conclusions

• Although MDR cases are decreasing in Russia, Indian and China the burden is still important (FSU)

• Case-detection and treatment proportions still below targets • Outcomes still unsatisfactory • Two core new drugs and several repurposed ones • ERS and WHO have developed a platform (the ERS/WHO

Consilium) to support clinicians (in different languages) • New evidence supporting Delamanid in children • We have the possibility to further strengthen what done to

achieve together TB Elimination but much resources and commitment are necessary.

THANK YOU !