Bedaquiline: Practical use and interim results in France Dr Mathilde Jachym [email protected] 17 th of February 2015 - Yerevan New treatments and approaches

Bedaquiline: Practical use and interim results in France

Dr Mathilde [email protected]

17th of February 2015 - Yerevan

New treatments and approaches to TuberculosisTuberculosis Symposium – Eastern Europe and Central Asia

RA Ministry of Health and Médecins Sans Frontières

French epidemiological contextProtocols preliminary results 2006 - June 2014TMC : 35 first patientsTMC : resistance



Content

2012 : TB incidence (4975 cases /Year) 7,6 ‰ Incidence among :

Native 3,5‰ Foreign Born 35,3‰ Sub Saharan Africa origin 103, 4‰ Homeless 173,5‰



French epidemiological context

l MDR-TB in France 2006-2012

C Bernard, F Brossier, W Sougakoff, N Veziris, M Frechet-Jachym, N Metivier, A Renvoisé, J Robert, V Jarlier, on behalf of the MDR-TB Management group of the NRC : C Andrejak, E Cambau, K Chadelat, B Dautzenberg, B Henry, D Le Dû, L Raskine, B Rivoire, G Thouvenin. A surge of MDR and XDR tuberculosis in France among patients born in the Former Soviet Union. 2013. Eurosurveillance. 18(33), August 15, 2013



XDR -TB in France 2006-20012



years 2007 2008 2009 2010 2011 2012 2013

Nb of Patients NCR(Georgian)

35

(1)

44

(1)

49

(4)

40

(1)

64

(5)

93

(16)

83

(18)

Bligny's patients

15 (43 %)

22 (50%)

24 (49%)

24 (60%)

30 (47%)

42 (45%)

34 (41%)

Nb XDR Bligny

0 0 0 0 2 12 11

Management of MDR-TB in Bligny's Sanatorium

Group drugs molecular biology Test Phénotype Serum levels

Group 1 Isoniazide (H)Rifampicine (R)Pyrazinamide (Z)Ethambutol (E)Streptomycine (S)

inhA, katG rpoB pncAembB

Initial MBInitial MB

SequencingMTBDRsl

YesYes

Yes (+/-)YesYes

Yes Yes Yes Yes No

Group 2 Amikacine (Amk)Kanamycine (Kan)Capréomycine (Cap)

rrs MTBDRsl Yes (NCR)Yes (NCR) Yes (NCR)

Yes NoNo

Group 3 Fluoroquinolones gyrAgyrB

MTBDRslSequencing

Yes (NCR) Yes

Group 4 Ethionamide (Eto)

ProthionamideCyclosérine (Cs)PASTerizidone

inhAethA, ethR

XXX

Initial MBSequencing

Yes (NCR)

Yes (NCR)Yes (NCR)

No

NoYes No No

Group 5 Linézolide (Lzd)Clofazimine (Clf)Amox - Ac clav (AC)Pénème – Ac clavClarythromycineThioacétazone

XXXXXX

Yes (NCR)NoNoNoNoNo

Yes No Yes Yes No

newdrugs Bedaquiline -TMC207Delamanid PA824

XXX

Not validated NoNo

NoNoNo

Availability of molecular test and drugs in Francenon available available

Treatment Protocols All cases are reviewed at the clinical staff meetings of the National Reference

Laboratory (CNRMyRA Pitié Salpétrière)l

Treatment protocol is designed with the genetic markers of resistance and adjusted with the second line DST

Moxifloxacine : 400mg/d if sensitive, 800 mg/d if low level of resistance

Initial phaseMDR only : 2 LI stop 3 or 4 months after culture conversionXDR : 2LI duration minimum 8 months

Total durationMDR : 18 months AND 12 months minimum after culture conversionXDR : 24 months

Bdq is added to the regimen if resistance to Aminoglycoside and/or Fluoroquinolone or if intolerance to one of those drugs. It can be used for more than 6 months if less than 3 active drugs



172 patientsMale 69 %Mean Age : 33Native from :

Homeless 39 %

53 patients are treated with Bdq since March 2011.

MDR Bligny's cohort : 2006 - June 2014

eastern Europe

Subsaharan Africa

Asia

France

North Africa

Western Europe

America

0 5 10 15 20 25 30 35 40 45

41

24

14

10

8

2

1



Pulmonary :77%Bilateral : 74 %Cavity : 75%

Associated with extra pulmonary lesions : 20%Extra pulmonary only : 3%

XDR, 31

basic MDR, 100

MDR + FQ, 25

MDR+ 2LI, 16

Bdq N=53 (%)

Control N=119 (%)

Previous 2Lttt 30 (57)) 27 (23)

Eastern Europe Native 42 (79) 29 (24)

XDR 29 (55) 2 (2)

Median number of drug resistance

7 drugs 3 drugs

MDR Bligny's cohort : 2006- June 2014 characteristic of TB

Retrospective cohort studyMDR-TB patientsReceiving Bedaquiline (≥ 6 mois)Compassionate useJanuary 2010 - July 2013Evaluated at 6 months of treatment.

L Guglielmetti, D Le Dû, M Jachym, B Henry, D Martin, E Caumes, N Veziris, N Métivier, J Rober, MDR-TB Management Group of the French National Reference Center for Mycobacteria and the Physicians of the French MDR-TB Cohortt.Compassionate use of bedaquiline for the treatment of MDR- and XDR-tuberculosis: Interim analysis of a French cohort.Clin Infect Dis. 2015 Jan 15;60(2):188-94

Country of birth

Eastern Europe

Africa

Asia

France

27 (77.1)5 (14.3)2 (5.7)1 (2.9)

HIV – infected 0

HCV – infected 18 (51.4)

Alcohol addiction 7 (20)

Intravenous drug use 13 (37.4)

Previous TB treatment on admission None First-line drugs only Second-line drugs

11 (31.4)7 (20)

17 (48.6)

Bligny's experience : 35 first patients

S Ofl Mxf Emb Eti PZA Cs Kan Cap Amk PAS Lzd0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Strains : resistance to a median of 9 (5-12) drugs



Lzd PAS Im/AC Amk Cap Cs Mx Lvf Emb Z Etio Clf0

5

10

15

20

25

30

35

Mean companion drug : 4 (2-5)



Resistance pattern*

MDR (FQ-S and 2LI-S)

MDR (FQ-R and 2LI-S)

MDR (FQ-S and 2LI-R)

XDR

2 (5.7)

10 (28.6)

4 (11.4)

19 (54.3)

Patients with culture conversion

At 3 Months (N=29)

At 6 Months (N=29)

21 (72.4)

28 (96.6)

Patients with smear conversion

At 3 Months (N=29)

At 6 Months (N=29)

14 (48.3)

20 (69)

Time to culture conversion 85 (42 - 101)

Time to smear conversion 92 (28 - 191)

Kaplan-Meier analysis of time to smear (solid line) and culture (dashed line) conversion of patients with positive smear and culture exams at the beginning of treatment with Bedaquiline (N=29).Median time to conversion lines are shown for both smear (solid) and culture (dashed). Dots indicate censorin

Bedaquiline : 35 first patients



Variables independently associated with culture conversion :treatment with a fluoroquinolone (p=0.01)absence of lung cavities (p<0.001)absence of HCV infection (p=0.001).

Tolérance :7 (20%) experienced a ≥60 ms increase in QT

interval2 (6%) discontinuation : QTc increased.2 (6%) had severe liver enzymes elevation.1 (3%) death occurred during the study period

(unrelated to TB or anti-TB treatment)

Bedaquiline : 35 first patients



Surgical treatment 9 (25.7)

Adverse effects supposed to be due to companion drugsNausea, vomiting : 22Hearing loss : 13Hepatitis : 12 Peripheral neuropathy : 6Arthralgia : 4Low platelet count : 4Anemia : 3

OutcomeBedaquiline ttt completed : 15 patientsMedian duration 189 daysBedaquiline ttt still underway : 20 patients Median duration 242 days



33 years old man, addiction, HCV• 2012 : First second line treatment in Georgia (Z, Cap Mxf, Eto, PAS, CS, Amox/AC, Bdq) • Poor adherence• DST in France sensitive to PAS, Lzd• Localised lesions upper right lobe but refuses

surgery• Treatment : Delamanid, PAS, Lzd, Cfz, T/AC

Suspicion of Bedaquiline resistance



PAC Adverse effect due to behavior





Thanks : Sanatorium's team : D. Le Dû, B. Lemaire,

D.Marigot Outtandy, D. Szmigiel

NRC : N Veziris, J Robert, C Bernard, L Guglielmetti

MDR-TB Management Group of the French National Reference

Center for Mycobacteria Physicians of the French MDR-TB Cohort.

Documents

Bedaquiline: Practical use and interim results in France Dr Mathilde Jachym [email protected] 17 th of February 2015 - Yerevan New treatments and approaches