Bedaquiline: Practical use and interim results in France Dr Mathilde Jachym 17 th of February Yerevan New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

French epidemiological context Protocols preliminary results June 2014 TMC : 35 first patients TMC : resistance New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières Content

2012 : TB incidence (4975 cases /Year) 7,6 ‰ Incidence among : Native 3,5‰ Foreign Born 35,3‰ Sub Saharan Africa origin 103, 4‰ Homeless173,5‰ New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières French epidemiological context

l MDR-TB in France 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 Eurosurveillance. 18(33), August 15, 2013 New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

XDR -TB in France New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

years 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 Management of MDR-TB in Bligny's Sanatorium

Groupdrugsmolecular biologyTestPhénotypeSerum levels Group 1Isoniazide (H) Rifampicine (R) Pyrazinamide (Z) Ethambutol (E) Streptomycine (S) inhA, katG rpoB pncA embB Initial MB Sequencing MTBDRsl Yes Yes (+/-) Yes No Group 2Amikacine (Amk) Kanamycine (Kan) Capréomycine (Cap) rrsMTBDRslYes (NCR) Yes No Group 3FluoroquinolonesgyrA gyrB MTBDRsl Sequencing Yes (NCR)Yes Group 4Ethionamide (Eto) Prothionamide Cyclosérine (Cs) PAS Terizidone inhA ethA, ethR X Initial MB Sequencing Yes (NCR) No Yes No Group 5Linézolide (Lzd) Clofazimine (Clf) Amox - Ac clav (AC) Pénème – Ac clav Clarythromycine Thioacétazone XXXXXXXXXXXX Yes (NCR) No Yes No Yes No newdrugsBedaquiline -TMC207 Delamanid PA824 XXXXXX Not validated No Availability of molecular test and drugs in France non 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 phase MDR only : 2 LI stop 3 or 4 months after culture conversion XDR : 2LI duration minimum 8 months Total duration MDR : 18 months AND 12 months minimum after culture conversion XDR : 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 New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

172 patients Male 69 % Mean Age : 33 Native from : Homeless 39 % 53 patients are treated with Bdq since March MDR Bligny's cohort : June 2014 New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

Pulmonary :77% Bilateral : 74 % Cavity : 75% Associated with extra pulmonary lesions : 20% Extra pulmonary only : 3% Bdq N=53 (%) Control N=119 (%) Previous 2Lttt30 (57))27 (23) Eastern Europe Native42 (79)29 (24) XDR29 (55)2 (2) Median number of drug resistance 7 drugs3 drugs MDR Bligny's cohort : June 2014 characteristic of TB

Retrospective cohort study MDR-TB patients Receiving Bedaquiline (≥ 6 mois) Compassionate use January July 2013 Evaluated 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 Jan 15;60(2): Country of birth Eastern Europe Africa Asia France 27 (77.1) 5 (14.3) 2 (5.7) 1 (2.9) HIV – infected0 HCV – infected18 (51.4) Alcohol addiction7 (20) Intravenous drug use13 (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

Strains : resistance to a median of 9 (5-12) drugs New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

Mean companion drug : 4 (2-5) New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

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 conversion85 ( ) Time to smear conversion92 ( ) 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 New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

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 interval 2 (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 New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

Surgical treatment 9 (25.7) Adverse effects supposed to be due to companion drugs Nausea, vomiting : 22 Hearing loss : 13 Hepatitis : 12 Peripheral neuropathy : 6 Arthralgia : 4 Low platelet count : 4 Anemia : 3 Outcome Bedaquiline ttt completed : 15 patients Median duration 189 days Bedaquiline ttt still underway : 20 patients Median duration 242 days New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

 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 New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

PAC Adverse effect due to behavior New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières

New treatments and approaches to Tuberculosis Tuberculosis Symposium – Eastern Europe and Central Asia RA Ministry of Health and Médecins Sans Frontières 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.