Bedaquiline and delamanid combination as part of a MDR-TB treatment regimen: Current evidence and practices Cathy Hewison, Médecins Sans Frontières RESIST-TB 5 th April 2018
Outline Current recommendations for Dlm and Bdq combination in MDR-TB treatment MSF-endTB experience Current evidence Practical advice and special populations
Current recommendations for Bdq and Dlm use in combination No evidence => No recommendation However experience exists and evidence increasing: Otsuka compassionate use program Ongoing clinical trials and drug-drug interaction studies Increasing numbers of individual cases world wide with increasing evidence on safety Observational cohort, retrospective studies, case series
What are expanded indications for Bdq/Dlm? Optimal use of new drugs using WHO principles Patient by patient decision by clinicians based on patient treatment needs Is not always off label Includes: - > 24 weeks Bdq and Dlm - Combination Bdq and Dlm - Bdq and Dlm in children and adolescents - Bdq in Pregnant women 4
WHO best practice on expanded indications («off-label» use) Off-label use is legal Off label is common (especially in special populations) Off-label use falls under the purview of national regulatory agencies Off-label use is usually case by case Ø No WHO recommendation does not equal off-label use Ø The concomitant use of bedaquiline and delamanid together is not regarded as off-label, since both drugs are being used according to their indications
Reminder: MDR-TB is an off-label disease No re-purposed drugs have an indication for the treatment of TB Linezolid Clofazimine Carbapenems Amoxicilline/Clavulanate. but also Fluoroquinolones and Second-line Injectables
Outline Current recommenations for Dlm and Bdq combination in MDR-TB treatment MSF-endTB experience Current evidence Practical advice and special populations
MSF and endtb experience of Bdq-Dlm combination Early experience of new drug use through compassionate use Support fromendtbmedical committee Patient needs based decision making by clinicians Following WHO recommendations and essentials principles of having sufficient number of effective drugs in a regimen => Making the best use of Bdq and Dlm 8
Combination of Bdq/Dlm use: pre-requisites to consider Pre-requisite No contraindication to the use of Dlm or Bdq Informed consent Closely monitored treatment Good adherence Good tolerability Comments Baseline QTcF > 500msec, known hypersensitivity Additional information given and informed consent Specific monitoring for the duration of Dlm andbdq exposure. Anticipate adherence issues and address No SAE linked to Bdq / Dlm If already started or SAE resolved
Indication for combined Bdq and Dlm use Indication for Bdq and Dlm combination Insufficient number of effective drugs in the treatment regimen Definition Ø < 4 effective drugs* in regimen if Bdq and Dlm are not included together (do not count HdH, ethambutol, Z) Ø Either during initial regimen design or during treatment if another drug stopped Ø < 4 effective drugs* includes ü the inability to administer imipenem ü adverse events to other drugs ü other contraindications * Effective drugs are drugs never used before in a failing regimen, susceptible to a reliable DST result, not likely to be resistant according to local resistant patterns, not used previously by a contact, and well tolerated by the patient
Bdq-Dlm combination: why? ANTIBIOGRAMME date : 18/11/2013 Géno Phéno INH Kat G S315T InhA -15C>T R RIF rpob S531L R EMB EmbB M306V R PZA pnca G97D R SM R AMK R KAN rrs 1401A>G R CAP R OFX GyrA D94G GyrB S R MXF ETH PAS CYC LNZ TMC207 CFZ IPM/AMX Géno Phéno GyrA D94G GyrB S R etha Q254 ethr S R R R rplc T460C rrl S R atpe S Rv0678 ins g140 R?
Outline Current recommendations for Dlm and Bdq combination in MDR-TB treatment MSF-endTB experience Current evidence Practical advice and special populations
Current evidence on Bdq-Dlm combination N=1 N=1 Good initial treatment response - QTc prolongation (<500 ms) Good initial treatment response - No QTc prolongation N=5 N=1 2 patients with QT > 500 msec - Combinationnot stopped, resolved - no arrythmia QT prolongation (> 450 or 60 increase) - combination stopped 1. Tadolini et al, Eur Resp J 2016 2. Lachatre et al, Lancet Inf Dis 2015 3. Maryandyshev A et al.2017 4. Kim et al. ERJ 2018
Current evidence on Bdq-Dlm combination N=11/30 1. Guglielmetti et al, Union Congress 2017 and ERJ 2018 N=28 2. Ferlazzo G et al. Lancet ID 2017 N=44 3. endtb symposium, Union conference, Mexico 2017
Early safety and efficacy of Bedaquiline and Delamanid combination for drug-resistant TB in Armenia, India and South Africa Ferlazzo G, Mohr E, Jonckheere S, Hewison C, Khachtryan N, De Avezedo V, Furin J, Isaakidis P
South Africa MSF cohort: context India Armenia Khayelitsha Urban township High HIV >70% coinfection High burden of MDR-TB Mumbai Urban setting including slum High burden of MDR-TB and second line resistance Armenia Rural and urban High MDRTB, increasing pre- XDR and XDR
MSF cohort: patient characteristics Patients receiving Dlm and Bdq combination: N=28 N (%) Median age at Dlm-Bdq combination start (years) 32.5 Historyof previoustb treatment No previous TB treatment history Previous 1st line TB treatment Previous 2 nd line TB treatment 3 (10.7) 4 (14.3) 21 (75) Drug sensibility MDR Pre-XDR(Injectables) Pre-XDR (Fluoroquinolones) XDR 2 (7.1) 2 (7.1) 10 (35.7) 14 (50) HIV positive 11 (39.3)
MSF cohort: treatment Drugs in the regimen at BDQ-DLM start, median (IQR): 7 (6-10) Main accompanying drugs Lzd 82% Imp Lfx Mfx Cfz 18% 50% 50% 68% Other QT prolonging drugs administered in 86% of the cohort: - 23 pts Cfz or Mfx - 1 pt Cfz AND Mfx 0 5 10 15 20 25
MSF cohort: culture conversion Positive Culture % 100 90 80 70 60 50 40 30 20 10 0 0 4 8 12 16 20 24 Weeks on treatment 23/28 culture positive at start Dlm-Bdq combination 17/23 (74%) culture converted by 6 months 5 culture negative at baseline: 4 remain negative, 1 death 26 patient alive and retained in care at 6 months (93%), 82% culture negative at 6 months
MSF cohort: Safety and QT prolongation Distribution of median QTcF values at each time point QTcF (ms) 300 350 400 450 500 W0 W2 W4 W6 W8 W10 W12 W16 W20 W24 N=27 N=21 N=23 N=18 N=21 N=15 N=24 N=20 N=19 N=17 MSF Ferlazzo et al Late Breaker Union Conference Mexico 2017 No patient had QTcF > 500 msec No clinically significant cardiovascular events/arrythmias
endtb combined Bdq and Dlm Use Analysis October 2017 46 patients ever received Dlm and Bdq in combination 22 (48%) started Dlm and Bdq combination within 7 days of each other 24 (52%) started Dlm and Bdq overlapping Dlm added to Bdq: 18 (75%) Bdq added to Dlm: 6 (25%) 8/11 (73%) culture +ve culture converted endtb symposium, Union World Conference on Lung Health, Guadalajara, 2017, Accelerating TB eliminationthrough access to bedaquiline and delamanid
endtb: Efficacy and safety of combined use with Bdq and Dlm Includes 22 patients who started Bdq and Dlm together AEI term (37 Aes of interest in the first 6 mos) N % Number in grade 3 or 4 Median [IQR] time to AEI Prolonged (corrected) QT interval 9 24 1 3.0 [1.5-4.6] Increased liver enzymes (ALT increased or AST increased ( 1.1 x ULN)) 8 22 0 2.1 [1.0-2.9] Peripheral Neuropathy 8 22 0 3.5 [1.3-5.0] No SAEs were reported in the first 6 months of treatment
Practically..what does it all mean Combination of delamanid and bedaquiline used widely on a case by case basis: with sufficient monitoring no safety issues identified good results in difficult to treat patients No WHO recommendations should not stop best medical judgement and use of basic principles of MDRTB treatment Difficult to treat certain cases without the combination of Dlm and Bdq XDR-TB or Pre-XDR Cases with adverse events ( especially to injectables ie «functional XDRTB») 23
Hospitalisation? Adapt to patient Practically..how is it done? Initially recommended Not necesary for the duration of combination if ECG monitoring adapted to patient Monitoring of Qt interval with ECG: Adapt to patient Weekly first 4 weeks then 2-4 weekly but adjust according to risk Electrolytes and albumin: important to control electrolytes especially on injectables or vomiting Albumin less important (and usually impossible to increase Albumin without treating MDRTB) 24
Practically..how is it done? Together, sequentially, overlapping? Best regimen is the strongest regimen, as early as possible Dont save drugs for later use sufficient effective drugs Replace drugs causing adverse events For how long? No limitation on duration if well tolerated and monitoring assured use combination as long as needed to maintain sufficient drugs ( most patients get for all regimen) 25
Bedaquiline and Delamanid combination in special populations Children Pregnant women Extrapulmonary TB HIV coinfected Diabetes Hepatitis C 26
Bedaquiline and Delamanid combination in special populations Children Dlm recommended from 6 years old Bdq used in adolescents endtb and MSF experience: Very little evidence on combination but the same principles should be used to avoid children receiving inferior treatment => if required then use combination with specialist advice ( paediatrician and DRTB committee) 27
Bedaquiline and Delamanid combination Pregnant women in special populations Dlm not recommended in pregnancy But if mother life in danger and no alternative it might be necessary Ask support for case by case decision Extrapulmonary Delamanid and bedaquiline probably do not penetrate CSF very well but limited evidence 28
Bedaquiline and Delamanid combination HIV co-infected Used currently in special populations Better tolerated than other MDRTB drugs such as Lzd, Cs, hdh with overlapping adverse events ARVs Diabetes No specific evidence Hepatitis C Could it be less hepatotoxic then other combinations? Treat hepatitis C ( DAA and new drugs well tolerated) 29
Conclusion Use the combination of delamanid and bedaquiline to ensure sufficient effective drugs in a MDR-TB regimen when needed Monitor appropriately to ensure safety Ask for support if required for special cases Collect and share your data and results 30