Tuberculose en Belgique: Quoi de neuf pour le praticien? Inge Muylle 10 septembre e CONGRES DE L A.M.U.B.

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1 Tuberculose en Belgique: Quoi de neuf pour le praticien? Inge Muylle 10 septembre e CONGRES DE L A.M.U.B.

2 Conflits d intérêt en rapport avec la présentation Honoraires de conférence : Johnson & johnson Participation à un «Advisory Board» : Johnson & johnson Etudes cliniques sponsorisées en cours : - aucun Consultance : Damien Foundation Voyages-Congrès : Johnson & johnson

3 Overview Presentation Epidemiologie Définitions résistance Transmission MDR-TB Méchanismes de résistance: Principes généraux Méchanismes moléculaires Diagnostic Traitement Recommendations Future

4 EPIDEMIOLOGIE

12 DEFINITIONS

13 Question Quelle est la définition d une tuberculose multirésistante? A. Résistance à 2 tuberculostatiques B. Résistance à 2 tuberculostatiques dont au moins Isoniazide (Nicotibine ) C. Résistance à au moins Isoniazide (Nicotibine ) & Rifampicine (Rifadine ) D. Résistance à au moins Isoniazide (Nicotibine ) & Streptomycine

Definitions Monoresistance Strain resistant to 1 of the 1 st line drugs Poly-resistance Multidrug-resistant (MDR) Extensively drugresistant (XDR) Pre-XDR Strain resistant to 2 1 st line drugs but

14 Definitions Monoresistance Strain resistant to 1 of the 1 st line drugs Poly-resistance Multidrug-resistant (MDR) Extensively drugresistant (XDR) Pre-XDR Strain resistant to 2 1 st line drugs but not both INH & RMP Strain resistant to both INH & RMP Strain resistant to both INH & RMP, any fluoroquinolone & at least 1 SLI Strain resistant to both INH & RMP, fluoroquinolones or at least 1 SLI

15 Definitions Acquired: Previous treatment with anti-tb medication Primary drug resistant: Infection with drug-resistant organism < infectious contact

16 Figure 3 The Lancet , DOI: ( /S (10) ) The Lancet , DOI: ( /S (10) )

17 Primary rate of resistance 1 st line drugs EMB 1 in INH 1 in SM 1 in 10 6 RMP 1 in 10 8 INH RMP 1 in

18 Figure 4 The Lancet , DOI: ( /S (10) )

19 Risk of Primary MDR Transmission of Multidrug-Resistant and Drug-Susceptible Tuberculosis within Households A Prospective Cohort Study 2015 Plos Medicine

20 MECHANISMS OF DRUG RESISTANCE

21 General Principles Inadequate TB-treatment due to: Incorrect treatment schemes (in 1 st line) Treatment incompliance by patient Malabsorption of 1 st line drugs Poor drug quality: poor bioavailability Drug-drug interactions 1 st resistance to one drug, subsequently to several drugs (e.g. MDR)

22 Factors influencing resistance to 2 nd line drugs High treatment costs 2 nd line drugs risks: Less adequate treatment regimen Risk of lower compliance Widespread use of fluoroquinolones might drive resistance to fluoroquinolones in TB Inadequate treatment of MDR-TB will lead to XDR-TB

23 Molecular Mechanisms

24 INH-resistance Pro-drug Conversion: katg-gene catalase necessary to process INH prodrug into functional form Deletion/mutation in katg: % of INH resistant strains Drug Target: inha-gene Gene coding for long-chain enoyl-acyl carrier protein reductase (mycolic acid synthesis) Usually low-level resistance (MICs = μg/ml)

27 Overview Molecular Mechanisms Drug Resistance Mechanism Corresponding Gene INH Prodrug Conversion Catalase katg INH & Eth/Pth Drug Target Mycolic acid production RMP Drug Target Mycobacterial RNA polymerase inha rpob PZA Prodrug Conversion Pyrazinamidase pnca EMB Drug Target arabinosyl transferase embb FQ Drug Target DNA gyrase gyra, gyrb Aminoglycosides Drug Target Ribosomal protein rrs Capreomycine Drug Target Ribosomal protein tlya Eth/Pth Prodrug Conversion Mono-oxygenase EtaA - EthA Cycloserine Drug Target D-alanine competion alr

28 DIAGNOSIS OF RESISTANCE

29 Diagnosis Clinical Suspicion Previous treatment for TBC: Compliance? Severe adverse events? Country of origin? Traveling history? Known contact with MDR-TB? Failure 1st line regimen in patient adherent to therapy?

30 DST Standard Techniques Solid medium : proportion method Results after 4 6 weeks No critical concentration for new substances Liquid media: MGIT 960 Results after 1-2 weeks All drugs except Cs

31 Line Probe Assays GenoType MTBDRplus assay (Hain Lifesciences) Excellent specificity & sensitivity for RMP-resistance, even for direct use on clinical specimens

32 Line Probe Assays GenoType MTBDRsl assay (Hain Lifesciences)

33 Real-time automated PCR: GenXpert Boehme, NEJM, 2010

34 GeneXpert sensitivity TB Migliori, ERS-online course, 2011

36 GeneXpert time to TB detection Migliori, ERS-online course, 2011

37 GeneXpert time to detection RMP-R Migliori, ERS-online course, 2011

38 Genotypic methods Disadvantages: High cost Detection of RMP ± INH- resistance no information on other drugs (except for Hainplus test, but lower sensitivity for 2 nd line drugs) No role in infection control / treatment monitoring (no info on smear positivity) Confirmation resistance by phenotypic methods needed

39 Genotypic methods Advantages: Early & rapid detection of resistance GenXpert: easy to use minimal biosafety level WHO 2011 guidelines for MDR-treatment: Recommendation 1: Rapid DST of INH and RMP or of RMP alone is recommended over conventional testing or no testing at the time of diagnosis of TB, subject to available resources.

40 Xpert MTB Rif Ultra Problems with Xpert MTB/RIF : limit of detection (LOD): 133 CFU/ml sputum sensitivity in smear negative TB: only 60 80% small numbers of false RIF-R : due to abnormal real-time PCR curves or miss-identification of RIF-susceptible (RIF-S) synonymous rpob mutants as RIF-R.

41 Xpert MTB Rif Ultra Xpert MTB/RIF Ultra: new sample processing cartridge doubled amount of purified DNA delivered to the PCR reaction. 4 newly designed probes that detect mutations in rpob gene replaced the 5 Xpert real-time probes. Real-time Mtb detecting probes targeting IS6110 and IS1081 were added. Optimising cartridge fluidics and PCR cycling Higher sensitivity than old Xpert sputum samples spiked with Mtb H37Rv: LOD Ultra 5 CFU/ml vs LOD Xpert 50 CFU/ml (p=0.001) sputum samples spiked with BCG: LOD Ultra 25 CFU/ml vs LOD Xpert 165 CFU/ml (p=0.01) Ultra : 100% sensitivity & specificity Rif-R

42 Xpert XDR

43 TREATMENT

44 Initiation of MDR-TB treatment Ideally based on DST-results often not available baseline start empiric MDR-treatment - based on previous treatment regimen - based on DST-result of contact patient

46 2016 WHO Recommendations Intensive phase of treatment ( 8 months) At least 5 effective drugs Including PZA One drug Group A, One drug Group B 2 group C Eventual agent from group D2, D3 to bring total to 5 drugs Strengthening of regimen with EMB or high dose INH Continuation phase of treatment (complete duration of treatment 20 months) Stop injectable (unless no/few other active drugs)

49 PAS: Inhibits synthesis DNA precursors Others: - Thioamides - Cycloserine Adapted from The Lancet Infectious Diseases , DOI: ( /S (13) ) Others: - Aminoglycosides - Cyclic Peptide

50 Bedaquiline = TMC 207 = Sirturo

51 Bedaquiline = TMC 207 = Sirturo Inhibition of mycobacterial ATP synthase

52 Bedaquiline = TMC 207 = Sirturo

1. Inclusion in WHO-recommended based MDR-regimen if a 4- drug 2 nd line drug regimen in addition to PZA can not be designed 2. Documented evidence of resistance to any FQ in addition to MDR 3.

54 1. Inclusion in WHO-recommended based MDR-regimen if a 4- drug 2 nd line drug regimen in addition to PZA can not be designed 2. Documented evidence of resistance to any FQ in addition to MDR 3. Proper patient selection: Use with caution in PLHIV Caution in patients with comorbidities (diabetes, alcohol/substance abuse) 18-65y; no pregnant/breastfeeding QTc < 500ms 4. Duration of treatment: maximum 6 months (400 mg daily for the first 2 weeks, followed by 200 mg three times per week) 5. BDQ should never be added as a single drug to a failing regimen 6. Baseline testing + monitoring for QTc prolongation; clinical monitoring/management co-morbidities 7. Pharmacovigilance: No phase III study results available yet 8. Use after obtaining Informed Consent by patient

56 Delamanid = OPC = Deltyba

58 1. Proper patient selection: PLHIV OK: were included in studies 18-65y; no pregnant/breastfeeding QTc < 500ms 2. Inclusion in WHO-recommended based MDR-regimen No addition of Delamanid alone in failing regimen Close monitoring 4. Pharmacovigilance: No phase III study results available yet 5. Use after obtaining Informed Consent by patient

59 Linezolid

60 Sutezolid = PNU Structural analogue of Linezolid More bactericidal than Linezolid Presumably less side effects than Linezolid SQ109-Bedaquiline-Sutezolid: probably best new TB regimen for all forms of TB (drug susceptible & drug resistant)

61 Carbapenems Carbapenems : imipenem and meropenem in vitro active against M. tuberculosis Limitation of use: Expensive IV administration 2 3 times daily often indwelling catheter needed Limited clinical experience Always co-administration clavulanate

62 MDR-tuberculosis = man-made disease New drugs: not the only solution to eliminate TB At least as important: good patient management social & political commitment required

63 New drug regimens Goal: Shorten treatment time Less frequent dosages Combination pills Probably benificial for treatment adherence & treatment outcome

64 Shorter regimens? nine months total treatment Throughout treatment: gatifloxacin, clofazimine, EMB and PZA Intensive phase (4 months): PTH, kanamycin, high dose INH relapse-free cure of 87.9%

65 In patients with RMP-resistant or MDR TB who have not been previously treated with 2 nd line drugs and in whom resistance to FQ and SLI has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen

66 Questions? Comments?

67 Aspects pratiques Consultations FARES/VRGT: Dispensaire à l hôpital St. Pierre Dépistage de contact Mise au point suspicion TBC Suivi traitement TBC chez patients à risque Suivi traitement MDR B

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