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1 Thank you for viewing this presentation. We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author by the author

2 Evidence provided by recent metanalyses on treatment: what is new? GB Migliori WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Tradate Italy

3 3 Aims To describe and discuss: Existing guidelines and definitions Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) The new information on MDR-TB diagnosis The new information on MDR-TB treatment deriving from recent meta-analyses The principles of MDR-TB control, with prevention and public health aspects

4 4 Aims To describe and discuss: Existing guidelines and definitions Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) The new information on MDR-TB diagnosis The new information on MDR-TB treatment deriving from recent meta-analyses The principles of MDR-TB control, with prevention and public health aspects

5

6 6

7 7 Guidelines for the programmatic management of drug-resistant tuberculosis (1) 1 Background information on DR-TB 2 Framework for effective control of DR-TB 3 Political commitment and coordination 4 Definitions: case registration, bacteriology and treatment outcomes 5 Case-finding strategies 6 Laboratory aspects 7 Treatment strategies for MDR-TB and XDR-TB 8 Mono- and poly-resistant strains 9 Treatment of DR-TB in special conditions and situations 10 DR-TB and HIV infection 11 Initial evaluation, monitoring of treatment and management of adverse effects

8 8 Guidelines for the programmatic management of drug-resistant tuberculosis (2) 12 Treatment delivery and community-based DR-TB support 13 Management of patients with MDR-TB treatment failure 14 Management of contacts of MDR-TB patients 15 Drug resistance and infection control 16 Human resources: training and staffing 17 Management of second-line antituberculosis drugs 18 Category IV recording and reporting system 19 Managing DR-TN through patient-centered care ANNEX 1Drug information sheets ANNEX 2Weight-based dosing of drugs for adults ANNEX 3Suggestions for further reading ANNEX 4Legislation, human rights, and patients right in TB care prevention and control ANNEX 5 Use of experimental drugs outside of clinical trials ANNEX 5 Methodology

9 9 Causes of DR

10 10 Causes of MDR Patient mismanagement

11 11 DOTSMDR-TB FUNDING: Government Commitment (10$/ case) > money Up to 20,000 $/ case DIAGNOSIS: SS microscopy, QA and safety measures +C, DST, SRL, QA, infection control TREATMENT: SCC,DOT, 6-8 months, no hospitalization 24 months, mandatory DOT & hospitalization in reference facilities TB drugs only, no AE relevant toxicity, need special drugs + expertise TREATMENT MONITORING: SS, standard outcome definitions C, DST, special outcome definitons

12 12 Definitions Mono-R Poly-R MDR XDR SS+, C+ Cure, failure Treatment monitoring

13 Definitions MDR-TB = Strains resistant to at least INH and RIF (most important 1st-line drugs) XDR-TB = MDR TB strains with additional resistance to any fluoroquinolone and any of the 3 injectable second-line drugs (amikacin, kanamycin, capreomycin) TDR, XXDR = Resistance to all drugs (not standardised defin) MDR TB XDR TB TB with any drug resistance TDR/XXDR TB

14 14 1 st -line oral INH RIF PZA EMB (Rfb) Injectables SM KM AMK CM Fluoroquinolones Cipro Oflox Levo Moxi (Gati) Oral bacteriostatic 2nd line Unclear efficacy ETA/PTA PASA CYS Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)

15 15 Aims To describe and discuss: Existing guidelines and definitions Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) The new information on MDR-TB diagnosis The new information on MDR-TB treatment deriving from recent meta-analyses The principles of MDR-TB control, with prevention and public health aspects

16 Estimated absolute numbers of reported cases with MDR-TB* *among reported pulmonary TB patients < – –9999 >10,000

17 Distribution of MDR-TB among new TB cases,

18 Distribution of MDR-TB among previously treated TB cases,

19 13 top settings with highest % of MDR-TB among new cases, Minsk, Belarus (2010) Preliminary results ERJ 2012

20 Notifications of MDR-TB increasing BUT only ~ 1 in 6 (16%) of estimated cases of MDR-TB among reported TB patients diagnosed and treated in 2010 Notified cases of MDR-TB 19,000 53,000 Global Plan target ~270,000 in 2015 MDR-TB cases treated and estimated numbers not treated for MDR-TB, among notified TB patients, ,000

21 Proportion of TB patients tested for MDR-TB remains low Global plan target for 2015 = 100% Previously treatedNew cases Global plan target for 2015 = 20%

22 22 Trend of MDR-TB among new cases, Estonia, Latvia and…Tomsk Oblast, RF % MDR among new Estonia Latvia TB notification rate Tomsk oblast, RF

23 Countries that had reported at least one XDR-TB case by Oct 2011

24 24 Aims To describe and discuss: Existing guidelines and definitions Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) The new information on MDR-TB diagnosis The new information on MDR-TB treatment deriving from recent meta-analyses The principles of MDR-TB control, with prevention and public health aspects

25 20/36 HBCs* have insufficient capacity to diagnose MDR-TB * HBC= high-burden country Countries = Afghanistan, Armenia, Azerbaijan, Bangladesh, Belarus, Brazil, Bulgaria, Cambodia, China, DR Congo, Estonia, Ethiopia, Georgia, India, Indonesia, Kazakhstan, Kenya, Kyrgyzstan, Latvia, Lithuania, Mozambique, Myanmar, Nigeria, Pakistan, Philippines, Republic of Moldova, Russian Federation, South Africa, Tajikistan, Tanzania, Thailand, Uganda, Ukraine, Uzbekistan, Viet Nam, Zimbabwe 1 <1 Culture and DST laboratories per 5M, 2010

26 The magic Gene Xpert

27 27 The message Any person at high risk of MDR-TB should undergo rapid testing to start an appropriate treatment immediately while an additional sputum specimen undergoes conventional culture and DST

28 28 Aims To describe and discuss: Existing guidelines and definitions Epidemiology of MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) The new information on MDR-TB diagnosis The new information on MDR-TB treatment deriving from recent meta-analyses The principles of MDR-TB control, with prevention and public health aspects

29 29 The challenge of MDR

30 30 Expensive and toxic drugs are necessary

31 31 1 st -line oral INH RIF PZA EMB (Rfb) Injectables SM KM AMK CM Fluoroquinolones Cipro Oflox Levo Moxi (Gati) Oral bacteriostatic 2nd line Unclear efficacy ETA/PTA PASA CYS Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid Group 1 Group 2 Group 3 Group 4 Group 5 Grouping drugs

32 32 How to design a MDR-TB regimen

33 33

34 Metanalysis of 9,153 cases from 32 Countries Treatment success vs. to failure/relapse, was associated with use of: later generation quinolones, ofloxacin, ethionamide or prothionamide use of 4 or more likely effective drugs in the initial intensive phase, and 3 or more likely effective drugs in the continuation phase. Maximum odds of success: initial intensive phase of months and total treatment duration of months

35 35 Changes to the recommendations on regimen composition between the 2008 and 2011 updates of WHO MDR-TB guidelines 2008 emergency update2011 update Include at least four anti-TB drugs with either certain, or almost certain, effectiveness during the intensive phase of Tx Include at least 4 2 nd -line anti-TB drugs likely to be effective as well as Z during the intensive phase of Tx Consider adding more drugs in patients with extensive disease or uncertain effectiveness No evidence found to support the use of > 4 2nd-line anti-TB drugs in patients with extensive disease. Increasing the number of 2 nd -line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain. The regimen should include Z and/or E one FQ, one parenteral agent and 2 nd -line oral bacteriostatic anti-TB drugs (no preference of oral bacteriostatic 2 nd -line anti-TB drug was made). The regimen should include Z a FQ, a parenteral agent, ethionamide (or prothionamide), and cycloserine, or else PAS if cycloserine cannot be used. E may be considered effective and included in the regimen if DST shows susceptibility E may be used but is not included among the drugs making up the standard regimen. Tx with Group 5 drugs is recommended only if additional drugs are needed to bring the total to 4 Group 5 drugs may be used but are not included among the drugs making up the standard regimen Intensive phase min 6 months (min 4 months after C conversion) for a total duration of min 18 months after C conversion Intensive phase min 8 months for a total duration>=20 months

36 Treatment monitoring Treatment failure was detected best with monthly culture in MDR-TB cases. Thus the available evidence does not support replacing monthly culture (or quarterly culture) with monthly smear

37 37

38 38

39 39

40 40 Consilium for MDR-TB case and programme management

41 41

42 42 XDR-TB MDR-TB, resistant to all FLD MDR-TB, suscep to at least one FLD Eur Respir J ,853 C+, 361 MDR, 64 XDR TDR-TB (MDR+FQ+ Gr IV)

43 43 Pooled Success = 0.54 (0.48 to 0.60) Inconsistency (I-square) = 97.4% Author N° Success N° Treated Avendano6472 Burgos3045 Chan Chiang72125 Cox5477 DeRiemer547 Escudero1418 Geerligs4043 Granich/Banerjee74100 Holts Kim(Shim) Kim(Yim) Kwon85129 Leimane/Riekstina Lockman Masjedi1627 Migliori1783 Mitnick Munsiff/Li Narita3966 ORiordan1928 Palmero70112 Park60131 Perez-Guzman1533 Quy79157 Schaaf2036 Shin Shiraishi5461 Tupasi97159 Uffredi2341 Van Deun Yew8499 Treatment Success vs Fail and Relapse and Death and Default

44 44 XDR TB (n=405) MDR-TB +FQr (n = 426) MDR-TB +INJr (n=1130) MDR-TB, suscept- to FQ & Inj (n=4763) Total Pooled Outcomes (From study level meta-analysis) Success 40% (27, 53)48% (36, 60)56% (45, 66)64% (57, 72)62% (54,69) Failed/Relapse 22% (15, 28)18% (14, 21)12% (9, 15)4% (2, 6)7% (4, 9) Died 15% (8, 23)11% (3, 19)8% (3, 14)8% (5, 11)9% (5, 12) Defaulted 16% (8, 24)12% (1,23)16% (7, 24)18% (12,24)17% (11, 22) Treatment outcomes by MDR-TB patient group

45 45 Association between clinical characteristics and treatment success vs. failure/relapse/death in the different MDR-TB sub-groups Characteristics Odds of success vs failure/relapse/death NaOR(95%CI) Male sex (vs female)* (0.9, 1.1) Older age (per 10 years older)* (0.8, 0.9) HIV positive (vs HIV neg.)*6150.3(0.2, 0.4) Extensive disease (vs not)* (0.4, 0.6) Prior TB treatment* None (Reference) FLD only (0.5, 0.8) FLD and SLD , 0.3) MDR sub-groups: Not resistant to a FQN nor a 2 nd line injectable (Reference) Resistant to a second-line injectable, but not a FQN (0.5, 0.7) Resistant to a fluoroquinolone, but not a 2 nd line injectable4260.3(0.2, 0.40 Resistant to both a fluoroquinolone and at least one 2 nd line injectable (XDR) , 0.3) Pulmonary resection surgery performed (vs not) (0.9, 2.6) Experienced a serious adverse event (vs not) (0.8, 1.2)

46 46 INTENS PHASE N° drugs XDRMDR–TB+FQrMDR–TB+INJrMDR-TB, susceptible to FQ & Inj NaOR(95%CI)NaOR (95%C I) NaOR(95%CI)NaOR(95%CI) (reference) (reference) (referenc e)451.0 (referenc e) (0.5, 5.2) (0.5, 2.3) (0.8, 4.3)491.6 (0.7, 3.8) (0.5, 3.1) (1.0, 3.7) (0.5, 6.6)351.4 (0.3, 6.4) (0.4, 3.4) (0.8, 3.8) (1.4, 16.6) (0.4, 2.9) (0.5, 3.3) (0.5, 1.8) CONT PHASE N° drugs XDRMDR–TB+FQrMDR–TB+INJrMDR, susceptible to FQ & Inj NaOR(95%CI)NaOR (95% CI) NaOR(95%CI)NaOR(95%CI) (ref)351.0(ref)461.0(ref)771.0(ref) (1.3, 8.5) (0.8, 7.4) (3.4, 44) (3.1, 11.0) (1.4, 26.3) (0.5, 21.1) (1.7, 8.2) (2.8, 13.1) (0.7, 7.6) (0.7, 7.2) (1.7, 6.0) (2.7, 8.1)

47 47 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 422No 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 625No Died 60 First tuberculosis cases in Italy resistant to all tested drugs GB Migliori G De Iaco, G Besozzi, R Centis, DM Cirillo WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate Eurosurveillance 2007

48 48

49 49 Treatment outcome XDR-aloneXDR+2sliXDR+sliG4XDR+sliG4EZ n = 301n = 68n = 48n =42 Cured1.0 (reference) 0.4 (0.2, 0.8) 0.6 (0.2, 1.6)0.5 (0.2, 1.7) Failed1.0 (reference)2.1 (1.0, 4.5)1.8 (0.7, 4.7)1.9 (0.7, 5.3) Died1.0 (reference)1.6 (0.6, 4.4)1.7 (0.6, 4.9)1.8 (0.6, 5.3) Failed or Died1.0 (reference) 2.6 (1.2, 4.4)2.6 (1.1, 6.7) 2.8 (1.0, 7.9) Defaulted1.0 (reference)1.0 (0.3, 2.6)0.5 (0.2, 1.8)0.5 (0.1, 2.0) Treatment outcome XDR aloneXDR+2sli XDR+sliG4 XDR+sliG4EZ n = 301n = 68n = 48n =42 Cured43 (27, 58)30 (17, 43)34 (-, -)19 (0, 48)* Failed20 (15, 25)29 (8, 50)33 (-, -)26 (14, 38) Died13 (6, 20)18 (7, 29)30 (18, 41)*35 (21, 50)* Failed or died35 (26, 45)54 (40, 69)*48 (-, -)49 (37, 61) Defaulted15 (5, 24)15 (3, 27)18 (-, -)19 (6, 32)

50 50

51 51

52 52

53 53 Building a regimen for XDR-TB

54 54

55 55

56 56 AE in Linezolid- containing regimens. Sotgiu et al, ERJ 2012

57 Meropenem (De Lorenzo S, Alffenar JW et al- ERJ 2012 in press) 57 Variables Cases: 37 Controlls: 61 Total Cases Meropenem/clavula nate -containing anti-TB regimen -Italian cohort Controls Meropenem/cla vulanate - sparing anti-TB regimen -Dutch cohort p- value Sputum smear conversion at 30 days of treatment, n (%) 16/50 (32.0) 7/32 (21.9)9/18 (50.0) 0.04 Sputum smear conversion at 60 days of treatment, n (%) 27/48 (56.3) 20/32 (62.5)7/16 (43.8)0.22 Sputum smear conversion at 90 days of treatment, n (%) 37/48 (77.1) 28/32 (87.5)9/16 (56.3) 0.02 Culture conversion at 30 days of treatment, n (%) 24/66 (36.4) 12/37 (32.4)12/29 (41.4)0.45 Culture conversion at 60 days of treatment, n (%) 37/62 (59.7) 24/37 (64.9)13/25 (52.0)0.31 Culture conversion at 90 days of treatment, n (%) 46/61 (75.4) 31/37 (83.8)15/24 (62.5) 0.06 Median (IQR) period from start of anti-TB therapy to sputum smear conversion, days 51 ( ) 52.5 ( )46.0 ( )0.85 Median (IQR) period from start of anti-TB therapy to culture conversion, days 42 ( ) 42.0 ( )46.0 ( )0.96

58 58 Aims To describe and discuss: Existing guidelines and definitions The epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation) The new information on MDR-TB diagnosis The new information on MDR-TB treatment The principles of MDR-TB control, with prevention and public health aspects

59 TB patients with inappropriate regimen have a 27- fold higher risk of developing MDR-TB 59 Multidrug resistance after inappropriate tuberculosis treatment: A meta-analysis Marieke J. van der Werf, Miranda W. Langenda, Emma Huitric, Davide Manissero ERJ 2012 in press

60 60 Global Policy: MDR-TB and XDR-TB 1.Strengthen basic TB control, to prevent M/XDR-TB 2.Scale-up programmatic management and care of MDR-TB and XDR-TB 3.Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB 4.Ensure availability of quality drugs and their rational use 5.Expand MDR-TB and XDR-TB surveillance 6.Introduce infection control, especially in high HIV prevalence settings 7.Mobilize urgently resources domestically and internationally 8.Promote research and development into new diagnostics, drugs and vaccines

61 61 Global Policy: MDR-TB and XDR-TB 1.Strengthen basic TB control, to prevent M/XDR-TB 2.Scale-up programmatic management and care of MDR-TB and XDR-TB 3.Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB 4.Ensure availability of quality drugs and their rational use 5.Expand MDR-TB and XDR-TB surveillance 6.Introduce infection control, especially in high HIV prevalence settings 7.Mobilize urgently resources domestically and internationally 8.Promote research and development into new diagnostics, drugs and vaccines

62 62 Global Policy: MDR-TB and XDR-TB 1.Strengthen basic TB control, to prevent M/XDR-TB 2.Scale-up programmatic management and care of MDR-TB and XDR-TB 3.Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB 4.Ensure availability of quality drugs and their rational use 5.Expand MDR-TB and XDR-TB surveillance 6.Introduce infection control, especially in high HIV prevalence settings 7.Mobilize urgently resources domestically and internationally 8.Promote research and development into new diagnostics, drugs and vaccines

63 63 Global Policy: MDR-TB and XDR-TB 1.Strengthen basic TB control, to prevent M/XDR-TB 2.Scale-up programmatic management and care of MDR-TB and XDR-TB 3.Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB 4.Ensure availability of quality drugs and their rational use 5.Expand MDR-TB and XDR-TB surveillance 6.Introduce infection control, especially in high HIV prevalence settings 7.Mobilize urgently resources domestically and internationally 8.Promote research and development into new diagnostics, drugs and vaccines

64 64 Global Policy: MDR-TB and XDR-TB 1.Strengthen basic TB control, to prevent M/XDR-TB 2.Scale-up programmatic management and care of MDR-TB and XDR-TB 3.Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB 4.Ensure availability of quality drugs and their rational use 5.Expand MDR-TB and XDR-TB surveillance 6.Introduce infection control, especially in high HIV prevalence settings 7.Mobilize urgently resources domestically and internationally 8.Promote research and development into new diagnostics, drugs and vaccines

65 , the last anti-TB drug was discovered

66 66 Bedaquiline Delamanid

67 67 Carlo Forlanini, first notes on Pneumothorax January 7th, 1907

68 68 Interventions over time: Interventions over time: old weapons might be useful again to manage XDR First sanatorium Germany, 1857 First Dispensary, Scotland, 1897 Koch, Mtb, 1882 Drugs, MMR, Fox:Ambulatory treatment, 1968 Styblo model, 1978 DOTS, 1991 sanatoria Outbreak Management, Risk Group Management screening BCG vaccination drug therapy Socio-economic improvement Pneumotorax, Italy, 1907

69 69

70

71 71 Pneumothorax

72 72 Nobody wants me around..

73 73

74 74 XDR and TB control: which future ?


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