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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. • 2012 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. 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. 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. 2000

  6. Guidelines for the programmatic management of drug-resistant tuberculosis (1) 1Background 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

  7. 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 1 Drug information sheets ANNEX 2 Weight-based dosing of drugs for adults ANNEX 3 Suggestions for further reading ANNEX 4 Legislation, human rights, and patient’s right in TB care prevention and control ANNEX 5 Use of experimental drugs outside of clinical trials ANNEX 5 Methodology

  8. Causes of DR

  9. Causes of MDR Patient mismanagement

  10. Definitions • Mono-R • Poly-R • MDR • XDR • SS+, C+ • Cure, failure • Treatment monitoring

  11. 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) TDR/XXDR TB TB with any drug resistance MDR TB XDR TB

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

  13. 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

  14. Estimatedabsolute numbers of reported cases with MDR-TB* <100 100–999 1000–9999 >10,000 *among reported pulmonary TB patients

  15. Distribution of MDR-TB among new TB cases, 1994-2010.

  16. Distribution of MDR-TB among previously treated TB cases, 1994-2010.

  17. 13 top settings with highest % of MDR-TB among new cases, 2001-2010 35.3 Minsk, Belarus (2010) Preliminary results ERJ 2012

  18. 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 MDR-TB cases treated and estimated numbers not treated for MDR-TB, among notified TB patients, 2010 Notified cases of MDR-TB Global Plan target ~270,000 in 2015 290,000 53,000 19,000

  19. Proportion of TB patients tested for MDR-TB remains low New cases Previously treated Global plan target for 2015 = 20% Global plan target for 2015 = 100%

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

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

  22. 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

  23. 20/36 HBCs* have insufficient capacity to diagnose MDR-TB Culture and DST laboratories per 5M, 2010 ≥1 <1 *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

  24. The “magic” Gene Xpert

  25. 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

  26. 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

  27. The challenge of MDR

  28. Expensive and toxic drugs are necessary

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

  30. How to design a MDR-TB regimen

  31. 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 7.1-8.5 months and total treatment duration of 18.6-21.5 months

  32. Changes to the recommendations on regimen composition between the 2008 and 2011 updates of WHO MDR-TB guidelines

  33. 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

  34. Consilium for MDR-TB case and programme management

  35. 4,853 C+, 361 MDR, 64 XDR MDR-TB, suscep to at least one FLD MDR-TB, resistant to all FLD XDR-TB TDR-TB (MDR+FQ+ Gr IV) Eur Respir J 2007

  36. Treatment Success vs Fail and Relapse and Death and Default Pooled Success = 0.54 (0.48 to 0.60) Inconsistency (I-square) = 97.4%

  37. Treatment outcomes by MDR-TB patient group

  38. Association between clinical characteristics and treatment success vs. failure/relapse/death in the different MDR-TB sub-groups

  39. First tuberculosiscases in Italy resistanttoalltesteddrugs GB Migliori (gbmigliori@fsm.it), G De Iaco, G Besozzi, R Centis, DM Cirillo WHO CollaboratingCentrefor TB and LungDiseases, Fondazione S. Maugeri, Care and ResearchInstitute, Tradate Eurosurveillance 2007