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.  2008 by the author

2. Common causes of treatment mismanagement Jean-Pierre Zellweger Swiss Lung Association

3. What is mismanagement of TB?

4. The « ideal » TB management Symptoms Suspicion of TB Bacteriological confirmation Treatment Cure (Thank you, doctor!)

5. The «real-life» TB management Symptoms Suspicion of TB Bacteriological confirmation Treatment Cure (Thank you, doctor!) Wrong diagnosis Delay

6. The «real-life» TB management Symptoms Suspicion of TB Bacteriological confirmation Treatment Cure (Thank you, doctor!) Incorrect assessment

7. The «real-life» TB management Symptoms Suspicion of TB Bacteriological confirmation Treatment Cure (Thank you, doctor!) Missing drug sensitivity testing

8. The «real-life» TB management Symptoms Suspicion of TB Bacteriological confirmation Treatment Failure, relapse, MDR/XDR-TB Inappropriate drug treatment

9. Delayed diagnosis

10. Mean patient’s and HCW’s delay (days) in 42 studies Patient’s delay Storla DG, BMC Public Health 2008;8:15 Mean total diagnostic delay: 21 – 136 days

11. Patient’s delay Frequency of symptoms before diagnosis: – Cough85% – Sputum67% – Fever65% – Weight loss 62% – Fatigue55% – Haemoptysis 25% – Sweating35%

12. Factors associated with delayed health-seeking behaviour Socioeconomic factors: – Low access to health care – Rural residence – Low income, poverty – Low education Sociopsychological factors: – Low-level health care facility – Traditional or unqualified practicioner – Private practicioner – Beliefs about TB Sociodemographic factors: – Old age – Female gender – Immigration – Illegal residency

13. Doctor’s delay Factors influencing delay: – HIV – Chronic cough – Negative sputum – Substance or alcohol abuse – Smoking – Poor health – Coexistent disease – Mild symptoms – No haemoptysis

14. Delay associated with health-care providers Repeated consultations with incompetent healthcare providers: – Governmental primary health posts – Private practicioners with low awareness – Unqualified traditional practicioners Overcentralization of govermental TB programme Repeated courses of inappropriate antibiotics Storla DG, BMC Public Health 2008;8:15

15. Diagnostic deficiencies Misinterpretation of clinical presentation – Other diagnosis: cancer, pneumonia, smoking, COPD Misinterpretation of chest X-ray – « inactive TB » – Incorrect interpretation : cancer, abscess TB diagnosis without evidence – No bacteriological examination (lymph node biopsies, surgical samples!) – Diagnosis based on chest X-ray only – Culture not available or not requested

16. Inappropriate treatment Single drug treatment of active TB Standard treatment (cat 1) of undetected MDR-TB – Ovelooking risk factors for MDR-TB Prior treatment Origin from region with high rate of MDR-TB Addition of a single drug to a failing regimen Insufficient doses Missing doses in intermittent treatment (1- weekly)

17. Case #13 Woman born in Portugal, 28 years Coughs since 3 weeks CXR Receives moxifloxacine

18. Case #13 Woman born in Portugal, 28 years Coughs since 3 weeks CXR Rx moxifloxacine Feels better 2 nd CXR after 2 weeks

19. Case #13 Woman born in Portugal, 28 years Coughs since 3 weeks CXR Rx moxifloxacine Feels better 2 nd CXR after 2 weeks Recurrent symptoms 3 weeks later Smear positive

20. Message: 3 errors 1. wrong interpretation of chest X-ray (it was TB, not cavitating pneumonia!) 2. incorrect choice of the antibiotic (no quinolone for possible TB!) 3. wrong interpretation of the improvement (bactericidal effect of moxifloxacin on M.tb)

21. Who has primary MDR-TB? Patients with prior TB treatment (10 times) Foreign-born patients Young patients Males HIV positives

22. Risk factors for MDR-TB in Europe a) patients with previous treatment Faustini A, Thorax 2006;61:158-63

23. Risk factors for MDR-TB in Europe b) previous treatment in E and W Europe

24. MDR-TB in immigrants arriving in UK: risk factors O’Riordan Ph, PLoS One 2008,3(9):e3173

25. Insufficient follow-up Irregular controls Undetected adverse effects of treatment Erratic changes in treatment schedule due to adverse events (replacement of H or R by second-line drugs) Undetected negative evolution

26. Uncertain cure End of treatment without documentation of cure

27. Mismanagement and creation of MDR/XDR-TB

28. Errors inducing MDR-TB – Inappropriate choice of drugs – Inappropriate regimen (twice-weekly without supervision) – Too low doses – Malabsorption of drug (low blood levels)

29. Creation of drug resistance: effect of drugs on mycobacteria with different growth speed Mitchison DA, IJTLD 1998;2(1):10-15

30. Creation of drug resistance: growth speed of sensitive and resistant mycobacteria

31. Creation of drug resistance: regrowth of of sensitive and resistant mycobacteria

32. Creation of drug resistance: impact of lag phase

35. Mismanagement and creation of MDR/XDR-TB Errors inducing MDR-TB Induction of MDR-TB without error under standard DOTS strategy – Initiation of standard therapy in new patients with undetected drug resistance No culture available or requested No DST DST inappropriate DST arriving too late (3-4 months) DST never transmitted to clinician

36. Situation at initiation of treatment Caminero JA, IJTLD 2008;12(8):869-77

37. Possible course of treatment

38. Initial resistance to H

39. Initial MDR-TB

40. Outcome of treatment and retreatment in sites with low MDR-TB prevalence Gninafon M, IJTLD 2004;8(19):1242-7

41. Outcome under correct DOTS in sites with high prevalence of MDR/XDR-TB 1999 (Bakou prisons, Azerbaïjan): all prisoners under correct treatment (cat 1, DOT) – Mortality during treatment: 11% – Sputum conversion obtained in 42% – Cure rate 54% (71% in completers) – 55% had strains resistant to 2 or more drugs Coninx R, Lancet 1999;353:969-73

42. Creation of new MDR/XDR-TB under correct DOTS 2901 new smear + pulmonary TB under DOTS in Vietnam 125 failures 2 nd DST in 40 failure with two positive cultures and identical RFLP pattern – 17 had MDR-TB at beginning of treatment – 15 without MDR at beginning developed MDR under DOTS 39 relapses – No primary MDR-TB – 3 had MDR-TB at relapse Quy HTW, IJTLD 2003,7(7):631-36

43. Outcome and acquired drug resistance in 1681 new TB patients in cat 1 DOTS (Tomsk) Seung KJ, Clin Infect Dis 2004;39:1321-8

44. Acquired drug resistance under DOTS Among 382 new pulmonary TB patients treated by a standard DOTS regimen – 62 were still smear positive at 2 months (with identical strains) – 24 had MDR-TB – 19/62 identical strains developed new or additional drug resistance during treatment – 3.5% of patients with DST other than MDR developed MDR-TB during treatment Cox HS, Clin Inf Dis 2007;44:1421-7

45. Amplification of drug resistance in patients under retreatment 410 patients in Uganda received retreatment for TB according to WHO: 2HRZES/1HRZE/5HRE – 12.5% had MDR-TB at the beginning of retreatment – 5.2% developed additional drug resistance during retreatment (half of them developed new MDR-TB) – Risk of acquired drug resistance was 10.4 for patients with H or R resistance 46.1 for patients with MDR-TB 42.4 for patients still C+ after 5 months of treatment Temple B, Clin Inf Dis 2008;47:1126-34

46. Outcome by rate of resistance and MDR in 6 sites in FSU Bonnet M, IJTLD 2005;9(10):1147-54

47. Initial drug resistance and treatment failure a) fully sensitive strains Lew W, Ann Int Med 2008;149:123-34

48. Initial drug resistance and treatment failure b) initial single drug resistance

49. Initial drug resistance and treatment failure c) polyresistant strains

50. Initial drug resistance and treatment failure

51. Initial drug resistance and treatment outcome. Duration of R treatment and outcome, by resistance

52. Initial drug resistance and treatment failure. Acquired drug resistance

53. Rate of failure in new and retreatment cases, by local rate of initial MDR-TB (source WHO data) Mak A, Am J Respir Crit Care Med 2008;178:306-12

56. Speed of detection of MDR-TB (in immigrants) and outcome of treatment O’Riordan Ph, PLoS One 2008,3(9):e3173

57. How to treat failure and relapse cases? Low MDR-TB prevalence: 2HRZES/1HRZE/5HRE (?) – Beware of any risk factor for drug resistance – Strict DOT – Obtain DST High MDR-TB prevalence: – Obtain rapid DST – Avoid using only first-line drugs as retreatment schedule – Consider using second-line drugs (injectables and quinolones)

58. Conclusions: how to avoid creating MDR/XDR-TB? Obtain a bacteriological confirmation whenever possible, at least in retreatment cases Obtain DST as soon as possible (consider using rapid amplification technology) Search for all possible risk factors for drug resistance Initiate appropriate drug treatment Supervise drug intake

59. The curse of MDR/XDR-TB « A mycobacterium for a mycobacterium » – Your mycobacterium is my mycobacterium – You and your children will be cursed to the seventh generation!