1. Management of MDR-TB patients in the hospital: LRS Institute Experience LRS Institute of TB and Respiratory Diseases Sri Aurobindo Marg, New Delhi

2. Inflow of patients in LRS Institute From outside Delhi From outside Delhi From Delhi, outside LRS area From Delhi, outside LRS area From LRS DOTS area From LRS DOTS area

3. Inflow of patients in OPD … I Cases from community ( Non- DOTS) - No DST - No DST - DST available (a) non- MDR - DST available (a) non- MDR (b) MDR (b) MDR

4. Inflow of patients in OPD … II Cases from DOT centers: (a) Cat I failure: (i) No DST (ii) Non-MDR (ii) Non-MDR (iii) MDR (iii) MDR (b) Cat II failure: (a) MDR (b) Non - MDR (b) Non - MDR

5. Inflow of patients in OPD… III Already taken second line drugs Treatment has to be individualized Treatment has to be individualized

6. Failure to Differentiate MDR-TB MDR-TB Treatment Failure Treatment Failure Suspected drug resistance Suspected drug resistance

7. Aims during Hospitalization Detailed evaluation of patients Detailed evaluation of patients Establish linkage with DOTS plus, if exists Establish linkage with DOTS plus, if exists Involve Health education officer, social worker, clinical psychologist Involve Health education officer, social worker, clinical psychologist Choose proper regimen Choose proper regimen Identify and treat any side effect/ toxicity Identify and treat any side effect/ toxicity Ensure proper follow up after discharge Ensure proper follow up after discharge

8. Sputum smear/ culture/ drug sensitivity studies Two pre-treatment DST specimens recommended Two pre-treatment DST specimens recommended Conventional methods take 3-4 months Conventional methods take 3-4 months Rapid culture methods: expensive, ? availability Rapid culture methods: expensive, ? availability DST for second line drugs not available routinely, standardization/ technical problems DST for second line drugs not available routinely, standardization/ technical problems

9. Regimen STR - Standardized treatment regimen STR - Standardized treatment regimen ITR - Individualized treatment regimen ITR - Individualized treatment regimen

10. DOTS-Plus LRS Treatment Regimen IP : - Kana, Cyclo, Ethio, PZ, Oflox IP : - Kana, Cyclo, Ethio, PZ, Oflox - 6-9 months - 6-9 months - 3 consecutive monthly spt culture negative - 3 consecutive monthly spt culture negative CP : - Cyclo, Ethio, Oflox CP : - Cyclo, Ethio, Oflox - Minimum 18 mth after sputum Conversion - Minimum 18 mth after sputum Conversion

11. Treatment Regimen at LRS… STR for DOTS Plus patients Duration of IP : Minimum of 6 months or until 3 consecutive months of negative sputum culture whichever is later, upto a maximum of 9 months Admission: at least for one month

12. STR Regimen at LRS Institute Constraints during IP: Waiting for 3 negative cultures prolongs IP 39% patients: injections for 6 months 39% patients: injections for 6 months 34% patients: injections for 9 months 34% patients: injections for 9 months Operational problems Operational problems Malnourished patient, poor muscle mass: difficult to give injections for 6-9 months Malnourished patient, poor muscle mass: difficult to give injections for 6-9 months

13. Other Treatment Regimen at LRS… ITR for some patients IP: 5-6 drugs (aminoglycoside, quinolone, ethionamide, pyrazinamide and 1-2 other drugs) IP: 5-6 drugs (aminoglycoside, quinolone, ethionamide, pyrazinamide and 1-2 other drugs) Continuation phase: 3-4 drugs Continuation phase: 3-4 drugs Hospitalization: usually prolonged Hospitalization: usually prolonged

14. Toxicity/ Side effects Severe psychosis: 4/56 patients Severe psychosis: 4/56 patients Ototoxicity: 6/90 patients Ototoxicity: 6/90 patients Hypothyroidism: 3/32 patients Hypothyroidism: 3/32 patients Minor: hepatitis, joint pains, nausea Minor: hepatitis, joint pains, nausea

15. Issues during Hospitalization STR vs ITR STR vs ITR Second line drugs are expensive Second line drugs are expensive Malnourished patients: 6- 9 months injections difficult Malnourished patients: 6- 9 months injections difficult Weight gain during treatment: ? Adjust dosage Weight gain during treatment: ? Adjust dosage Waiting for 3 negative culture, IP is extended Waiting for 3 negative culture, IP is extended

16. Issues during Hospitalization … Actions in case of drug intolerance: no defined protocol Actions in case of drug intolerance: no defined protocol Toxic reactions may need referral to other specialties e.g. psychiatrist, endocrinologist, ENT Toxic reactions may need referral to other specialties e.g. psychiatrist, endocrinologist, ENT If one/two drugs not tolerated- limited choice for alternative drugs If one/two drugs not tolerated- limited choice for alternative drugs Limited experience with alternative drugs e.g. Amox- clauvulanic acid, clofazimine, Clarithromycin Limited experience with alternative drugs e.g. Amox- clauvulanic acid, clofazimine, Clarithromycin

17. Issues during Hospitalization … Difficult to calculate requirement for alternative drugs with limited expiry period Difficult to calculate requirement for alternative drugs with limited expiry period Conventional DST take 3-4 months Conventional DST take 3-4 months Too many cultures - adds to load on laboratory Too many cultures - adds to load on laboratory Not sure of DOT after discharge: prolonged hospitalization Not sure of DOT after discharge: prolonged hospitalization

18. Other Issues Management of MDR-TB with HIV Management of MDR-TB with HIV Management of MDR-TB with co-morbid conditions e.g. liver/ kidney problems Management of MDR-TB with co-morbid conditions e.g. liver/ kidney problems Prolonged hospitalization: social problems, extra-marital relationships, broken marriages, loss of job Prolonged hospitalization: social problems, extra-marital relationships, broken marriages, loss of job Preventive therapy to pediatric/ adult contacts Preventive therapy to pediatric/ adult contacts Preventive measures for spread of MDR-TB in hospitals Preventive measures for spread of MDR-TB in hospitals

19. Thank you

20. DOTS-Plus LRS Resistance Pattern of S,Z,E m MDR Patients

21. DOTS-Plus LRS Resistance Pattern

22. % DOTS-Plus LRS Time to Conversion Cohort 2002-03 (2 year) n = 26

23. DOTS-Plus LRS Treatment Outcome 2002 Cohort n = 13

24. DOTS-Plus LRS Hospitalization Minimum one month Minimum one month Linkage with TBHV in field Linkage with TBHV in field Health education & social support Health education & social support Ascertain tolerability to drugs Ascertain tolerability to drugs

25. DOTS-PLUS LRS Age Distribution Age Group

26. DOTS-Plus LRS Sex Distribution n = 58 Gender Proportion

27. DOTS-Plus LRS Sputum Conversion Cohort 2002-03 (2 year) n = 38

28. DOTS-Plus LRS Treatment Regimen Resistance / Toxicity to any drug - replace it with PAS Resistance / Toxicity to any drug - replace it with PAS Capreo replaces Kana Capreo replaces Kana Premature termination - Committee Premature termination - Committee

29. DOTS-PLUS LRS Age Distribution Age Group

30. DOTS-Plus LRS Sex Distribution n = 58 Gender Proportion

31. DOTS-Plus LRS Resistance Pattern of S,Z,E m MDR Patients

32. DOTS-Plus LRS Treatment Outcome 2002 Cohort n = 13

33. Actions during Hospitalization Detailed history of previous regimen & doses Detailed history of previous regimen & doses List the drugs already taken/ not taken List the drugs already taken/ not taken H/o contact with MDR in family/work place H/o contact with MDR in family/work place Previous DST if available Previous DST if available Co-morbid conditions e.g. diabetes, liver/ kidney problems, psychiatric illness etc Co-morbid conditions e.g. diabetes, liver/ kidney problems, psychiatric illness etc

34. Discrepant results of DST Consider laboratory technique (reference laboratory more reliable) Consider laboratory technique (reference laboratory more reliable) Discuss with laboratory incharge Discuss with laboratory incharge Review treatment history and assess resistance amplification Review treatment history and assess resistance amplification Therapy to be based on most resistance antibiogram. Therapy to be based on most resistance antibiogram.

36. Investigations Hemogram Hemogram Blood Sugar F, PP Blood Sugar F, PP LFT, KFT, Serum electrolytes LFT, KFT, Serum electrolytes HIV test with consent and counseling HIV test with consent and counseling X-Ray Chest: cavity, extent of lesion X-Ray Chest: cavity, extent of lesion ECG ECG Other specific tests if required Other specific tests if required

37. Initial approach to MDR-TB Management (a) Suspicious of MDR-TB Stop failing therapy Stop failing therapy Preferably wait for DST studies - but require 3-4 months by conventional methods Preferably wait for DST studies - but require 3-4 months by conventional methods If condition very poor, start empiric MDR TB treatment If condition very poor, start empiric MDR TB treatment Prior to empiric MDR TB treatment, at least confirm positive culture Prior to empiric MDR TB treatment, at least confirm positive culture Keep Amplification of Drug Resistance in mind Keep Amplification of Drug Resistance in mind

38. Initial approach to MDR - TB Treatment (b) Documented MDR – TB Stop failing therapy Stop failing therapy If patient received treatment after last DST, repeat DST before starting treatment If patient received treatment after last DST, repeat DST before starting treatment Start MDR - TB treatment Start MDR - TB treatment

39. Principals of ITR Consider past history of drugs, contact, DST Consider past history of drugs, contact, DST Cost e.g cycloserine is very expensive Cost e.g cycloserine is very expensive Tolerance e.g. cycloserine, thiacetazone, PAS Tolerance e.g. cycloserine, thiacetazone, PAS Cross resistance e. g. quinolones, aminoglycosides Cross resistance e. g. quinolones, aminoglycosides Choose drugs as per efficacy Choose drugs as per efficacy Start with at least four, preferably five, drugs with one parenteral drug Start with at least four, preferably five, drugs with one parenteral drug Adjust to definitive regimen according to DST report later Adjust to definitive regimen according to DST report later

40. Principals of STR Consider regional Epidemiology Consider regional Epidemiology Consider cost, tolerance, availability of drugs Consider cost, tolerance, availability of drugs Foundation of at least 4, ideally 5, drugs including one parenteral agent Foundation of at least 4, ideally 5, drugs including one parenteral agent

41. Regimen at LRS Institute Continuation phase Drugs : Ethionamide, Cycloserine, ofloxacin Duration : At least 18 months after sputum conversion

42. Sputum examination during hospitalization During Intensive Phase Two sputum specimen smear and culture on consecutive days every month Two sputum specimen smear and culture on consecutive days every month If sputum positive at 6 months ; continue IP and repeat DST to look for augmentation of drug resistance and review by DOTS plus committee If sputum positive at 6 months ; continue IP and repeat DST to look for augmentation of drug resistance and review by DOTS plus committee (Recommended is repeat DST every 3 months till sputum is negative) (Recommended is repeat DST every 3 months till sputum is negative)

43. Sputum examination during continuation phase Once every two months - two specimens of smear and culture on consecutive days Once every two months - two specimens of smear and culture on consecutive days After initial conversion during CP if one culture is positive, repeat sputum at monthly intervals till 3 cultures are negative After initial conversion during CP if one culture is positive, repeat sputum at monthly intervals till 3 cultures are negative

44. Monitoring of side effects Identify common side effects Identify common side effects Define protocols for the management of known side effects Define protocols for the management of known side effects Preventive therapy/ investigations for known side effects Preventive therapy/ investigations for known side effects Replace drugs, if required and not tolerated as a last resort Replace drugs, if required and not tolerated as a last resort