DOTS PLUS IN DEVELOPING COUNTRIES EXPERIENCES & IMPLICATIONS

1. DOTS PLUS IN DEVELOPING COUNTRIESEXPERIENCES & IMPLICATIONS Dr. Nirmal Kumar Jain MD, DNB(RM) Professor & Head and Medical Superintendent Hospital for Chest Disease & Tuberculosis SMS Medical College, Jaipur

2. DOTS PLUS • A case management strategy under development, designed to manage MDR-TB using second line drugs within the DOTS strategy in low – and middle – income countries. To prevent further development and spread of MDR-TB.

3. DOTS-PLUS PREREQUISITES • The potential DOTS-Plus pilot project site should : • DOTS strategy is in place and is functioning well. • Government commitment and adequate funding. • Co-ordinated project management plan. • Adequate laboratory services. • Rational treatment strategy. • Adequate information (data) management system.

4. DOTS REFERALS

5. PATIENT PUT ON MDR-TB TREATMENT

6. FACTORS RESPONSIBLE FOR TREATMENT FAILURE AMONG PATIENTS ON DOTS REGIMEN BY Dr. N.K. Jain Dr. Himanshu Garg Dr. Shubhranshu Dr. S.P. Agnihotri Dr. N. Joshi Dr. S. Koolwal Deptt. of Chest Diseases & Tuberculosis, SMS Medical College, Jaipur.

7. DISTRIBUTION OF PATIENTS ACCORDING TO CATEGORY OF TREATMENT

8. MYCO BACTERIAL CULTURE & SENSITIVITY PATTERN OF CATEGORY I FAILURE PATIENTS H= Isoniazid, R= Rifampicin, E= Ethambutol, S= Streptomycin, Q= Quinolones

9. DISTRIBUTION OF CATEGORY II FAILURE PATIENTS ACCORDING TO HISTORY OF CHEMOTHERAPY

10. MYCO BACTERIAL CULTURE & SENSITIVITY PATTERN OF CATEGORY II FAILURE PATIENTS Ed=Ethionamide, T=Thioaceteazone, P=Para Amino Salicylic Acid

11. DRUGS FOR MDR-TBRESERVE ANTI-TUBERCULOSIS DRUGS. • Aminoglycosides. Amikacin. 7.5mg/kg Hearing loss, ataxia, b.i.d. Nystagmus,Azotemia, Protein urea etc. Kanamycin 15 mg/kg --do-- Capreomycin 15 mg/kg --do-- • Others. PAS 200 mg/kg Nausea, Vomiting, Diarrhea, Hepatitis Ethionamide 15 mg/kg Nausea, Vomiting, Hepatitis Prothionamide 15 mg/kg --do-- Cycloserine 15 mg/kg Neurotoxicity, Heart failure

12. Newer Anti-tuberculosis Drugs. • Quinolones. Ciprofloxacin. 1000-1500 mg/day Nausea, Vomiting, Ofloxacin. 200-800 mg/day Diarrhoea, Insomnia, Pefloxacin. 400-800 mg/day Headache, Skin Rash, Lomefloxacin. 400-800 mg/day Tremulous, Sparfloxacin. 200-400 mg/day Drug Interactions. Levofloxacin. 500 mg/day - Gatifloxacin. 400 mg/day - Moxifloxacin. 400 mg/day -

13. Newer and ExperimentalAnti-tuberculosis Drugs. • Macrolides. Roxithromycin. 300 mg/day G.I. Disturbances, Nausea, Diarrhoea, Dyspepsia & Pain Clarithromycin . 500-2000mg/day Abdomen, Dysphoria, Enzyme (High Dose). Azithromycin. 500 mg/day • Rifamycin Derivatives. Rifabutin. 300 mg/day Nausea, Vomiting, Hepatitis, Flulike, Syndrome, Renal failure, Rifabutin. 600 mg/day Thrombocytopenia, Haemolytic anemia. Rifalazil. - -

14. Newer and ExperimentalAnti-tuberculosis Drugs. • B-Lactamase Inhibitors. Amoxycillin + 500+125 (625mg)/ Skin rash, Anaphylaxis, Clavulanate. 750 to 2gm Diarrhea, Candidiasis, PM, Collitis, Hepatitis Ticarcillin + - & Cholstatic Jaundice. Clavulanate. • Immunophenazine Derivatives. Clofazemine 100-200 mg/day. Skin pigmentation, GI upset. • Oxazolidinones.- - • Nitroimidazopyrans. - -

15. Management of Multi Drug Resistant Tuberculosis. 1.Retreat with at least 3 or 4 new drugs for first 3 to 6 months (Total 5 to 7 drugs). 2. Continue chemotherapy with 2 to 3 new drugs. 3. Previously used drugs may be used in addition. 4. Use combinations with little potential of cross resistance. 5. A single drug should never be added.

16. Management of Multi Drug Resistant Tuberculosis. 6. Start with small dosage, increase to maximum. 7. Treatment should be initiated in hospital/directly supervised. 8. Careful bacteriological monitoring essential. 9. Surgery/ Immunotherapy should be considered in patients poorly responding to medical treatment. 10. All measures – not to stop treatment. 11. Intermittent therapy usually not effective. • Optimal duration, 18-to-24 months after culture conversion.

17. MDR TB treatment regimens Resistance profile Initial phase Continuation phase drugs months drugs months Isoniazid Aminoglycoside 3-6 Ethambutol 18-24 +rifampicin Ethambutol ± pyrazinamide (ASCC) ± streptomycin Pyrazinamide Quinolone Quinolone Ethionamide Ethionamide Comments • Aminoglycoside not previously used as injectable drug for 3 to 6 months • ETB dose may be increased to 25 mg/kg • PZA in the continuation phase may add to response rate • Inclusion of ETB & PZA – associated with favourable outcome • Consider surgery if no conversion after 6 months

18. MDR TB treatment regimens Resistance profile Initial phase Continuation phase drugs months drugs months Isoniazid Aminoglycoside 3-6 ± pyrazinamide 18-24 + rifampicin Pyrazinamide Quinolone (ASCC) + ethambutol Quinolone Ethionamide ± streptomycin Ethionamide PAS/Cycloserine PAS/ Cycloserine Comments • Aminoglycoside not previously used as injectable drug for 3 to 6 months • PZA in the continuation phase may add to response rate • Consider surgery if no conversion after 6 months

19. MDR TB treatment regimens Resistance profile Initial phase Continuation phase drugs months drugs months Isoniazid Aminoglycoside 3-6 Ethambutol 18-24 + rifampicin Ethambutol Quinolone (ASCC) + pyrazinamide Quinolone Ethionamide ± streptomycin Ethionamide PAS/Cycloserine PAS/ Cycloserine Comments • Aminoglycoside not previously used as injectable drug for 3 to 6 months • ETB dose may be increased to 25 mg/kg with careful monitoring for retrobulbar neuritis • PZA in the continuation phase may add to response rate • Consider surgery if no conversion after 6 months

20. MDR TB treatment regimens Resistance profile Initial phase Continuation phase drugs months drugs months Isoniazid Aminoglycoside 3-6 Quinolone 18-24 + rifampicin Quinolone Ethionamide (ASCC) + ethambutol Ethionamide PAS + pyrazinamide PAS Cycloserine ± streptomycin Cycloserine Comments • Aminoglycoside not previously used as injectable drug for 3 to 6 months

21. Potential Regimen for Patients with Multi Drug Resistant Tuberculosis. Resistance. Suggested Duration. Regimens. HR (+ S)* AEZQ 24 months. HER (+ S)* AZQ+2 24 months. ASC HRZ (+ S)* AEQ+2 24 months. ASC HRZ (+ S)* AQ+3 24 months. ASC A=Aminoglycoside - SM/KM/CM/AM Q=Quinolones - Cipro/Oflo/Spar/Levo/Gati + = 2 or 3 drugs among ETH/PTH/PAS/CYC/Macrolides/-lactam inhibitor/Others. * = Surgery may be considered.

22. PRIORITY RESEARCH AGENDA FOR DOTS-PLUS FOR MDR-TB • Primary topics • Identify optimal standardised protocols to treat MDR-TB. • Identify optimal protocols for diagnostic testing. • Identify the minimum requirement for constructing and implementing DOTS-Plus. • Secondary topics • Identify threshold indicators for implementing DOTS-Plus. • Other operational issues.

23. EFFICACY OF DIFFERENT REGIMENS IN TREATMENT OF DOTS CATEGORY II FAILURE OF PULMONARY TUBERCULOSIS BY Dr. N.K. Jain Dr. Shubhranshu Deptt. of Chest Diseases & Tuberculosis, SMS Medical College, Jaipur.

24. RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 6 MONTHS *Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration.

25. RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 12 MONTHS *Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration. Contd…

26. RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 12 MONTHS *Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration.

27. RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 18 MONTHS *Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration. Contd…

28. RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 18 MONTHS *Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration.

29. COMPARISON OF OVERALL RESPONSE OF DOTS CATEGORY II FAILURE ON DIFFERENT REGIMEN AT THE END OF 18 MONTHS

30. ISSUES DOTS MDR-TB TB Suspects -H/O cough for 3 weeks -Failure of RNTCP Cat.II(Chronic case) or more duration -Patients receiving inappropriate, incomplete, irregular teratment, 2 or more time against NTCP policy. Diagnostic -3 sputum examination -Direct microscopy modalities (Spot-Early Morning-Spot) 0,2,3,4,5,6,9,12,15,18,21,24 - Early Morning-Spot - Myco C/S test Cat.I 2,4,6 0,3,6,9, --- Cat.II 3,5,8 -X-ray Cat.III 2,6 0,3,6,9,12,15,18,24 Outcome -Cure rate in new smear +ve -40-60% cases=85% or more -Cure rate in re-treatment cases=70% or more

31. ISSUES DOTS MDR-TB Management -IP: 3/7 (Thrice a week on alternate day) -IP: 7/7 (Daily) -CP: 1/7 (Thrice a week on alternate day, -CP: 7/7 (Daily) one dose supervised) Cost on Investigation -Rs. 0-100/- -10,000/- Cost -Cat. I 2(HRZE)3/ 4(HR)3 Rs.600/- - KHEZQEd/HEZQEd Rs.21688 -Catt.II 2(SHRZE)3/ 1(HRZE)3/ - KHEZQP/HEZQP Rs.28996 5(HRE)3 Rs.760.78/- - KHEZQPEd/HEZQPEd Rs.37096 -Cat.III 2(HRZ)3/ 4(HR)3 Rs.411.90/-

32. DRAFT POLICY SUGGESTIONS • Emphasis should be given to prevent MDR-TB by wider use of DOTS by medical professionals and to achieve cure rate of more than 85% in new sputum positive cases and more then 70% in retreatment cases. • Wider community participation by identifying their strengths. • II line drugs should be used only when resistance to I line drugs exists or patients fails on WHO Category II regimen. • Drugs under EDL should be used on priority basis, as these are effective, less toxic, affordable and well tolerated by patients. Kanamycin and Ethionamide be included in EDL. • Treatment of MDR-TB should be supervised and drugs should be made available for not more than 15 days. Treatment should be supervised by the nearest DOT provider and empty strip/blister packs be deposited fortnightly. 6. In intensive phase: 1 injectable & 3-4 oral drugs may be administered for 3 to 6 months. In continuation phase: 3 oral drugs preferably those not used in past may be administered for 18 months. Contd. …

33. DRAFT POLICY SUGGESTIONS 7. II line drugs should be guaranteed available in specialized units attached with laboratories having culture & sensitivity facility. 8. II line drugs should be available on prescription of highly skilled specialist (Prof./Ass.Prof. of TB & Chest Hospitals). 9. MDR-TB prescription can be scrutinized by EDL committee made for rational use on Anti-TB drugs. 10. EDL committee be asked to submit report on rational use of II line drug in terms of combination, intermittency and length of time, cost incurred, cost effectiveness and prohibitory cost. 11. Since MDR-TB treatment is a last crusade against TB for survival, as per WHO recommendations, II line drugs need to be administered under strict supervision of a personnel who is highly skilled.

38. DOTS PLUS IN DEVELOPING COUNTRIES • Ensure effective DOTS – No further MDR-TB. • Early diagnosis of MDR-TB High index suspicion - smear +ve at 3rd month Mycobacterial C/S - continuation of DOTS • Standardized treatment regimens possible I-KHEZQP/HEZQP II-KHEZQEd./ HEZQEd. III-KHEZQPEd./ HEZQPEd. • Reliable supply of high quality II line anti-TB drugs • All measures of strict adherence to therapy • Rigorous quality assurance, monitoring & evaluation Most cost effective According to pattern of local resistance.

39. THANKS