1. Group II Treatment regimens, hospitalization. DOT provision, outcome definitions, management of adverse drug reactions

2. Presumptions at the onset …before we start, we presume that group-I’s recommendations would probably include the following: The intake would be of only Cat II failures from RNTCP – DOTS PLUS RNTCP accredited labs would do the smear and culture results for investigations and follow-up The Drug Sensitivity testing (investigation stage) would be done for the following drugs only: HRES

3. Requirement for hospitalisation It is recommended all patients be admitted to the designated specialised institution for at least 2 to 4 weeks with the objective to: –Undertake necessary investigations –Initiate MDRTB treatment –Monitor drug tolerance –Motivation, counseling, health education –Developing linkages in the field –Contact assessment Subsequent hospitalisation may be required for management of ADR, complications and to assess need for surgical intervention, social reasons etc

4. STR versus ITR STR was chosen for operational reasons

5. Number of drugs in IP The “HR resist. only” group and “HR+one drug resist” group together would probably constitute more than 60% in any given cohort of MDR cases Therefore a five drug IP regimen would give an armamentarium of at least four effective drugs to most patients One drug would be kept as reserve as a fall-back choice in case any adverse drug reaction necessitated withdrawal of one drug One injectable and four oral drugs

6. IP regimen - Aminoglycoside The group felt that Kanamycin was the better choice for Aminoglycoside: –Only about 50% of patients who have taken RNTCP cat II are likely to be sensitive to streptomycin –It may not be possible to give streptomycin for 9 months as the vestibulo-cochlear toxicity would be too much –Capreomycin is prohibitively costly and difficult to store To minimise cross resistance: decision is to be taken as such: If resistant to SM Kana/Amikacin; If resistant to Kana/ Amika use Capreo.

7. IP regimen - Quinolones The group noted that quinolones especially Oflox and Ciproflox are used universally in OPDs in the country for common illnesses like URI, pyrexia etc. However the limited literature available shows that resistance to quinolones in India is very less Ofloxacin was recommended as the drug of choice for the DOTS plus regimen because of: –Most widely studied drug in MDR-TB –Less toxicity as compared to newer quinolones like Gatiflox and Moxiflox (Gati & Moxi need CCT in Indian scenario) –Cost factor - affordable –Availability

8. IP Regimen – Others Ethionamide – Cheap, available, tolerance good Pyrazinamide – Only drug which acts in acidic pH Ethambutol – The group raised concerns about the standardisation of Etambutol resistance; however ethambutol is a valuable drug to be used in IP Thiacetazone is not available any more; bacteriostatic The following were kept as reserve drugs in case of resistance/ intolerance to any drug: 1.PAS – Toxic, doubtful bio-availability in some, bacteriostatic Will be kept as a reserve drug 2.Cycloserine – Bacteriostatic, Toxicity is too much: Therefore it is not being included as mainline drug.– will be kept as second reserve drug

9. The agreed to IP regimen consists of : Five mainline drugs: –Kanamycin –Ofloxacin –Ethionamide –Pyrazinamide –Ethambutol One reserve drug: –PAS –Cycloserine

10. IP regimen: Modality of administration All drugs would be given as Daily DOT for 6 days a week; EVERY DOSE IN DOTS PLUS SHOULD BE SUPERVISED

11. IP regimen- Duration The group came to the consensus that the intensive phase should be given for a minimum duration of 6 months, upto 9 months. Monthly sputum smear examination and sputum culture would be conducted to monitor response to therapy IP regimen would be given till at least three consecutive negative smears AND last available culture is negative. If the above two results are not available, IP will be extended till such result is obtained; upto a maximum of 9 months Decision to stop IP and start CP will be ratified by the hospital’s DOTS Plus Committee In rare cases where the patient remains sputum positive by culture at 9 month and patient is tolerating injectable drugs, injectable will continue till sputum conversion???

12. CP- Duration The group recommends that the continuation phase should be: -for at least 18 months after culture conversion CP- Drugs The three drugs are: Ethionamide, Ofloxacin, Ethambutol These are to be given as daily doses for 6 days a week; all doses would be DOT Intolerance to any drug in CP: offending drug may be replaced by PAS/ Cycloserine

13. DOTS Plus regimen: Dosages The average body weight of the MDR TB patient in India is 40 kgs. So two weight bands are recommended: Drugs< 40 kg body wt.> 40 kg body wt. Kanamycin 500 mg750 mg Ofloxacin 600 mg800 mg Ethionamide 500 mg750 mg Ethambutol 800 mg1200 mg Pyrazinamide 1500 mg1750 mg PAS 10 gm12 gm Cycloserine 500 mg750 mg

14. Outcome Definitions Cure : Patient has completed treatment and is culture negative for the last 12 months of treatment. A single intervening positive culture should be ignored provided it is followed by 3 consecutive negative cultures. Treatment completed. A patient who has completed entire treatment but due to lack of bacteriological results does not fulfill the definitions of cure Default: A patient who interrupted treatment for two or more consecutive months Death: A patient who died from any cause during treatment

15. Outcome Definitions Failure: A patient with more than one positive culture in the last 12 months of treatment with a minimum of five cultures performed in last 12 months. A patient will also be considered treatment failure if one of the last three culture during treatment is positive or if he/she is persistently culture positive and decision has been taken to terminate treatment early by the DOTS plus committee. Adverse reactions: A patient who could not continue STR due to severe adverse drug reactions as decided by the DOTS plus committee

16. Outcome Definitions Transfer out: A patient has been transferred to another MDR-TB unit and whose outcome will be reported by the receiving unit Still on treatment: A patient who is still on treatment at the time of the cohort reporting

17. Adverse drug reactions The document circulated by TRC endorsed by the group RNTCP should make provisions for making ancillary drugs available Training on management of ADR should be incorporated at all levels Decision to change/stop treatment should be by the DOTS plus committee

18. MDRTB- special situations MDRTB with pregnancy MDRTB in Pediatric/EP site MDRTB with HIV infection MDRTB in patients with renal/hepatic failure Preventive therapy to paediatric and adult contacts