1. Trials and evidence in relation to health policy: The case of tuberculosis in Nepal and India Ian Harper

2. Rifampicin

3. Overview of presentation Rifampicin, and its history in TB control Rifampicin, and its history in TB control Regulation Regulation –DOTS –Procurement for NTPs Relations between the private sector and NTP (India and Nepal) Relations between the private sector and NTP (India and Nepal) Conclusion Conclusion

4. Summary of TB treatment in the pharmaceutical era Monotherapy doesn’t work, and treatment has to be a combination of chemotherapy agents Monotherapy doesn’t work, and treatment has to be a combination of chemotherapy agents The discovery and production of rifampicin key in bringing TB out of the sanitorium and the development of ambulatory treatment. The discovery and production of rifampicin key in bringing TB out of the sanitorium and the development of ambulatory treatment. Length of treatment means the question of adherence is crucial Length of treatment means the question of adherence is crucial

5. Drugs currently used for TB treatment FIRST LINE DRUGS Isoniazid (H) Isoniazid (H) Rifampicin (R) Rifampicin (R) Ethambutol (E) Ethambutol (E) Pyrazinamide (Z) Pyrazinamide (Z) Streptomycin (S) Streptomycin (S) SECOND LINE DRUGS Kanamycin (KM) Kanamycin (KM) Amikacin (AMK) Amikacin (AMK) Capreomycin (CM) Capreomycin (CM) Quinolones (FQ) – Cipro, Ofx, Gfz, Mfx Quinolones (FQ) – Cipro, Ofx, Gfz, Mfx Ethionamide or Prothionamide (Thiamides) Ethionamide or Prothionamide (Thiamides) Cycloserine (CS) or Terizdone (Tzd). Cycloserine (CS) or Terizdone (Tzd). Para-aminosalicylic Acid (PAS) Para-aminosalicylic Acid (PAS)

6. Current Treatment recommendations (first line) Treatment based on the idea of a “intensive phase” (IP) and then “continuation phase” (CP) Treatment based on the idea of a “intensive phase” (IP) and then “continuation phase” (CP) At least two bacteriacidal drugs in the IP. Adding pyrazinamide decreases overall treatment to 6 months At least two bacteriacidal drugs in the IP. Adding pyrazinamide decreases overall treatment to 6 months CP mops up residual bacilli and results in less likelihood of relapse CP mops up residual bacilli and results in less likelihood of relapse

7. Drug Resistance MDR defined as resistance to at least rifampicin and isoniazid MDR defined as resistance to at least rifampicin and isoniazid Rifampicin key to the debate, and has to be “protected” (including): Rifampicin key to the debate, and has to be “protected” (including): –Limit availability to national regimes –Make it only available in FDCs –Observation of patients taking drugs

9. India and Nepal’s national regimes India has an intermittently administered regime (3x per week) India has an intermittently administered regime (3x per week) Nepal has daily therapy (and till 4 months ago) had no rifampicin in the continuation phase Nepal has daily therapy (and till 4 months ago) had no rifampicin in the continuation phase Each has three categories of treatment (i, ii, iii) Each has three categories of treatment (i, ii, iii) Each must have a “directly observed” component (rephrased in 2006 as “patient support”) Each must have a “directly observed” component (rephrased in 2006 as “patient support”)

10. Why intermittent therapy? (India) DOT seen as an absolute must for rifampicin based combinations DOT seen as an absolute must for rifampicin based combinations Logic is that it is therefore easier on the patients to have this only three times per week, rather than daily Logic is that it is therefore easier on the patients to have this only three times per week, rather than daily Cost Cost

11. Evidence base? Friedman (2004) in a review suggests that intermittent therapy is as good as daily, and that animal model experiments suggest there is an increase in efficacy of HRZ, and is “perhaps slightly more effective than the daily regime” Friedman (2004) in a review suggests that intermittent therapy is as good as daily, and that animal model experiments suggest there is an increase in efficacy of HRZ, and is “perhaps slightly more effective than the daily regime” Cochrane (2005) argue no evidence to support assertions that IR is better than daily (need more research) Cochrane (2005) argue no evidence to support assertions that IR is better than daily (need more research)

12. Why eight month regime? (Nepal) WHO and IUATLD don’t like rifampicin through whole regime (“protect the rifampicin”) WHO and IUATLD don’t like rifampicin through whole regime (“protect the rifampicin”) Less likely to get rifampicin resistance should patients relapse Less likely to get rifampicin resistance should patients relapse Claims of less DOT burden on the patient (two months rather than six) Claims of less DOT burden on the patient (two months rather than six) Cost Cost (NB Nepal’s regime changed in Dec 2008 to rifampicin based in the continuation phase) (NB Nepal’s regime changed in Dec 2008 to rifampicin based in the continuation phase)

13. Methods Interviews with prescribers (chest physicians and GPs) Interviews with prescribers (chest physicians and GPs) Interviews and visits to DOTS clinics, and government officials Interviews and visits to DOTS clinics, and government officials Interviews with retailers etc. Interviews with retailers etc. Interviews with company representatives Interviews with company representatives (Nepal, West Bengal, Delhi and UP)

14. Perceptions of the regime and DOTS (prescribers) Very inconvenient for patients Too cumbersome and rigid in implementation (e.g. not good for migrants) DOTS only for poor patients, and not the best Intermittent regime based on costs, not science: India is a “poor” country Not enough dosage flexibility

15. Category 2 is adding one drug to a “failing regime” and contradicts WHO’s own policy DOTS policy based on “irrational optimism” Don’t know MDR levels, regime may be wrong and feeding further resistance (India) Free drugs a bad idea- people don’t take it seriously Perception that the WHO and the NTP don’t listen to their concerns and take them seriously

16. Why private sector better? (self perceptions) Flexibility on dose and weight schedules Flexibility on dose and weight schedules Regime too short Regime too short Easier on patients (no DOT), “why go the clinic when you could go to work”? Easier on patients (no DOT), “why go the clinic when you could go to work”? Accountability Accountability Poor performance and quality of the government system; lack of trust Poor performance and quality of the government system; lack of trust Trust in certain company products (Lupin in particular) Trust in certain company products (Lupin in particular)

17. In Nepal… Widespread resistance to the national regime because no rifampicin in the CP Widespread resistance to the national regime because no rifampicin in the CP Greater flexibility for patients Greater flexibility for patients Distrust of the claims made by the NTP Distrust of the claims made by the NTP

18. Differences between Nepal and India Scale Scale DOTS in Nepal much more widely known DOTS in Nepal much more widely known Nepal: Reports of decreased sales of TB drugs from retailers (e.g. where there are well functioning DOTS clinics) Nepal: Reports of decreased sales of TB drugs from retailers (e.g. where there are well functioning DOTS clinics) Major Indian TB drug producers dominate the Nepal market (Lupin, MacLeods, Concept, Cadilla) Major Indian TB drug producers dominate the Nepal market (Lupin, MacLeods, Concept, Cadilla) As such rifampicin now mainly available as either FDCs or is “strip” packs As such rifampicin now mainly available as either FDCs or is “strip” packs Complaints by prescribers of lack of availability of uncombined rifampicin on the market (eg Paediatric formulations) Complaints by prescribers of lack of availability of uncombined rifampicin on the market (eg Paediatric formulations) Criticisms of each regime are technical and specific to each Criticisms of each regime are technical and specific to each

19. Discussion points Don’t ignore the perceptions of private practitioners, because Don’t ignore the perceptions of private practitioners, because –They confirm the lack of flexibility of DOTS and its failure to respond to patient needs –They adapt to patient demands –BUT variability of treatments a problem –Never sure what the financial incentives are DOTS must be more flexible AND consistent DOTS must be more flexible AND consistent