1. The Challenge of MDR Meeting with Journalists Organizer: National Press Foundation Lille, October 27, 2011 Presenter: Hans L Rieder The Union, Paris, France University of Zurich, Switzerland

5. Drug A kills susceptible organisms Drug A kills Drug B-resistant mutants Drug B kills Drug A- resistant mutants Drug B kills susceptible organisms

9. Probability of resistant mutant: 1 in 10 6 for drug A 1 in 10 6 for drug B (1 in 10 6 ) x (1 in 10 6 )= 1 in 10 12 for both drug A and drug B  2 drugs to which the organism is susceptible should suffice

11. Potential Risks for Acquisition of MDR oSettings with a high prevalence of initial isoniazid resistance oSettings with a high prevalence of HIV infection among tuberculosis patients oSettings with self-administered fixed-dose combinations

13. 1954 2004

14. World Health Organization. WHO Expert Committee on Tuberculosis. Eighth Report. Tech Rep Ser 1964;290:1-24 “Drug resistance is a man-made problem…” From poor policy…. i.e., 2 SH / 10H or 2 PH / 10H is “acceptable practice” …or is that’s why we now have a mess 40 years later?

15. National Tuberculosis Institute Bangalore. Bull World Health Organ 1974;51:473-89 Responsible for conduct and report include: A Geser (WHO Epidemiologist) and T Olakowsi, WHO Medical Officer “Drug resistance is a man-made problem…” …to bad practice

16. Monoresistance: 1 drug Polyresistance: 2 or more drugs Isoniazid Other drugs Other polyresistance INH-RMP = “MDR” MDR “simple”: RMP-INH only XDR: RMP-INH-FQ-Injectable MDR “plus”: RMP-INH-FQ or RMP-INH-Inj Schematic: not a real quantitative distribution!

17. Principle of the cascade of regimens Provide a clinical trial-established first-line regimen with high likelihood of success to all new patients Provide a second-line regimen with high likelihood of success to all patients with a non-successful prior treatment outcome requiring re-treatment (failure, return after default, recurrent tuberculosis)

19. H res ? R res ? FQ-K res ? H monoresistance XDR MDR yes no 8- or 18-mo INH-throughout regimen: 2 S-H-PAS / 16 H-PAS 2 S-H-R-Z / 6 H 2 E-H-R-Z / 8 E-H ≥ 90% effective 9- to 12-mo FQ-throughout regimen: 4(+) K-G-T-C-H-E-Z / 5 G-C-E-Z ≥ 90% effective 6- or 8-mo RMP-throughout regimen: 2 S-E-H-R-Z / 6 E-H-R-Z 2 E-H-R-Z / 4 H-R ≥ 90% effective Complex! Toxic! 21-mo regimen – poor effectiveness (50%) The Regimen Cascade

20. Anti-Tuberculosis Drugs Essential drugs:Other drugs / classes: IsoniazidOther aminoglycosides RifampicinPolypeptides PyrazinamideThioamides EthambutolCycloserine StreptomycinPara-aminosalicylic acid ThioacetazoneFluoroquinolones Oxazolidinones Diarylquinolines

21. Treatment of MDR tuberculosis in Damien Foundation Projects, Bangladesh, 1997-2007 Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684-92

23. The (minimum) 9-month regimen for MDR in Bangladesh (220 €) Gatifloxacin Ethambutol Pyrazinamide Clofazimine Kanamycin Prothionamide Isoniazid 4-month intensive phase prolonged if still smear-positive after 4 months Fixed 5-month continuation phase Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684-92

24. Conclusions oA well-tolerated, effective treatment regimen for MDR tuberculosis has been developed over an 11-year period in Bangladesh among patients without HIV infection, naïve to prior use of second-line drugs oThe regimen is affordable (220 €) for low-income countries oThe regimen is simple enough to be prescribed, observed, and managed at regional or even peripheral level

25. Where to go from here? 1)Apply the regimen in multiple settings in which success is likely, to alleviate quickly the sorry state of affairs that only 2% of patients with MDR are estimated to currently obtaining treatment 2)Implement the appropriate research agenda: oSufficiently powered clinical trials to confirm or refute findings (funding?) oObservational studies in other countries with and without HIV infection among their tuberculosis patients (in progress) oDevelopment of sequentially adaptive regimens in settings which have lost fluoroquinolone or injectable drug activity oAny new regimen must retain drug affordability for the owners of the national programs

26. HrHr {HR} r {HR+} r {HRF} r {HRI} r {HRIF} r No 2 EHRZ / 6 EH Yes 2 EHRZ / 4 RH Bangladesh-type regimen Cascade of regimens XDR “MDR-plus” 90% effective Established with available generic drugs Requires new drug classes

27. Establish the frequency of MDR subsets HrRrHrRr HrRrFrHrRrFr HrRrIrHrRrIr HrRrFrIrHrRrFrIr Simple to cure Difficult to cure Almost impossible to cure ? 70%-90% ??1%-15% 1 1 Centers for Disease Control and Prevention. Morb Mortal Wkly Rep 2006;55:301-5

28. S SH PH SP SPHERHERHZ StreptomycinIsoniazidRifampicinFluoroquinolones Time axis of introduction of drug Regimen preferred by majority S: Streptomycin P: Para-aminosalicylic acid H: Isoniazid E: Ethambutol Z: Pyrazinamide Semiquantitative presentation of emergence of drug resistance

29. H-res Fully susceptible MDR XDR

30. 2 EHRZ / 4 HR 2 SEHRZ / 6 HR 4+ KPGHZEC / 5 GZEC HrRrIsFsHrRrIsFs HrRrIrFsHrRrIrFs HrRrIsFrHrRrIsFr HrRrIrFrHrRrIrFr The Union’s proposed revised cascade of regimens ????? Identical with WHO (also 2 EHRZ / 4 EHR) Different from WHO (2 SEHRZ / 1 EHRZ / 5 EHR) Aït-Khaled N, Alarcón E, Armengol R, Bissell K, Boillot F, Caminero J A, Chiang C Y, Clevenbergh P, Dlodlo R, Enarson D A, Enarson P, Fujiwara P I, Harries A D, Heldal E, Hinderaker S G, Monedero I, Rieder H L, Rusen I D, Trébucq A, Van Deun A, Wilson N. Management of tuberculosis. A guide to the essentials of good practice. (Sixth edition). Paris: International Union Against Tuberculosis and Lung Disease, 2010. Diarylquinolines? World Health Organization. Word Health Organization Document 2010;WHO/HTM/TB/2009.420:1-147

31. When is direct observation of treatment necessary? Direct observation of treatment is always recommended in the following cases: oTwo months initial phase of all new smear-positive cases; oFour months continuation phase of rifampicin- containing regimens, for all new smear-positive cases; Quoted from: World Health Organization 1997; WHO/TB/97.220:44

34. Just three core drugs * have emerged in almost 70 years of chemotherapy oIsoniazid oRifampicin o4 th generation fluoroquinolones (gatifloxacin, moxifloxacin) * Note: the notion of a “core drug” is a hypothetical research concept

35. Core drug-based * principles of chemotherapy oAchieve failure- and relapse-free cure through use of a core drug oEnsure that the core drug is safely protected by well-tolerated companion drugs against emergence of resistance against it * Note: the notion of a “core drug” is a hypothetical research concept