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The Challenge of MDR Meeting with Journalists Organizer: National Press Foundation

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. Drug A kills Drug B -resistant mutants. Drug B kills Drug A- resistant mutants. Drug A

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The Challenge of MDR Meeting with Journalists Organizer: National Press Foundation

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  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

  2. Drug A killsDrug B-resistant mutants Drug B killsDrug A- resistant mutants Drug A killssusceptible organisms Drug B killssusceptible organisms

  3. Probability of resistant mutant: 1 in 106 for drug A 1 in 106 for drug B (1 in 106) x (1 in 106 )= 1 in 1012 for both drug A and drug B  2 drugs to which the organism is susceptible should suffice

  4. 1954 2004

  5. “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? World Health Organization. WHO Expert Committee on Tuberculosis. Eighth Report. Tech Rep Ser 1964;290:1-24

  6. “Drug resistance is a man-made problem…” …to bad practice 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

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

  8. 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)

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

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

  11. Van Deun A, et al. Am J RespirCrit Care Med 2010;182:684-92

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

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

  14. Establish the frequency of MDR subsets HrRr HrRrFr HrRrIr HrRrFrIr Almost impossible to cure Simple to cure Difficult to cure ? 70%-90% ? ? 1%-15% 1 1 Centers for Disease Control and Prevention. Morb Mortal Wkly Rep 2006;55:301-5

  15. Semiquantitative presentation of emergence of drug resistance Regimen preferred by majority SH PH SP S SPH ERH ERHZ Streptomycin Isoniazid Rifampicin Fluoroquinolones Time axis of introduction of drug S: Streptomycin P: Para-aminosalicylic acid H: Isoniazid E: Ethambutol Z: Pyrazinamide

  16. Fully susceptible H-res MDR XDR

  17. The Union’s proposed revised cascade of regimens 2 EHRZ / 4 HR Identical with WHO (also 2 EHRZ / 4 EHR) Different from WHO (2 SEHRZ / 1 EHRZ / 5 EHR) 2 SEHRZ / 6 HR HrRrIsFr HrRrIrFr HrRrIrFs HrRrIsFs 4+ KPGHZEC / 5 GZEC ? ? ??? Diarylquinolines? 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. World Health Organization. Word Health Organization Document 2010;WHO/HTM/TB/2009.420:1-147

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