Hisoniazid R=rifampicin Z=pyrazinamide E=ethambutol S=streptomycin MDRDSTdrug sensitivity test 2HRZES/1HRZE/5HRE D D D Der Zauberberg Die Zauberfloete

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1 () Tuberculosis the Lancet, July2, 2011 H23.8 Stephen D Lawn: Alimuddin Zumla the Lancet, July2, 2011 HIV 2 Newsweek Newsweek 1950 X X A3aA3b X CT CT Felson 2010 WHO the Lancet (2010WHO, Treatment of tuberculosis guidelines4 th edition160 ) 1 2HRZE/4HR ( 2 HRZE HR ) 2HRZE/4HE strong evidence INH 2HRZE/4HER 1/23

2 Hisoniazid R=rifampicin Z=pyrazinamide E=ethambutol S=streptomycin MDRDSTdrug sensitivity test 2HRZES/1HRZE/5HRE D D D Der Zauberberg Die Zauberfloete Lindenbaum Der Lindenbaum 2/23

3 12 HIV HIV HIV RA TNF MDR:multidrug resistant MDR INH Rifampicin XDRextensively drug resistant XDR fluoroquinolone 3 amynoglycoside ( capreomycinkanamaycinamikacin ) MDR 50 XDR 5 HIV perfect storm KwaZulu Natal province HIV WHO 16 tuberculosis immune reconstitution disease KwaZuluNatal Blood River 3/23

4 Blood River 1834 KwaZuluNatal D m salvo 500m Blood River Blood River m 4/23

5 M tuberculosism africanumm bovis M microtim canetti pasteurisation M bovis 6 BCG 1921 Mycobacterium bovis() 1 BCG Bacillus Calmette-Guerin : Guerin e BCG variable BCG HIV transcriptomics messenger RNA transcript signature RNA sodium hydroxide LED MDRXDR LPAs(line probe assay) LPAs GenoType MTBDRplus GenoTypeMTBDRsl XDR LPAs 2008 WHO Hain Xpert MTB/RIF assay rifampicin /23

6 M tuberculosisbcg mycobacteria Quanti-FERON T-SPOT Quanti-FERON T-SPOT Nitroimidazole the Lancet, 50 the Lancet, 1. 4/ HIV 5 HIV DM 3 6. HIV 7. RA TNF D 9MDRmultidrug resistant INH rifampicin 10XDR fluoroquinolone 3 amyoglycoside(capreomycin, kanamaycin,amikacin) MDR 50 XDR 5 12HIV perfect storm M tuberculosism africanumm bovism microtim canetti ] 6/23

7 18BCG 1921 Mycobacterium bovis() 19 D 20. D HIV transcript signature 27sodium hydroxide 28LED 29 30MDRXDR LPAs(line probe assay) 31LPAs GenoType MTBDRplus GenoTypeMTBDRsl 32 33Xpert MTB/RIF assay 2 rifampicin 99.2% M tuberculosisbcg mycobacteria 36Quanti-FERON T-SPOT 37 38Quanti-FERON T-SPOT diarylquinolonenitroimidazole 41motifloxacingatifloxacin WHO rifampicin HRZE 4 HR 44 4 HR HRE 45MDR empirical 2HRZES/1HRZE/5HRE 46BCG 47BCG variable 48HIV Nitroimidazole 7/23

8 () Tuberculosis the Lancet, July2, 2011 H23.8 Stephen D Lawn: Alimuddin Zumla HIV HIV 5 4 endemic 100 epidemic 21 Introduction John Bunyan( ) The Captain among these men of death HIV-1 pandemic 21 8/23

9 HIV 5 4 HIV HIV MDR inextricable HIV TNF RA natural resistance-associated macrophage protein1, interferonnitric oxide synthase 2AVitaminD receptor only moderate polymorphism 20 MDRmultidrug resistant XDR (extensively drug resistant) MDR INH rifampicin mycobacterium tuberculosis XDR MDR fluoroquinolone 3 capreomycin kanamycinamikacin MDR 50 XDR 5 MDR 30 primary drug resistance 20 acquired drug resistance 9/23

10 MDR MDR XDR WHO HIV intersection perfect storm KwaZulu Natal province HIV BMI D 2 2 Silicosis 3 40g/ natural resistance-associated macrophage protein1, interferon Nitric oxide synthase 2AVitaminD receptortoll-like receptor TNF 1.5 Mycobacterium tuberculosis M. tuberculosis Robert Koch M. tuberculosis complex M tuberculosism africanumm bovism microti M canetti pasteurisation M bovis 6 M bovis 1921 BCG M tuberculosis acid-fastnonmotilenon-encapsulated non-spore forming bacillus 10/23

11 phenol M tuberculosis acidified organic solvents Nontuberculous mycobacteria Nocardia mycolic acid M tuberculosis 20 M tuberculosis M tuberculosis M tuberculosis 6 Beijing family W W-like family M tuberculosis genome M tuberculosis 10 immunocompetent 90 M tuberculosis macroscopic 20 HIV interferon- T innate immune system M tuberculosis pattern recognition receptors M tuberculosis mannosylated lipoarabinomannnantrehalose dimycolaten-glycolyl muramyl dipeptide 11/23

12 M tuberculosis Cathelicidin LL37 M tuberculosis M tuberculosis D D pleiotropic effect D D D D polymorphism D M tuberculosis T M tuberculosis Mycobacteria epithelioid macrophage T HIV M tuberculosis M tuberculosis M tuberculosis niche M tuberculosis necrosis 12/23

13 HIV HIV M tuberculosis CD4 type-1 cytokine M tuberculosis HIV-1 M tuberculosis M tuberculosis HIV transcriptomics messenger RNA transcriptomic study signature 393 transcript signature 86 transcript signature signature RNAtranscriptional HIV 13/23

14 X point- of- care test 10 WHO bleach sodium hydroxide 13 Ziehl-Neelsen 10 LED (light emitting diodes) 2009 WHO automated liquid culture system WHO WHO 2009 MODSmicroscopically observed drug susceptibility nitrate reductase asssay MDR WHO 2008 LPAs(line probe assays) LPAs GenoType MTBDR plus assay (Hain Lifescience GmbH, Nehren,Germany) 2009 Genotype MTBDRsl assay GenoType MTBDRplus GenoTypeMTBDRsl XDR MDRXDR 14/23

15 lipoarabinomannnann HIV disappointing HIV NAATs : nucleic acid amplification tests NAATloop mediated isothermal amplification NAAT Xpert MTB/RIF assaycepheid, Sunnyvale, CA, USA M tuberculosis rpo B rifampicin 2 rifampicin 1 Xpert MTB/RIF assay M tuberculosis BCG mycobacteria 10 IGRAs in vitro M tuberculosis complex ESAT-6 CFP-10 immunodominant antigen 15/23

16 IGRAs T-SPOT.TB test (Oxford Immunotech, Abingdon, UK) QuantiFERON-TB Gold in tube (Cellestis Ltd, Carnegie, Australia) IGRABCG IGRAs T protein 10interleukin 10monocyte chemotactic protein 1 4 HIV CD4 2, HIV HIV 25 aspiration biopsy initial phase WHO /23

17 regimens 2010 WHO 6 DSTdrug sensitivity test DST MDR default MDR XDR HIV XDR MDR HIV XDR 2008 MDR WHO WHO MDR XDR HIV HIV HIV 2009 HIV 26 HIV 2009 HIV 53 Co-trimoxazole ART CD4 ART CD4 median 25/l ART WHO CD4 HIV 2 8 ART 17/23

18 ARTefavirenz protease inhibitor ART rifampicin rifabutin ART tuberculosis immune reconstitution disease 1695CI self-limiting 3% 10 diarylquinolonetmc-207 mycobacteria ATP synthetase phase2 MDR Nitroimidazoles (PA-824OPC ) Nitroimidazole Motifloxacin, gatifloxacin, TMC WHO Hisoniazid R=rifampicin Z=pyrazinamide E=ethambutol S=streptomycin DOTS=directly observed treatment, short course a rifampicin 2HRZE/4HR ()2 HRZE 4 HR b. continuation phase 2 INH 4 HR HRE 18/23

19 c. intensive phase continuation phase 3 DOTS () 2HRZE/4(HR)3 6 3 DOTS HIV HIV () 2 (HRZE)3/4(HR)3 e. isoniazid rifampicin rapid molecular DST empirical MDR empirical MDR regimen 1 2HRZES/1HRZE/5HRE f. WHO, Standard treatment regimens Isoniazid(H) 5 (4-6)mg/kg, (8-12)mg/kg, 900 / Rifampicin (R) 10 (8-12)mg/kg, (8-12)mg/kg, 600 / Pyrazinamide(P) 25 (20-30)mg/kg, 3 35 (30-40)mg/kg Ethambutol(E) 15(15-20)mg/kg 3 30(25-35)mg/kg Streptomycin(S) 15(12-18)mg/kg 3 15(12-18)mg/kg 1000mg 60 50kg mg/kg 19/23

20 BCG % BCG 10 variable M tuberculosis Mycobacterium vaccae (vaccae ) 3 HIV BCG M vaccae BCG 1993 WHO DOTS (Directly Observed Therapy-Short Course) DOTS STOP TB Strategy Global Plan to Stop TB( ) HIV MDR /100 / HIV MDR 1991 WHO Millenium Development Goal6 (MDG6) /23

21 DOTS Global Plan to Stop TB HIV DOTS 4 INH IPTisoniazid preventive therapy ART 4 ART HIV INH IPT 0.2 WHO Is INH IPTintensified case findingsinfection control 3 ART HIV DOTS HIV 6795CI ART CD4 3I ART Global Plan to Stop TB /23

22 the Lancet, 1. 4/ HIV 5 HIV DM 3 6. HIV 7. RA TNF D 9MDRmultidrug resistant INH rifampicin 10XDR fluoroquinolone 3 amyoglycoside(capreomycin, kanamaycin,amikacin) MDR 50 XDR 5 12HIV perfect storm M tuberculosism africanumm bovism microtim canetti 18BCG 1921 Mycobacterium bovis() 19 D 20. D HIV transcript signature 27sodium hydroxide 28LED 29 30MDRXDR LPAs(line probe assay) 22/23

23 31LPAs GenoType MTBDRplus GenoTypeMTBDRsl 32 33Xpert MTB/RIF assay 2 rifampicin 99.2% M tuberculosisbcg mycobacteria 36Quanti-FERON T-SPOT 37 38Quanti-FERON T-SPOT diarylquinolonenitroimidazole 41motifloxacingatifloxacin WHO rifampicin HRZE 4 HR 44 4 HR HRE 45MDR empirical 2HRZES/1HRZE/5HRE 46BCG 47BCG variable 48HIV Nitroimidazole 23/23

(1) 5 (2) VNTR IS6110RFLP, VNTR35loci JATA(12) JATA(12) MIRU(12) Supply(15) (3) INH inha 22 (4) 5 5 INH RFP 95% 90% 90% 11 (5) 5

(1) 5 (2) VNTR IS6110RFLP, VNTR35loci JATA(12) JATA(12) MIRU(12) Supply(15) (3) INH inha 22 (4) 5 5 INH RFP 95% 90% 90% 11 (5) 5 (1) 5 (2) VNTR IS6110RFLP, VNTR35loci JATA(12) JATA(12) MIRU(12) Supply(15) (3) INH inha 22 (4) 5 5 INH RFP 95% 90% 90% 11 (5) 5 (6) 30-50 2006 MDR 97 XDR 43.3 15-optimized MIRU VNTR 17 gralnulysin 15k

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