Clinical spectrum and standard treatment of tuberculosis

Transcription

1 Clinical spectrum and standard treatment of tuberculosis Graham Bothamley Homerton University Hospital, London, UK 2 nd European Advanced Course in Clinical Tuberculosis 1

2 Plan of talk Why is there a clinical spectrum of TB? Does the clinical spectrum have a bearing on the treatment of TB? Why does the standard treatment for TB work? Why has MDRTB arisen? 2

3 Why does it occur? CLINICAL SPECTRUM OF TB 3

4 Clinical spectrum and pathogenesis Mycobacterium tuberculosis The human host Environment 4

5 Host factors Pre-existing immunity Immunodeficiency HIV Anti-TNF Rare IFNγ pathway genetics Co-morbidities Diabetes Malnutrition 5

6 The human immune response to TB Primary TB TB with no pre-existing immunity Non-infectious High mortality Often outside lung Children and elderly HIV co-infection Post-primary TB TB with pre-existing immunity Infectious (not LN) Cavities with TB biofilm Surprisingly well tolerated Young adults Immunocompetent CD4 CD8 6

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8 Interferon-γ Defects in IFNγR and IL-12 associated with disseminated disease, BUT unlike normal TB IGRAs positive in active TB IGRAs positive in latent TB IGRAs predict the development of active TB Conclusion: IFN γ is not protective 8

9 Tumour Necrosis Factor TUBERCULOSIS ASSOCIATED WITH INFLIXIMAB. A TUMOR-NECROSIS FACTOR α-neutralizing AGENT JOSEPH KEANE, M.D., SHARON GERSHON, PHARM.D., ROBERT P. WISE, M.D., M.P.H., ELIZABETH MIRABILE-LEVENS, M.D., JOHN KAZNICA, M.D., WILLIAM D. SCWIETERMAN, M.D., JEFFREY. N. SIEGEL, M.D., AND M. MILES BRAUN, M.D., M.P.H. 70 cases: 40 EPTB 17 disseminated 11 LN 4 peritoneal 2 pleural 1 each of meningeal, paravertebral, bone, enteric, genital, bladder Need to screen for LTBI The New England Journal of Medicine 2001; 345:

10 HLA associations Only sputum smear-positive pulmonary TB Only if controls exposed HLA-DR15, DQ5 Aspartate at DQβ-57 with DRB1*0801, 0802, 1401? Family studies Singh et al. J Infect Dis 1983; 148:676 Bothamley et al. J Infect Dis 1989; 159: 549 Khomenko et al. Tubercle 1990; 187 Brahmajothi et al. Tubercle 1991; 72: 123. Siram et al. Indian J Med Res 2001; 113: 117 Dubaniewicz et al. Thorax 2003; 58: 890 Delgado et al. J Immunol 2006; 176: 1090 Contini et al. Sarcoidosis Vac Dif Lung Dis 2008; 25: 21 Goldfeld et al. JAMA 2009; 226 Shi et al. Genet Mol Res 2011; 10:

11 Do they have a bearing on each other? CLINICAL SPECTRUM AND TREATMENT 11

12 Life cycle of M. tuberculosis Air Intracellular Granuloma Cavity Number single ,000s Oxygen high low low high Carbon dioxide low high high medium ph neutral low low unknown Water risk of desiccation unlimited unlimited diffusion Nutrients none limited unlimited? diffusion Killing UV light phagosome? T cell immunity fibrosis Majority state dormant slowly dividing slowly dividing rapidly dividing 12

13 LTBI IGRA-/PPD- IGRA+/PPD+ Latent infection Active disease Affected 6 billion 3 billion 300 million 10 million Bacteria/host > 1 million BCG Immune response to TB Treatment Immune deviation: IGRA, PPD Natural immunity Unnecessary/ chemoprophylaxis Th1 Treg Unnecessary /preventive Unknown Th1 Treg 6-12H or 4R or 3RH or 3RpH or 2RZ No effect Th2 Th17 2RHZ/4RH 13

14 Populations of M. tb High H (R, S) Rate of Bacterial growth Continuous growth Z Acid inhibition R Spurts of metabolism Biofilm Aerobic respiration Extracellular Intracellular Low Dormant Mitchison. Chest 1979; 76:

15 Populations of M. tb High Rate of Bacterial growth Continuous growth H (R, S) Z Acid inhibition Latent TB? R Spurts of metabolism Biofilm Aerobic respiration Extracellular Intracellular Low Dormant Latent TB? Mitchison. Chest 1979; 76:

16 Why does it work? STANDARD TREATMENT 16

17 Standard treatment Initial phase - 2RHEZ Continuation phase 4RH 17

18 Isoniazid Bactericidal Target: cell wall (mycolic acid) 1950s, Navajo (no streptomycin) Activated by katg Radicals produced e.g. NO Binds to inha when coupled with NADH Blocks fatty acid synthase Peak not AUC 18

19 Rifampicin Bacteriostatic Target: RNA polymerase 1967: for TBM (!) Lowest effective dose MIC vs dose-response Peak not AUC van Ingen et al. Clin Infect Dis 2011; 52:

20 Isoniazid and rifampicin together 100 patients Sputum cfus Killing Sterilizing Jindani et al. AJRCCM 2003; 167: 1348 Isoniazid most effective first 2-5 days, Grosset et al. AJRCCM 2013; 188:608 20

21 Pyrazinamide Analogue of nicotinamide (vitamin B3; H, Eto) Low in vitro, high in vivo activity (Cornell Model) Not M. bovis Converted via PZase (pnca) Excreted and acidified to pyrazinoic acid Re-enters bacillus, accumulates, poisons (ph) Only extracellular bacteria (granulomas) SHR and SHZ equal culture negative at 2 months Chorine. Comp Rend Acad Sci 1945; 220: 150 McCune et al. J Exp Med 1956; 104: 737, 763. East African/British MRC. Lancet June 16, 1973: 7816 OH 21

22 Effect of pyrazinamide Animal model Human sputum cfus 22

23 Change in lung CFU counts in mice treated with increasing doses of isoniazid (H) given alone (A) or in combination with 10 mg/kg rifampin (R) and 150 mg/kg pyrazinamide (Z) (B). Almeida D et al. Antimicrob. Agents Chemother. 2009;53:

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25 Why did it occur? MDRTB 25

26 Ethambutol Bacteriostatic Target: arabinosyl transferase (cell wall) Slows rate of kill with RHZ No difference SHRZ to RHZE 2 months 12.4% relapse 2HRZE/6EH cf 2.7% 2HRZE/4RH (2SHRZ/TH 0%; 2SHRZ/H 3%) Jindani et al. AJRCCM 2003; 167: 1348 Hong Kong Chest Service/BMRC. Tubercle 1982; 62: 89 East African BMRC. Tubercle 1986; 67: 5 East Afrcan/BMRC. Am Rev Respir Dis 1981; 123:

27 Relative efficacy of drugs preventing resistance Regimen Patients Failures (%) Country H+R 183 <1 E. Africa +S 114 <1 Singapore +E Madras +P Madras & Africa +T Madras & Africa T+H Rhodesia +S S+P Madras/Africa +Z Mitchison. Chest 1979;

28 Relative efficacy of drugs preventing resistance Rapid killing RNA polymerase Ribosomal RNA Regimen Patients Failures (%) Country H+R 183 <1 E. Africa +S 114 <1 Singapore +E Madras +P Madras & Africa +T Madras & Africa T+H Rhodesia +S S+P Madras/Africa +Z Mitchison. Chest 1979;

29 Doctors Treating active TB with isoniazid alone Intermittent drug supply Adding a single drug to a failing regimen Lack of holistic approach Poor health systems Coca Cola and the cold chain Stigma Poverty 29

30 Conclusions The physiology of the TB bacillus has yet to inform our treatment The pathogenesis of TB has yet to inform our treatment Standard treatment of a social disease must include social elements We have been lucky for the last 40 years, but our luck has finally run out! 30