Traguardo: la TB nel futuro                  EDUCAZIONE CONTINUA IN MEDICINA                  Per ottenere l’attribuzione ...
The goals of TB control:                                            World Health Organization                             ...
Global Plan will not eliminate TB by 2050                              10000                               1000    TB inci...
The goals of TB control:       World Health Organization                               Regional Office for Europe  ….ma il...
2006 - 2015 Stop-TB (OMS)•    Ridurre il carico di malattia tubercolare in linea     con i target relativi alla TB inclusi...
Estimated TB prevalence by region
Estimated mortality rates
How to achieve the goalContagious persons must be detected and their             TB diagnosed ….. Identificazione   forme ...
The Need for New Diagnostics:“Mind the Gap” in TB case detection                                    8.8                   ...
Decentramento dei centri di salute e dei laboratori sul territorioCentro de Salud Lima Norte: support, DOT, cure
Esame dell’escreatoCollection of sputum on home        visit in Kosovo        • Risultati rapidi                          ...
Diagnosi radiologica•  Alterazioni radiologiche caratteristiche delle   forme attive di TB•  È una diagnosi di presunzione...
Esame colturale• Usato per conferma diagnostica• Identifica concentrazioni batteriche molto basse (100 bacilli/mL)• Ritard...
Availability of culture and drug susceptibilitytesting in TB/HIV high-burden countries    Country                Culture  ...
Methods for Diagnosing TB Among HIV+ Patientsin Rio de Janeiro Clinics, 2005-2010  Diagnostic Method         Number      P...
TB Diagnostics: Potential•    New culture platforms•    Nucleic acid amplification•    Antigen detection•    Cytokine expr...
Cepheid GeneXpert MTB/RIF TestBoehme CC et al. N Engl J Med 2010;363:1005-1015
GeneXpert MTB/RIF Performance                   Characteristics    No. Sputums Tested                             Sensitiv...
Performance of Xpert MTB/RIF vs. other    diagnostic modalitiesBoehme et., Lancet 2011
http://www.who.int/tb/laboratory/GeneXpertrolloutJune2012.jpg
How to achieve the goalContagious persons must be detected and their TB            diagnosed, treated ……                  ...
Strategie di management centralizzato operiferico Centralizzato: Registrazione dei casi, strategie di trattamento in base ...
The Global Drug Facilitys MDR TB Scale Upactivities 2007 until now...2001 - Accesso ai farmaci antitubercolari di prima li...
Low TB transmission settings  •  most TB disease arises from latent infection  •  treatment of latent TB is central to TB ...
Effect of isoniazid preventive therapy (IPT)on TB for HIV+:meta-analysis of clinical trials                               ...
Rifapentine+INH vs. INH                              N=7731 (MITT)       Rp/INH weekly (DOT)                              ...
Rifapentine+INH vs. INH:    results to 33 months                                     9H: 15 TB cases                      ...
Shorter preventive regimensunder investigation    •  rifampicin x 4m vs. INH x9m      –  adults, TST+ or IGRA+ (excluding ...
TB prevention: high transmission settings
Earlier TB treatment is TB prevention                                                  symptomatic, seeks                 ...
The long and winding road to TB treatment                                     TB test Treatment                           ...
Earlier test result is TB prevention……..                                    TB test Treatment                             ...
…providing positive test results leadto treatment                                     TB test Treatment                   ...
Initial default and time to                                     treatment: Thibela TB                             0.00 0.2...
TB preventive therapy:high TB transmission settings        •  shorter regimens desirable        •  but is longer better?
Botswana: IPT 36 vs. 6m                          N=1995 HIV+      INHx36m N=1006                INHx6m N=989             7...
36m vs. 6m IPT: 43% less TB during trial                                  In trial n=1995  Cumulative TB incidence        ...
TB incidence post-trial: no difference for 36m vs. 6m INH arm                                 In trial n=1995             ...
Soweto: novel TB preventive therapyregimens           N=1148 HIV+, TST>5mm, not needing ART RPT/INH wkly         RIF/INH t...
Soweto study: HIV+, TST+Martinson NEJM 2011;365:11
Soweto study: HIV+, TST+                             as treated analysisMartinson NEJM 2011;365:11
ART for TB preventionSuthar PLoS Medicine 2012;9:e1001270
ART for TB prevention: necessary but not sufficient Gupta PLoS ONE 2012;7:e34156
IPT plus ART: Brazil •  Retrospective cohort, N=11,026 HIV+ clinic    attendees, Brazil                      pyrs   TB    ...
High TB transmission settings    •  IPT has limited durability in Southern Africa       •  continuous IPT for HIV+ people ...
How to achieve the goalContagious persons must be detected and their TBdiagnosed, treated, and rendered non-contagious    ...
DOT e DOTS•    La tubercolosi è una malattia curabile     attraverso un ciclo di trattamento adeguato•    Trattare i pazie...
DOT e DOTSEssenziali 5 componenti: 1.  Politiche di finanziamento durature 2.  Identificazione dei casi mediante     tecni...
How to achieve the goalContagious persons must be detected and their TBdiagnosed, treated, and rendered non-contagious    ...
2010 – updated global plan to stop -TB
Rationale for New Drugs forTuberculosis •  500,000 cases annually of MDR TB    –  1 in 10 TB patients in China has MDR •  ...
Timeline	  for	  Development	  of	  Moxifloxacin	             for	  Shortening	  TB	  Treatment	   1998          	  2000   ...
The	  Future?	           2016	  DHHS/WHO	  Guidelines	  for	  Treatment	  of	          Tuberculosis	  in	  Adults,	  Adole...
2016	  DHHS/WHO	  Guidelines	  for	  Treatment	  of	     Tuberculosis	  in	  Adults,	  Adolescents	  and	  Children	     P...
TB vaccines: what is on the horizon?               Tom Evans, MD         Chief Scientific Officer, Aeras        IAC, Washi...
Predicted	  Impact	  of	  a	  60%	                   Efficacious	  TB	  Vaccine	                                            ...
Key	  Challenges	  –  Lack	  of	  validated	  animal	     models	  or	  clear	                   Ac#ve	                   ...
Better TB Vaccines: Reasons to be Optimistic‒    Most people (80-90%) do not get disease when infected‒    Evidence of BCG...
Decade to come     ‒  First efficacy data from        proof-of-concept trials        that are underway     ‒  Better under...
Very Brief (and rushed) Conclusions •  After a long gap, science is being applied to TB •  Enormous progress has been made...
Getting to Zero                  Let’s ADD another                  zero to the level of                  funding for TB d...
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
PPT Rizzardini "The goal: the future of TB"
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PPT Rizzardini "The goal: the future of TB"

  1. 1. Traguardo: la TB nel futuro EDUCAZIONE CONTINUA IN MEDICINA Per ottenere l’attribuzione dei crediti formativi E.C.M. è necessario partecipare all’intera durata dei lavori s op Venerdì, 21 settembre è2012 lapomeriggio scientifici - per i quali prevista verifica delle presenze - compilare completamente il fascicolo E.C.M., rispondere Sabato, 22 settembre 2012 mattino correttamente ad almeno l’80% delle domande e SI RINGRAZIA PER IL CONTRIBUTO restituire il fascicolo alla segreteria organizzativa al CON CONDIZIONANTEIII SESSIONE termine dei lavori. Presidente Al termine dell’attività formativa sarà consegnato un attestato di partecipazione, mentre il certificato IV SESSIONE Giorgio BESOZZI (Milano)LA GARA DELLA RICERCA riportante i crediti ECM sarà inviato successivamente al completamento della procedura di correzione dei TB E SOCIALE questionari.Moderatori: D. 10 CREDITI G. Besozzi Falzon - FORMATIVI ECM Moderatori: A. Mangiacavallo - M. Migone per le seguenti professioni e discipline14.30 La corsa a tappe della tubercolosi Presentazione del museo Board scientifico NAZIONALE MEDICO CHIRURGO Malattie dell’apparato respiratorio, malattie infettive, C. Grassi Giorgio BESOZZI (Milano) TUBERCOLOSI: medicina generale (medici di famiglia), igiene, epide- miologia e sanità pubblica, pediatria, microbiologia e 8.30 Malattie infettive e impatto mediatico virologia A. Gori Lucio CASALI (Perugia)14.50 I tappa: da Koch a Xpert ASSISTENTE SANITARIO D. Cirillo BIOLOGO 8.50 Le micro-epidemie UNA MALATTIA(Lugano) Andrea GORI (Monza) Antonio MESSA M. Faccini SOCIALE EDUCATORE PROFESSIONALE15.10 II tappa: da Von Pirquet agli IGRA, INFERMIERE la diagnosi di infezione 9.10 Il disagio sociale dell’ammalato TECNICO SANITARIO DI LABORATORIO BIOMEDICO CONdella famiglia DI: e IL PATROCINIO M. Bugiani SANITARIO DI RADIOLOGIA MEDICA TECNICO G. Besozzi Moderatori e Relato15.30 III tappa: dall’isolamento al linezolid F. Scaglione 9.30 La TB nelle aree metropolitane L. R. Codecasa 21-22 SETTEMBRE 2012 (Milano) Giorgio BESOZZI Massimo BUGIANI (Torino) CONVEGNO15.50 IV tappa: TB DEL CONVEGNO SEDE e immunodepressione: 9.50 La malattia e il medico di famiglia Lucio CASALI (Perugia) abbraccio drammatico ACQUARIO M.G. Manfredi Mauro CERUTI (Bergamo) P. Grossi Civica Stazione Idrobiologica Milano e V.le Gadio, 2 10.10 Discussione ACQUARIO CIVICO (Milano) Daniela CIRILLO16.10 20121 Milano Traguardo: la TB nel futuro tel. +39 0288465750 10.40 Coffee break M I L A N O Luigi Ruffo CODECASA (M fax +39.02.88.46.57.51 G. Rizzardini Marino FACCINI (Milano) http://www.acquariocivicomilano.eu/ Dennis FALZON (Ginevra)16.30 Discussione METROPOLITANA V SESSIONE ORGANIZZATIVA SEGRETERIA Fabio GABRIELLI (Lugano) 300 mt dalla fermata LANZA della linea verde M2 770 mt dalla fermata CAIROLI della linea rossa M1 NUOVI MODELLI ID 246 PROVIDER ECM DOC CONGRESS srl Andrea GORI (Monza) 1,5 km da Piazza del Duomo Via Giovanna D’Arco, 47 20099 Sesto San Giovanni (MI) Carlo GRASSI (Milano) Moderatori: A. Gori - G. Besozzi 3° LINEE DI SUPERFICIE Tel: +39/02/24.44.91 - Fax: +39/02/24.44.92.27 3, 4, 7, 12, 14, 45, 57, 61 E-mail: info@doc-congress.com - www.doc-congress.com Paolo GROSSI (Varese) Nuove idee di partnership Giuseppe LAPADULA (Mon 11.10 La disponibilità politica Maria Grazia MANFREDI (M
  2. 2. The goals of TB control: World Health Organization Regional Office for Europe Ridurre la mortalità, la morbilità e la trasmissione della malattia, prevenendo la diffusione della farmacoresistenza, fin quando non sia più una minaccia per la salute pubblica An Expanded DOTS Framework for Effective TB control. WHO/CDS/TB/ 2002.297
  3. 3. Global Plan will not eliminate TB by 2050 10000 1000 TB incidence/million/yr 100 Projected incidence in 2050 >100x elimination threshold 10 Elimination -16% /yr Global Plan -6% /yr Current trajectory -1% /yr 1 2000 2010 2020 2030 2040 2050 Year Chris Dye, WHO; London 2009
  4. 4. The goals of TB control: World Health Organization Regional Office for Europe ….ma il futuro forse è già iniziato
  5. 5. 2006 - 2015 Stop-TB (OMS)•  Ridurre il carico di malattia tubercolare in linea con i target relativi alla TB inclusi nel Millennium Development Goals –  2015 – ridurre il tasso di prevalenza e di mortalità del 50% rispetto al tasso del 1990 –  2050 – eliminare la TB come problema di salute pubblica (ridurre il tasso di TB attiva a meno di 1 caso/1.000.000 abitanti/anno)•  Componenti della strategia –  perseguire lespansione e la qualità della terapia DOTS –  Controllo di TB/HIV, MDR-TB nelle popolazioni povere e vulnerabili –  contribuire al rafforzamento del sistema sanitario basato sulle cure sanitarie primarie; –  coinvolgere tutti gli operatori sanitari –  Migliorare le condizioni delle persone malate e delle comunità attraverso partnership –  attivare e promuovere la ricerca.
  6. 6. Estimated TB prevalence by region
  7. 7. Estimated mortality rates
  8. 8. How to achieve the goalContagious persons must be detected and their TB diagnosed ….. Identificazione forme attive 1. Campagne informative 2. Punti diagnostici distribuiti sul territorio 3. Training del personale sanitario World Health Organization Regional Office for Europe
  9. 9. The Need for New Diagnostics:“Mind the Gap” in TB case detection 8.8 7.6 Estimated incidenceTB cases (millions) 5.8 Cases detected and notified 3.7 1990 2000 2010 9
  10. 10. Decentramento dei centri di salute e dei laboratori sul territorioCentro de Salud Lima Norte: support, DOT, cure
  11. 11. Esame dell’escreatoCollection of sputum on home visit in Kosovo • Risultati rapidi • Correla con la contagiosità • Permette la decentralizzazione • Basso costo AFB (shown in red) are tubercle bacilli
  12. 12. Diagnosi radiologica•  Alterazioni radiologiche caratteristiche delle forme attive di TB•  È una diagnosi di presunzione, non conferma il sospetto diagnostico•  Gioca un ruolo importante nel limitare i ritardi terapeutici•  Non sempre disponibile sul territorio come Primary health care (PHC) Arrow points to cavity in patients right upper lobe.
  13. 13. Esame colturale• Usato per conferma diagnostica• Identifica concentrazioni batteriche molto basse (100 bacilli/mL)• Ritardo diagnostico elevato (risultati attesi in 10 – 30 giorni per le coltureclassiche, 4 – 14 giorni per colture in mezzo liquido• Necessita di attrezzature costose ed è, quindi, centralizzato Colonies of M. tuberculosis growing on media
  14. 14. Availability of culture and drug susceptibilitytesting in TB/HIV high-burden countries Country Culture Drug Susceptibility Testing N of Labs N per 5 million N of Labs N per 10 Target = 1 million Target = 1 South Africa 15 1.5 10 2.1 Nigeria 2 0.1 1 0.1 Ethiopia 1 0.1 1 0.1 DR Congo 1 0.1 1 0.2 Kenya 5 0.7 1 0.3 Tanzania 3 0.4 1 0.2 Uganda 3 0.5 2 0.6 Zimbabwe 1 0.4 1 0.7 Mozambique 1 0.2 1 0.5 Cambodia 3 1.0 1 WHO Global 0.7 Report, 2009 TB
  15. 15. Methods for Diagnosing TB Among HIV+ Patientsin Rio de Janeiro Clinics, 2005-2010 Diagnostic Method Number Percent Smear + only 208 24% Culture + 49 6% Chest X-ray only 473 55% Clinical Diagnosis only 76 9% Total 853 100%
  16. 16. TB Diagnostics: Potential•  New culture platforms•  Nucleic acid amplification•  Antigen detection•  Cytokine expression (e.g., IGRAs)•  RNA transcriptional signatures•  Volatile compound detection•  Novel imaging techniques
  17. 17. Cepheid GeneXpert MTB/RIF TestBoehme CC et al. N Engl J Med 2010;363:1005-1015
  18. 18. GeneXpert MTB/RIF Performance Characteristics No. Sputums Tested Sensitivity 3 Sputum Samples •  Sensitivity Sensitivity, all 97.4% HIV+ à 93.9% Smear-positive 99.8% •  Sensitivity Smear-negative 90.2% HIV- à 98.4% 1 Sputum Sample Sensitivity, all 92.2% Smear-positive 98.2% Smear-negative 72.5% Specificity 98.1 – 99.2% Sensitivity for RIF-resistance 99.1%Boehme CC et al. N Engl J Med 2010;363:1005-1015
  19. 19. Performance of Xpert MTB/RIF vs. other diagnostic modalitiesBoehme et., Lancet 2011
  20. 20. http://www.who.int/tb/laboratory/GeneXpertrolloutJune2012.jpg
  21. 21. How to achieve the goalContagious persons must be detected and their TB diagnosed, treated …… Terapia conIdentificazione farmaci forme attive adeguati 1. Strategie di management centralizzato e periferico 2. Fornitura costante e completa (Global Drug facility – GDF) 1. Campagne informative 2. Punti diagnostici distribuiti sul territorio 3. Training del personale sanitario World Health Organization Regional Office for Europe
  22. 22. Strategie di management centralizzato operiferico Centralizzato: Registrazione dei casi, strategie di trattamento in base alle caratteristiche territoriali e alla diffusione della MDR-TB o XDR-TB, approvvigionamento di farmaci, monitoraggio, gestione dei dati, supervisione Decentralizzato: Identificazione e trattamento dei pazienti, controllo della aderenza al trattamento
  23. 23. The Global Drug Facilitys MDR TB Scale Upactivities 2007 until now...2001 - Accesso ai farmaci antitubercolari di prima linea2007 - distribuzione di farmaci di seconda linea (per il trattamento di MDR-TB)2009 - distribuiti più di 2.4 milioni di trattamenti antitubercolari che portano il N globale di pazienti trattati da GDF a più di 16.5 milioni Countries served through GDFs MDR‐TB mechanism 2007‐2010
  24. 24. Low TB transmission settings •  most TB disease arises from latent infection •  treatment of latent TB is central to TB elimination •  INH x 9 months is long, completion rates are poor •  shorter regimens preferable if effective, safe
  25. 25. Effect of isoniazid preventive therapy (IPT)on TB for HIV+:meta-analysis of clinical trials Relative risk, 95% CI 1.0 Placebo 0.67 Overall 0.36 TST+ 0.86 TST- Akolo 2010, Cochrane review
  26. 26. Rifapentine+INH vs. INH N=7731 (MITT) Rp/INH weekly (DOT) INH daily (self) x 9m x3m N=3986 N=3745 89% US/Canada 89% US/Canada 2% HIV+ 2% HIV+ 72% TB contacts 70% TB contacts 82% completion 69% completionSterling NEJM 2011;365:2155
  27. 27. Rifapentine+INH vs. INH: results to 33 months 9H: 15 TB cases 0.16/100pyrs non-inferior 3RpH: 7 TB cases 0.07/100pyrsSterling NEJM 2011;365:2155
  28. 28. Shorter preventive regimensunder investigation •  rifampicin x 4m vs. INH x9m –  adults, TST+ or IGRA+ (excluding HIV+ on incompatible ART) –  currently recruiting, high and low burden settings •  rifapentine/INH daily x1m vs. INH daily x 9m –  HIV+, TST≥5mm OR IGRA+ OR resident in high burden country –  self-administered –  started recruitment 2012
  29. 29. TB prevention: high transmission settings
  30. 30. Earlier TB treatment is TB prevention symptomatic, seeks symptomatic, does care not seek care asymptomatic morbidity smear pos, culture pos smear neg, culture pos smear neg, culture neg infectiousness
  31. 31. The long and winding road to TB treatment TB test Treatment sent start Attends Has health TB cured Infectious symptoms centre TB test result infectiousness
  32. 32. Earlier test result is TB prevention…….. TB test Treatment sent start Attends Has health TB curedInfectious symptoms centre TB test result infectiousness
  33. 33. …providing positive test results leadto treatment TB test Treatment sent start Attends Has health TB cured mind the Infectious symptoms centre TB test gap….. result infectiousness
  34. 34. Initial default and time to treatment: Thibela TB 0.00 0.25 0.50 0.75 1.00 S-C- proportion not on Rx Smear neg, median = 5.1 months culture neg S-C+ Smear neg, culture pos S+C+ Smear pos median = 12 days 0 3 6 9 12 follow-up time (months)Churchyard et al, SA TB conference 2012
  35. 35. TB preventive therapy:high TB transmission settings •  shorter regimens desirable •  but is longer better?
  36. 36. Botswana: IPT 36 vs. 6m N=1995 HIV+ INHx36m N=1006 INHx6m N=989 71% female 73% female 25% TST>5mm 22% TST>5mm Median CD4 307 Median CD4 288 48% started ART 47% started ARTSamandari Lancet 2011;377:1588
  37. 37. 36m vs. 6m IPT: 43% less TB during trial In trial n=1995 Cumulative TB incidence 43% reduction in TB p=0.047 6H 36H 6H 36HSamandari Lancet 2011;377:1588
  38. 38. TB incidence post-trial: no difference for 36m vs. 6m INH arm In trial n=1995 Post-trial (no IPT) n=1678 Cumulative TB incidence 43% reduction in TB Hazard ratio 0.82 p=0.047 p=0.52 6H 6H 36H 36H 6H 36HSamandari CROI 2012
  39. 39. Soweto: novel TB preventive therapyregimens N=1148 HIV+, TST>5mm, not needing ART RPT/INH wkly RIF/INH twice INH INH x6m x3m wkly x3m continuous N=328 N=329 N=164 N=327 85% female 81% female 85% female 84% female median CD4 median CD4 median CD4 median CD4 471 498 476 490 median FU 4.0y median FU median FU median FU 4.1y 3.9y 3.9y Martinson NEJM 2011;365:11
  40. 40. Soweto study: HIV+, TST+Martinson NEJM 2011;365:11
  41. 41. Soweto study: HIV+, TST+ as treated analysisMartinson NEJM 2011;365:11
  42. 42. ART for TB preventionSuthar PLoS Medicine 2012;9:e1001270
  43. 43. ART for TB prevention: necessary but not sufficient Gupta PLoS ONE 2012;7:e34156
  44. 44. IPT plus ART: Brazil •  Retrospective cohort, N=11,026 HIV+ clinic attendees, Brazil pyrs TB IR* IR IRR (95% CI) cases Neither 3865 155 4.01 1.0 ART only 11627 221 1.90 0.48 (0.39-0.59) IPT only 395 5 1.27 0.32 (0.10-0.76) ART+IPT 1253 10 0.80 0.20 (0.09- 0.91) (0.09-0.91) *per 100 pyrsGolub AIDS 2007;21:1441
  45. 45. High TB transmission settings •  IPT has limited durability in Southern Africa •  continuous IPT for HIV+ people •  Combination TB prevention •  earlier treatment via better diagnostics •  improving systems to minimise treatment delay •  maximising ART coverage •  optimising TB preventive therapy
  46. 46. How to achieve the goalContagious persons must be detected and their TBdiagnosed, treated, and rendered non-contagious Terapia conIdentificazione Trattamento farmaci forme attive completo adeguati 1. Monitoraggio della 1. Strategie di management assunzione della terapia centralizzato e periferico (strategia DOT e DOTS) 2. Fornitura costante e completa (Global Drug facility – GDF) 1. Campagne informative 2. Punti diagnostici distribuiti sul territorio 3. Training del personale sanitario World Health Organization Regional Office for Europe
  47. 47. DOT e DOTS•  La tubercolosi è una malattia curabile attraverso un ciclo di trattamento adeguato•  Trattare i pazienti con una tubercolosi attiva (presenza di bacilli tubercolari nell’escreato) che possono trasmettere la malattia ad altri, è il metodo più efficace per ridurre la diffusione della TB•  DOTS (Directly Observed Treatment Short course) è la strategia raccomandata a livello internazionale per il controllo della tubercolosi•  È una strategia efficace e a basso costo
  48. 48. DOT e DOTSEssenziali 5 componenti: 1.  Politiche di finanziamento durature 2.  Identificazione dei casi mediante tecniche batteriologiche di elevata qualità 3.  Trattamento standardizzato con supervisione e supporto per il paziente 4.  Sistema di approvvigionamento e e gestione dei farmaci efficace 5.  Monitoraggio e valutazione del sistema e dell’impatto delle misure adottate
  49. 49. How to achieve the goalContagious persons must be detected and their TBdiagnosed, treated, and rendered non-contagious Terapia conIdentificazione Trattamento farmaci forme attive completo adeguati 1. Monitoraggio della 1. Strategie di management assunzione della terapia centralizzato e periferico (strategia DOT e DOTS) 2. Fornitura costante e completa (Global Drug facility – GDF) 1. Campagne informative 2. Punti diagnostici distribuiti sul territorio 3. Training del personale sanitario World Health Organization Regional Office for Europe
  50. 50. 2010 – updated global plan to stop -TB
  51. 51. Rationale for New Drugs forTuberculosis •  500,000 cases annually of MDR TB –  1 in 10 TB patients in China has MDR •  15% of TB is HIV-related –  Drug-drug interactions problematic •  15% of TB is in children –  Formulations inadequate, dosages poorly understood •  5-20% of TB patients experience adverse effects –  Safer agents needed •  6-month regimen is miraculous, but not miraculous enough –  Faster cures are essential
  52. 52. Timeline  for  Development  of  Moxifloxacin   for  Shortening  TB  Treatment   1998  2000  2002  2004  2006  2008  2010  2012  2014  Ac@vity  of  Moxi  shown  in  Mice   JHU/Brazil  trial   OfloTub  trial   Study  26   Study  28   ReMox  TB   OfloTub  II  
  53. 53. The  Future?   2016  DHHS/WHO  Guidelines  for  Treatment  of   Tuberculosis  in  Adults,  Adolescents  and  Children   An#tuberculosis  Drugs   Approved  Agents   DNA-­‐dependent  RNA  Polymerase  Inhibitors  –   Rifampin,  Rifapen@ne,   DRPIs     Rifabu@n   Topoisomerase/Gyrase  Inhibitors  –  TGIs   Moxifloxacin,  Levofloxacin   ATP  Synthase  Inhibitors  –  ASIs     Bedaquiline,  ?clofazimine   Protein  synthesis  Inhibitors  –  PIs     Sutezolid,  amikacin  and  others   Nitric  Oxide  Producers/Electron  Transport   PA-­‐824,  Delamanid     Supressors  –  NOPETS     Mycolic  Acid  Synthesis  Inhibitors  –  MASIs   INH,  Ethionamide   Drugs  with  Uncertain  Mechanisms  of   Pyrazinamide,  SQ109     Bacteriolysis  –  DUMBs  DHHS/WHO – available online at www.curingtb.notyet; ©2012, JHU Center for TB Research
  54. 54. 2016  DHHS/WHO  Guidelines  for  Treatment  of   Tuberculosis  in  Adults,  Adolescents  and  Children   Preferred  regimens  for  pa#ents  with  ac#ve  and  latent   tuberculosis   Preferred  regimens  –all  pa@ents   DRPI  +  ASI  +  TGI  +  NOPET  for  2  months     Genotypic  DRPI  resistance   ASI  +  TGI  +  NOPET  +  PI  for  3  months     Genotypic  DRPI  +  TGI  resistance   ASI  +  NOPET  +  PI  +  DUMB  for  3  months     Mul@ple  resistance   Use  TB  Phenosense  to  customize  regimen     Latent  TB  Infec@on  –DRPI   Rifapen@ne  for  1  month   suscep@ble   Latent  TB  –  DRPI  resistant   Bedaquiline  for  3  months  DHHS/WHO – available online at www.curingtb.notyet; ©2012, JHU Center for TB Research
  55. 55. TB vaccines: what is on the horizon? Tom Evans, MD Chief Scientific Officer, Aeras IAC, Washington, D.C., July 27, 2012
  56. 56. Predicted  Impact  of  a  60%   Efficacious  TB  Vaccine   39% 52% 37% 80% 92%Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD,Longini IM Jr, Dye C, Halloran ME Proc Natl Acad Sci USA.2009
  57. 57. Key  Challenges  –  Lack  of  validated  animal   models  or  clear   Ac#ve   Disease   correlates  of  protec#on   of  immunity   Latent  –  Large and expensive trials needed to prove efficacy Pre-­‐ BCG   infec#on  –  Diversity of BCG, Infants   Adolescents   Adults   HIV+  All   populations, and Ages   environmental factors Covered  by  exis#ng   No  coverage  or  impact  from   vaccine   exis#ng  vaccine   may require more than one vaccine
  58. 58. Better TB Vaccines: Reasons to be Optimistic‒  Most people (80-90%) do not get disease when infected‒  Evidence of BCG vaccine efficacy in children‒  New TB vaccine candidates protect in animal models‒  There are clinical clues to guide immunologic hypotheses •  Low CD4+ T cells are more susceptible to M.tb infection •  Anti-TNF treatment is associated with reactivation‒  New TB vaccines boost cellular immune responses in multiple clinical studies
  59. 59. Decade to come ‒  First efficacy data from proof-of-concept trials that are underway ‒  Better understanding of correlates of immunity, accelerating the testing of future vaccines ‒  Start of multiple phase III studies ‒  Possibility of TB vaccine licensure70
  60. 60. Very Brief (and rushed) Conclusions •  After a long gap, science is being applied to TB •  Enormous progress has been made with TB diagnostics –  Major challenges with cost and implementation •  There is great potential for new TB drugs, but considerable challenges remain –  Evaluating regimens is a key priority •  The pipeline is underpopulated, and substantial investment and commitment are needed
  61. 61. Getting to Zero Let’s ADD another zero to the level of funding for TB drugs, diagnostics, vaccines and elimination! à $6,300,000
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