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Tuberculosis Contact Investigations

Tuberculosis Contact Investigations. Turkish Thoracic Society Meeting Antalya, April 14-17, 2011 Dick Menzies MD, MSc Montreal Chest Institute, McGill University. Overview of Talk. Definitions Contact investigations – WHY? Contact investigations – WHO? WHEN? And HOW?

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Tuberculosis Contact Investigations

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  1. Tuberculosis Contact Investigations Turkish Thoracic Society Meeting Antalya, April 14-17, 2011 Dick Menzies MD, MSc Montreal Chest Institute, McGill University

  2. Overview of Talk • Definitions • Contact investigations – WHY? • Contact investigations – WHO? WHEN? And HOW? • Risk of Active TB – Immediate, and Future • Treatment

  3. Contacts - Definitions • Source case – Person with active TB – that was source of transmission to others • Index case – Active TB that signals transmission has occurred • Usually first case diagnosed • Often same as source case • But could be infant with TB meningitis

  4. Contacts - Definitions • Close contact – person with >4 hours per week contact with source case • Household contact – person sleeping in same house – at least once a week • Casual contact - <4 hours per week of contact • Location specific contact – eg work contact, school contact

  5. Contact investigations: WHY? • 1. To identify persons with new active TB • 3-5% of close contacts will have active TB • Often sub-clinical, and early • BUT – May also find true source case

  6. Contact investigations: WHY? • 2. To identify persons with Latent TB Infection (LTBI) • Future risk of active TB is increased • May benefit from LTBI therapy • 3. To identify contacts at very high risk of disease • Very young (<5 years) • HIV infected

  7. Contact investigations: WHEN? • Immediate • Highest risk = Close contacts & Young or HIV • – as soon as index/source case confirmed • Highest priority – young children or HIV infected who are close contacts • 8 weeks after contact is broken • This is when source case found / isolated / treated • For all casual contacts, • Work and school contacts

  8. Contact investigations: When is it necessary? • What makes a source case contagious? • Contagious = Respiratory • Pulmonary – most common • Laryngeal – can be very contagious • Sputum AFB smear – reliable and simple indicator • Smear positive > Smear neg/Cult Pos > Clinical • Other factors – More frequent cough • Also younger and males (stronger cough?)

  9. Contact investigations: When is it necessary? • Closeness and duration of contact • And environment itself - Interior, dark, poorly ventilated • Characteristics of contacts? • Young children, HIV infected, Other immune compromised

  10. Contact investigations: HOW?The concentric circle approach • The 1st Circle - the closest contacts • Closest in space, and/or longest duration • How many with disease? • How many with infection? Especially young children • Extend to 2nd circle if: • ANY secondary cases of disease • More infection than expected

  11. Contact investigations: HOW?Extending to the 2nd and 3rd circles • The 2nd circle • Casual contacts – but with regular contact • Work or school contacts • Decide to extend to 3rd circle if: • More infection than expected • This is unusual – and is a lot of work • Plus may lead to unnecessary LTBI treatment • The 3rd circle • All other identified contacts – social, community, transport

  12. Schematic of the concentric circle approach

  13. Risk of TB in Contacts – Which Test? • Recent systematic review – prospective studies of untreated contacts • Tested for LTBI at start of follow-up • – IGRA (QFT or T-Spot) and / or TST • Followed for 1-3 years – Confirmed active TB • 15 published studies found with 23,673 participants

  14. Actual incidence of active TB - by IGRA statusIGRA+ 0.4% – 4.2% // IGRA- 0.2% – 1.6%

  15. Relative risk of active TB: IGRA+ / IGRA-Overall RR: 3.5 High quality studies RR: 2.2

  16. Which is the best predictor of active TB?IGRA RR= 2.4 TST 5mm RR= 2.1 TST 10mm RR=2.0

  17. Judging if IGRA or TST are better?Using gradients of exposure in contacts • In a contact investigation there are differences in exposure: • Same bedroom/intimate • Same house/family • Regular social • Community / no contact • Or differences in source case • Smear+ / Smear- / Clinical case • Better test should correlate with exposure better

  18. Correlation of tests with Gradient of exposure – Pediatric contacts

  19. Summary – IGRA vs TST in contacts? • No difference with gradient of exposure • Minimal difference in predicting active TB • No test is highly accurate for prediction • Majority of TEST positive do NOT develop active TB • Decision which to use based on: • If BCG used after infancy (specificity) • Local resources (lab vs nursing)

  20. Is it necessary to do a test for Latent TB in contacts? (TST or IGRA) Studies of benefit from treatment of persons with positive vs negative tests

  21. Meta-Analysis: INH protects against TB In HIV (+) who are TST (+) (Pooled estimates: 0.4 (0.24-0.65)) AIDS 1999;13:501-7

  22. Meta-Analysis: INH does not protect against TB in HIV (+) who are TST (-) (Pooled estimates: 0.84 (0.54-1.30)) AIDS 1999;13:501-7

  23. 19 controlled trials in 11 countries: United States Canada Greenland Mexico Japan Netherlands France Over 100,000 participants 25%-92% protection HEPATITIS NOT REPORTED OR NOT RECOGNIZED INH: Placebo-Controlled Trials of Isoniazid for Treatment of Latent TB Infection, 1955-1965 Tunisia Kenya India Philippines

  24. Problems with INH 1. Length - 9 months ideal (90% efficacy) • Results in poor compliance - less than 50% in most programs. • Drug induced hepatitis - - Less common now, but deaths still occur. • Also rash, neuropathies 3. Costs - INH is cheap but close follow up is necessary. This is expensive

  25. LTBI treatment • 9 months INH • The 2RIF-PZA story • 4 months RIFampin • 2-3 months INH-RIF • 3 months once weekly INH&Rifapentine

  26. The 2RZ story Part 1a:Experimental Study of Short-Course Preventive Therapy in Mice Lecour HF, et.al. Am Rev Respir Dis 1989:140:1189-93

  27. International Study of 12INH vs 2RIF-PZA in HIV Infected patients - OUTCOMES Regimen 2 RIF/PZA 12 INH RR (CI) No. enrolled 791 790 Confirmed TB 19 26 0.7 (.4,1.2) Conf/Probable TB 28 29 0.95 (.6,1.2) Death 139 159 0.9 (.7,1.1)

  28. Completion of therapy – 6 INH vs 2RZ(From Gao et al, IJTLD; 2006:10:1080-1090) AuthorLocation6 INH2 RZ Halsey Haiti 55% 74% Mwinga Zambia 66% 75% Jasmer USA 57% 61% Leung Hong Kong 89% 83% Tortajada Spain 77% 82%

  29. Serious Adverse Events – 6INH vs 2RZ(From Gao et al, IJTLD; 2006:10:1080-1090) AuthorMean Age6-12 INH2 RZ Halsey 31 0 0 Mwinga 31 3% 4% Jasmer 37 3%9% Leung 60 6%35% Tortajada nr 4%12%

  30. LTBI Treatment • The INH story - efficacy and risks • The 2RIF-PZA story • 4 months RIFampin • 3-4 months INH-RIF • 3 months INH-Rifapentine

  31. The 2RZ story Part 1a:Experimental Study of Short-Course Preventive Therapy in Mice Lecour HF, et.al. Am Rev Respir Dis 1989:140:1189-93

  32. Efficacy of 3 months of Rifampin for the Prevention of TBPatients with Silicosis Hong Kong Chest Service. Am Rev Respir Dis 1992;145:36-41

  33. RCT of 4RIF vs. 9INH for LTBI – Phase 2Completion of Therapy

  34. RCT of 4RIF vs. 9INH for LTBI – Phase 2Serious Drug Related Adverse Events * Severity, type + relationship to study drug by independent blinded 3-member panel

  35. RCT of 4RIF vs 9INH for LTBI – Phase 3Objectives of Phase 3 Primary objective (effectiveness) Compare incidence of confirmed active TB in all randomized in the 28 months post-randomization “Pragmatic” trial – estimate under programme conditions.

  36. RCT of 4RIF vs 9INH for LTBI – Phase 3 Planned enrolment is almost 6,000 persons Enrolment for next 2½ years Last follow-up will end in 5 years Publication in ? years Wish us luck (even just to survive!!)

  37. LTBI Treatment • The INH story - efficacy and risks • The 2RIF-PZA story • 4 months RIFampin • 3-4 months INH-RIF • 3 months weekly INH&Rifapentine

  38. INH INH/RIF (Diff. %) Hong Kong (silicotics) 25/173 26/167 (+1.1%) Martinez (Spain – HIV) 0/98 1/98 (+1.0%) Martinez (Spain - HIV) 4/64 2/69 (- 3.3%) Rivero (Spain – HIV) 3/83 3/82 (+0.1%) Whalen (Uganda – HIV) 7/536 9/556 (+0.3%) Pooled estimates 39/954 41/972 (+0.1%) 3-4 Rifampin-INH vs 6-12 INH A meta-analysis of 5 RCT’s Occurrence of active TB(Ena & Valls, Clin Inf Dis; 2005; 40: 670-676)

  39. INH INH/RIF (Diff. %) Hong Kong (silicotics) 13/173 8/167 (- 2.7%) Martinez (Spain – HIV) 9/98 7/98 (- 2.0%) Martinez (Spain - HIV) 15/64 5/69 (- 16%) Rivero (Spain – HIV) 6/83 15/82 (+11%) Whalen (Uganda – HIV) 3/536 13/556 (+1.7%) Pooled estimates 46/954 48/972 (+0.1%) 3-4 mos Rifampin-INH vs 6-12 mos INH A meta-analysis of 5 RCT’s Serious Adverse Events(Ena & Valls, Clin Inf Dis; 2005; 40: 670-676)

  40. LTBI Treatment • The INH story - efficacy and risks • The 2RIF-PZA story • 4 months RIFampin • 3-4 months INH-RIF • 3 months weekly INH&Rifapentine

  41. 3 months once weekly INH & Rifapentine • Large scale trial almost completed • 9INH vs 3 mos once weekly INH/RPT • Over 8,000 enrolled • Included large pediatric and HIV populations • Follow-up will end in September • Results expected…..

  42. What is needed - if LTBI treatmentis to have a real impact? • Better tests – To identify those at risk • TST and IGRA – fail on this point • Better treatment – absolutely • Shorter – for patients AND programmes • SAFER – this is essential • Patients and providers will never accept therapy if there a serious risk of adverse events

  43. Treatment of hypertension vs LTBI Hypertension LTBI Asymptomatic condition Very serious complications Death, Major disability AND transmission Treatment is 9 months Cheap medications Potential serious side effects Requires close monitoring and FU WHY the debate about Treating • Asymptomatic condition • Very serious complications • Death, Major disability • No Transmission • Treatment is for years • Expensive medications • Potential serious side effects • Requires close monitoring and FU • BUT – no debate about Treating

  44. İlginiz için teşekkürlerThanksMerciGraciasObrigado

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