2. TB chemoprophylaxis Graham Bothamley Clinical Director, NE London TB Network

3. Questions 1.Do we know who will develop TB? 2.Who should take treatment? 3.How many will receive unnecessary treatment? 4.How many actually take treatment? 5.Is it cost-effective? 6.Is isoniazid the right treatment?

4. Latent TB infection or long-lasting TB immunity? Cochrane review: 1.68% over 5 years HIV+ PPD+ cohort: 4% over 22 months (7.9 cases per 100 person years) Human macrophages cannot kill Mtb 1-3 tubercle bacilli required for disease Selwyn et al. 1989. NEJM 320: 545

5. Children: tuberculin responses, risk of TB over first 9 years and timing of exposure Horsburgh. NEJM 2004; 350:2060 US data: 1962-1974

6. Adults: tuberculin responses, risk of TB over first 9 years and timing of exposure Horsburgh. NEJM 2004; 350:2060 US data: 1962-1974

7. Progression to TB Immigrant contacts of S+ve cases >16 yrs in Holland CriterionTB cases/ positives % (95% CI) Sensitivity (%) PPD  10 mm 9/2883.1 (1.3-5.0)100 PPD  15 mm 7/1843.8 (1.7-5.9)88 QFT-GIT5/1782.8 (1.0-4.6)63 T-SPOT.TB6/1813.3 (1.3-5.3)75 All IGRA patients had PPD>10 mm; 1/8 patients missed if 15 mm Kaplan Meier for progression, pos vs. neg: even PPD >15 mm P=0.081 812 contacts from 380 index cases Kik et al. Eur Respir J 2010; (in press)

8. Predictive values of IGRA Subjects (n) Tests (n) False results Mean % Range % NPV224232574098.882.1 - 100 PPV1034146717/4004.256 - 32 PPV-HIV+1031 5/568.931.2 - 32 TBNET review: Diel et al (ECDC)

9. PPD+: NNT to prevent 1 case TB ConditionNNTConditionNNT Transplant5Diabetes53.5 HIV+13.5Silicosis61 Gastrectomy23.5Unexplained WL66.5 Child contact24.5CRF on dialysis67 PPD conversion24.5Leukaemia91 IVDU30.5Immigrants93 Steroids98.5 No risk123.5 Rose. Arch Intern Med 2000; 160:1513

10. Treatment and harm Treat 72 to prevent one case of TB Treat 333 to cause isoniazid induced hepatitis (varies with age)

11. Hepatotoxicity of isoniazid Comstock & Edwards. Am Rev Respir Dis 1795; 111: 573

12. Adherence Horsburgh et al. Chest 2010; 137: 401-9 32 clinics 123/720 declined (17.1%: 14.5 - 20%) 1045/1994 (52.4%) failed to complete IJTLD 2008; 12: 1235 & 1352 3582 seen 8 had TB (0.2%) PPD+ = 996 227 refused and only 40% eligible (>35 yrs) 320 (8.9% total; 67% who started) completed

13. Isoniazid Active against rapidly dividing population Course longer than TB treatment Most hepatotoxic of TB drugs Cheap

14. Chemoprophylaxis? 3 year old Mother has smear-positive pulmonary tuberculosis BCG vaccinated PPD 5 mm response

15. Chemoprophylaxis? 16 year old Somali Mother had LN TB BCG vaccinated PPD 12 mm response

16. Chemoprophylaxis? 34 year old Russian Screened as a new entrant to EU Chest x-ray normal PPD 35 mm response

17. Chemoprophylaxis? 45 year old health care worker Occupational health screening To work with HIV+ Born in UK Visited relatives in India for 3m last year Chest x-ray normal PPD 16 mm response

18. Chemoprophylaxis? 37 year old from Guinea-Bissau HIV+ BCG vaccinated PPD 15 mm response

19. Chemoprophylaxis? 45 year old from Turkey Screened as new entrant BCG vaccinated Chest x-ray: one calcified granuloma PPD 12 mm response Quantiferon: 0.52 IU/ml (>0.35 IU/ml)