1. Effect of community-wide isoniazid preventive therapy on tuberculosis among South African gold miners “Thibelo TB” Aurum Health Research LSHTM JHU Gold mining companies Dept. of Health, SA

2. Study outline To investigate the effect of community-wide TB preventive therapy (TBPT) in setting of high HIV prevalence (gold mines in South Africa) Community randomised controlled study community-wide TBPT vs. standard TB control (targeted TBPT for high risk groups) Community = mine shaft(s) and associated hostel Paired design

3. Study outline (2) Primary outcome: TB incidence measured 12 months after enrolment (over a 12 month period) Secondary outcomes – TB incidence among HIV infected individuals, measured 12 months after enrolment (over a 12 month period) –TB case notifications, over the 24 month period –TB culture prevalence at the end of the follow-up period

4. Study month 0- 3 4-67-910- 12 13- 15 16- 18 19- 21 22- 24 25- 27 28- 30 31- 33 34- 36 37- 39 40- 41 42- 45 46- 48 49- 51 52- 54 Recruitment of clusters Prevalence survey Primary outcome measurement period 9 months of TBPT Measure primary outcome over 12 months, from 13-24 months after enrolment Enrol clusters over 15 months 9 months of TBPT

5. Eligibility criteria for communities Expanded DOTS program which includes –Active TB case finding using chest x-ray –Standardised monitoring and reporting VCT – same-day confidential testing and counselling –Individuals found to be HIV-infected are offered referral for HIV care Isoniazid and cotrimoxazole preventive therapy for HIV-infected individuals

6. Baseline data TB case notifications rates measured over the 6 month preparation phase Baseline Survey (at recruitment) –Sampling ~ include everyone on certain days ? –TB and silicosis prevalence (using latest chest x-ray) measured at the time of recruitment from a random sample [n=1000 per cluster] –Baseline HIV prevalence (using saliva) measured at the time of recruitment from a random sample [n=1000 per cluster]

7. Paired versus stratified design? Important confounders are –Baseline TB case notification rates –Prevalence of HIV infection –Prevalence of silicosis –Baseline TB prevalence –Trends in the proportion of the HIV-infected workforce receiving ART over the study period Paired design –mining company and baseline TB case rates

8. Sample Size (1) Primary outcome: TB incidence over 12 months, measured amongst hostel dwellers –90% power, type I error of 5% –K=0.25, paired design –Average community size of 2500 (80% live in hostels) –Factored in a potential effect of ART –Assumed a 60% reduction in the community wide PT arm Indicates 7 matched pairs

9. Sample Size (2) Secondary outcomes: –80% power, type I error of 5%, K=0.25, paired design –Average community size of 2500 –Factored in a potential effect of ART HIV-specific TB incidence ~ 60% reduction in the community wide PT arm (over 12 months) TB case notification rates ~ 50% reduction in the community wide PT arm (over 24 months) TB culture prevalence ~ 50% reduction in the community wide PT arm, based on community size of 750

10. Enrolment Intervention and control enrolment teams will work at one pair of clusters at a time Both arms –Consent to use data –Baseline survey [previous x-ray for TB radiological prevalence and silicosis score; saliva sample for HIV testing] Intervention arm –Symptom screen

11. Intervention (1) TB screening to exclude active TB using symptom questionnaire and new and previous chest x-ray Investigated further if new abnormality or symptoms All consenting participants offered 9 months of IPT Monthly visits to Dispense IPT Monitoring for toxicity and side effects

12. Intervention (2) IPT adherence enhancing measures –Patient education –Self-adherence –Treatment supporters –incentives? Monitoring of adherence to IPT –Questionnaire (monthly); pill count etc –Urine testing for INH

13. Measuring primary outcome TB incidence measured over a 12 month period Human Resources –List of miners living at each hostel (cluster) –Redundancies and death information TB database –All TB diagnoses collected –Case definitions applied

14. Measuring secondary outcomes TB incidence measured over a 12 month period, amongst HIV-infected As before All TB diagnoses will be offered anonymous- unlinked HIV testing Use the HIV prevalence from baseline survey

15. Measuring secondary outcomes (2) TB case notification rates over a 24 month period Human Resources (info. collected every 6 mths) –List of miners living at each hostel (cluster) –Redundancies and death information TB database –All TB diagnoses collected Also calculate TB case notification in four 6 month intervals

16. Statistical Analysis Unadjusted Analysis Point estimate (GM of the pairwise estimates) –Log(RR)=(1/c)∑log(RR j )=(1/c) ∑log(r 1j /r 0j ) where r 1j = TB incidence in cluster j, intervention arm and r 0j = TB incidence in cluster j, control arm –And 95% CI Paired t test, applied to the log(rates)

17. Statistical Analysis (2) Poisson regression model fitted to the individual data, including all a priori confounders and an indicator variable for matched pairs Calculate the observed (O ij ) and fitted (E ij ) numbers of TB events for each cluster Calculate the GM of O ij /E ij

18. Other Issues Document TBPT use in the control arm (though the “Wellness” clinics offering care for HIV- infected individuals Pilot study of quantiferon & TST to measure TB infection