“Thibelo TB” Aurum Health Research LSHTM JHU Gold mining companies Dept. of Health, SA

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. Primary outcome measurement period 9 months of TBPT Recruitment of clusters Prevalence survey Enrol clusters over 15 months • 9 months of TBPT • Measure primary outcome over 12 months, from 13-24 months after enrolment

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(RRj )=(1/c) ∑log(r1j /r0j) where r1j = TB incidence in cluster j, intervention arm and r0j = 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 (Oij) and fitted (Eij) numbers of TB events for each cluster • Calculate the GM of Oij/Eij

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