ZAMSTAR - the Zambian South African TB and AIDS Reduction trial

1. ZAMSTAR - the Zambian South African TB and AIDS Reduction trial ZAMBART, UNZA Centre for TB Research, Univ Stellenbosch CBOH, Zambia LDHMT, Zambia City of Cape Town, SA LSHTM, UK

2. To evaluate novel public health strategies to reduce the prevalence of tuberculosis in communities where the existing international tuberculosis control strategy is insufficient due to the interaction between the tuberculosis and HIV epidemics. Objective

3. Does improved tuberculosis case finding (ICF) by a strategy of community mobilisation and improved access to sputum microscopy, reduce prevalence of tuberculosis in the community? (arms 1+3 Vs. 2+4) Do combined TB/HIV activities at the household level (HH), reduce prevalence of tuberculosis? (arms 1+2 Vs. 3+4) Does ICF plus HH (ICF+HH), yield additional benefits for tuberculosis control through additional case detection, improved case holding, treatment/prophylaxis of latent infection and reduction in HIV incidence? (arm 1 Vs. 4) Specific primary aims

4. 4-arm Community Randomised Trial of Improved Tuberculosis Case Finding (ICF) or Household level TB/HIV intervention or ICF plus HH (ICF+HH) Vs. control (strengthened DOTS, access to VCTs) Control arm Strengthened DOTS VCT TB/HIV at health centre access (offering isioniazid preventive therapy) Basic HIV care HIV prevention (condoms, STI management) Improved Tuberculosis Case Finding (ICF) Open access to sputum smear at health centre Schools education campaign Community mobilisation and mobile tuberculosis laboratory Household level TB & HIV combined activities (HH) Household counsellor visiting all TB households Household members encouraged to test for HIV TB preventive therapy for HIV+ve and children <6 Methods – Study Design

5. Does ICF reduce the prevalence of tuberculosis in the community?

6. Does HH reduce the prevalence of tuberculosis in the community?

7. Primary Outcome: TB prevalence in adults (>14yrs old) measured by community prevalence survey after 3 years of intervention. Survey to be completed on a random sample of 8,000 adults from each community with sputum cultures. Methods – Outcomes

8. Methods – Sampling design

9. Secondary Outcomes: At community level Prevalence of TB infection in 6 year olds measured by tuberculin skin testing (TST) to be negative at baseline TB treatment outcomes (cure, failure, death, etc.) measured by cohort analysis of strengthened TB registers Number of additional TB cases identified by ICF and HH Uptake of HIV testing & counseling (TC) and adherence to TB preventive therapy measured by strengthened TC registers Costs and cost-effectiveness Methods - Outcomes

10. Secondary Outcomes: At household level (measured on a cohort of TB households) Cumulative HIV incidence in >14 year olds TB treatment outcomes measured by cohort analysis of strengthened TB registers Uptake of HIV TC and adherence to TB preventive therapy measured by strengthened TC registers TB transmission within the household measured by TST or Quantiferon-3g conversion rates Cumulative TB incidence Stigma levels as measured by Kanayaka study indicators Methods - Outcomes

11. Secondary endpoints TST prevalence TST prevalence measured again in schools in the evaluation areas that were used at baseline Same team of TST readers will perform the readings Cut-off will depend on local profiles HIV Incidence in households Dried blood spots collected at baseline, year 2 and year 4 HIV measured by ELISA TB, HIV TC & IPT uptake and outcomes Standardised, adapted registers used in all sites to compare uptake, adherence and TB outcomes Methods - Endpoints

12. Primary outcome: Assumptions Prevalence of tuberculosis in control community 1% (adults) Reduction in prevalence to 0.7% in arm 2, 3 and 0.49% in arm 4 after 3 years of intervention Total population sampled in each cluster 8,000 80% power, 95% precision k==0.2, stratified design using the formula for the measurement of rates in cluster randomised studies: C=1+(z/2 + z)2 [{ p0 (1- p0 )+p1 (1-p1)}/n + k2 (p02+p12)]/ (p0 - p1)2 We need 6 quadruplets of communities i.e. 24 communities Methods – Sample Size and Biostatistical Considerations

13. Expected reduction in prevalence rates per arm Non-ICF Vs. ICF non-HH Vs HH

14. Secondary Outcomes Prevalence of TB infection in 6 year olds: Sample size 400 per community (2,400 per arm) 10% infection in control arm Reduction of 30% between arms Loss to follow-up 20% 80% power, 95% precision 24 communities, k=0.2 HIV Incidence in households: Sample Size 147 households per community (882 per arm) 2-3 HIV negative adults per household at the baseline HIV incidence in control 0.7% per year Cumulative HIV incidence ( 3 years) 2.1%, 40% reduction loss to follow up of 20% reduction in cumulative HIV incidence of 50%, (with at least 80% power and 95% precision) Methods – Sample Size and Biostatistical Considerations

15. Randomisation unmatched stratified according to urban/rural and country constrained according to baseline surveys, tuberculosis notification rate and estimated HIV prevalence Analytical Plan stratified community randomised study primary outcome will be TB prevalence after 3 years odds ratios for intervention versus control will be estimated allowing for the community-randomised design. Methods – Sample Size and Biostatistical Considerations

16. Timelines