C R E A E

1. C R E A E Consortium to Respond Effectively to the AIDS-TB Epidemic An International Research Partnership Supported by the Bill and Melinda Gates Foundation http://www.tbhiv-create.org

3. DOTS and TB Control in Botswana • National TB Control Program – DOTS • Cases diagnosed by microscopy • All therapy supervised, short course rifampin-based • No drugs available outside program • High rates of treatment completion (>90%) • Low rates of drug resistance (<2%) A highly successful medical intervention Kenyon et al. Int J TB Lung Dis 1999;3:4-11

4. TB Incidence and HIV Prevalence, Botswana Failure of a “Successful” DOTS Program to Control TB Kenyon et al., Int J TB Lung Dis 1999;3:4-11

5. Reported TB Case Rates in Malawi 1988-2001 WHO TB Surveillance Report, 2003

6. DOTS and HIV-Related TB • DOTS is a critically important strategy for effective management of TB • DOTS increases cure rates, reduces mortality and prevents emergence of drug resistance • In the setting of HIV prevalence, DOTS alone is not sufficient to control TB incidence

7. C R E A E • A brief history • Autumn 2001 – concept sheet submitted • June 2002 – pilot grant for $3 million • September 2002 – Annecy meeting • February 2003 – proposals reviewed • June 2003 – London meeting on case finding • August 2003 – Seattle meeting with BMGF • November 2003 – 2nd Seattle meeting • January 2004 – final proposal submitted

8. End of the CREATE Meeting at the Bill and Melinda Gates Foundation, November 2003

9. Gates Foundation Press Briefing on TB and HIV at the Bangkok AIDS ConferenceJuly 15, 2004

10. C R E A E Mission To organize, implement and evaluate novel public health strategies to reduce tuberculosis incidence in populations with high rates of HIV and TB co-infection.

11. CREATE Objectives • Design, implement and evaluate a portfolio of community-level trials of new strategies designed to reduce TB incidence in communities with high HIV prevalence. • Transform global policies for HIV-related TB through evidence-based advocacy.

12. Strategies to Reduce TB/HIV in Addition to DOTS • Active or intensified case finding • to identify cases transmitting infection, and who may die without treatment • Treatment of latent TB infection • to prevent disease in HIV+ (and HIV-) persons • Household HIV/TB interventions linked to cases • to promote active case finding, identify candidates for TB preventive therapy (and antiretroviral drugs), and reduce HIV transmission • Combined ARV and IPT treatment programs • to reduce probability of developing primary or reactivation TB

13. The CREATE Portfolio: Current Studies

14. Thibelo TB – Preventing TB Gavin Churchyard, AURUM Health, South Africa

15. Mass Preventive Therapy with INH in South African Gold Miners • Design: Cluster randomized trial • Setting: 24 mine shafts with 1-3000 workers • Intervention: INH for all vs. standard of care (VCT with INH for HIV+, silicotics) • Endpoint: TB incidence and prevalence after 5 years

16. ZAMSTAR – Zambia and South Africa Tuberculosis and AIDS reduction trial Helen Ayles – ZAMBART Project, Lusaka; Nulda Beyers – Stellenbosch University, South Africa University of Zambia and Central Board of Health, Zambia City of Cape Town and Provincial Department of Health, South Africa London School of Hygiene and Tropical Medicine

17. ZAMSTAR Study Design 4-arm Community Randomised Trial • Control • Improved standard of care • Enhanced Tuberculosis Case Finding (ECF) • Community level intervention (schools, market-places, open access diagnosis) • Household level TB and HIV combined activities (HH) • Household counselling intervention • Both ECF and HH 24 communities (16 in Zambia, 8 in Western Cape) Primary endpoint: prevalence of culture proven tuberculosis after 4 years.

18. Study embedded in district health system • Control Communities will have • DOTS strengthening • TB/HIV Combined Activities (ProTEST) • Reporting to Study and National TB Control • All study communities will have enhanced monitoring and evaluation using standard indicators (TB; HIV; TB/HIV) and targets by evaluation team. • All interventions will be conducted by study staff embedded in the district health system working as additional TB/HIV coordinators

19. Cluster-randomized Trial of INH Preventive Therapy in HIV Clinics in Rio de JaneiroBetina Durovni, Rio City Health Department Intervention: • Implementation of a comprehensive policy of screening for and treating latent TB in all HIV-infected patients • TST and INH PT for all TST+ • Incentives/enablers to promote adherence • One clinic phased-in each month until ALL clinics are receiving intervention

20. Methods – Study Design Control group: • Clinic populations that have not yet been phased-in to begin implementation Outcome – TB incidence over 3 years 29 4 Control Clinic 3 Follow-up 2 Intervention 1 1 2 3 4 5 30 36 42 Month

21. ZAMSTAR WithHIV (10%) --_-_--_- ZAMSTAR > Thibelo TB and Brazil 1.1 Infectious cases 18 HIV-ve 2 HIV+ve 1.8 cases 20 contacts Goldmines> ZAMSTAR and Brazil 0.8 cases An Epidemic 1.5 Non-Infectious

22. All IPT involves some targeted case finding Mass ACF Mass IPT Symptomatic ACF Thibelo TB CREATE Research portfolio Targeted ACF ZAMSTAR - Household Community IPT Community ECF ZAMSTAR - ECF Brazil Health centre ECF Stigma of HIV and TB Clinic based IPT DOTS- passive CF Spectrum of Case Finding for TB Spectrum of TB prevention

23. Education and Training core Reduction in tuberculosis through transformed policies Biostatistics core Mass ACF Mass IPT New Knowledge Symptomatic ACF CREATE Research portfolio Targeted ACF Community IPT Community ECF Health centre ECF Policy and Advocacy core Stigma Clinic based IPT DOTS- passive CF Existing TB and HIV policy and practice Administration core

24. Executive Committee Richard Chaisson, Chair and PI (JHU) Betina Durovni (SMS, Rio) Peter Godfrey-Faussett (LSHTM) Gavin Churchyard (Aurum Health Research) Larry Moulton (JHU) Paul Nunn (WHO) Peter Small (BMGF)* * Ex-Officio