1. Adult AIDS Clinical Trials Group International Therapeutic Initiative

2. AACTG Funded by NIAID/DAIDS (NIH) Established in 1986 Mission: conduct investigator-initiated, hypothesis-driven and pathogenesis-based clinical trials of the treatment of HIV infection and its sequelae Approximately 75 multi-center studies active at any time at 35 US sites 2,000 - 3,000 subjects enrolled per year

3. AACTG International Therapeutic Clinical Trials Initiative Announced late 2001Announced late 2001 Goals:Goals: –Conduct research to elucidate the most effective approaches to HIV-1 therapy in resource limited international settings –Transfer technology and develop infrastructure to conduct clinical trials in resource limited settings –Support NIAID/DAIDS prevention research efforts (HPTN, HVTN) –Accelerate access to state-of-the-art care in resource limited settings through resource, training and technology transfer and infrastructure development –Study the impact of state-of-the-art care and treatment on persons with HIV-1 infection in resource limited settings

4. AACTG ICTU Locations UNAIDS 2001

5. ACTG A5175 Partnership with HPTN Hypothesis: An all NRTI regimen and a once-daily regimen are as safe and effective as a standard three drug, twice-daily regimen of 2 NRTIs and an NNRTI Sites: 12 ICTUs in 8 resource-limited countries Population: HIV-1-infected persons with < 300 CD4+ cells/  L Design: Randomized, open-label, 3 arms Primary endpoint: plasma HIV RNA Duration: 2.5 years

6. A5175 long-term objectives Technology transfer Simplified measures for monitoring efficacy of antiretroviral therapy

7. A5175 Standard of Care Issues Development of research objectives that are locally relevantDevelopment of research objectives that are locally relevant –Avoid exploitation –Study design by an international committee with representatives from each site –Use ARVs that are/will be available for use in the countries where the study is conducted –Priority questions: 1)Evaluation of PI- and NNRTI-sparing regimens 2)Evaluation of once-daily regimens

8. A5175 Standard of Care Issues Post-trial drug accessPost-trial drug access –Sponsors (NIH, pharmaceutical companies) will not provide drugs after the study is over –Standard of care is diverse across the study sites –Standard of care is dynamic –Each site will develop a plan for post-study ARV access in coordination with local governmental and non-governmental agencies

9. A5175 Standard of Care Issues Effects of results of studies conducted in developed countries on study designEffects of results of studies conducted in developed countries on study design –Planned DSMB interim review of A5095 found that ZDV/3TC/ABC provided inferior HIV suppression compared to ZDV/3TC/EFV –Atlantic study found that d4T/3TC/ddI provided inferior HIV suppression compared to d4T/3TC/NVP –A5175 team felt it was unethical to randomize participants to a comparison of ZDV/3TC/ddI with ZDV/3TC/EFV (or NVP) –ZDV/3TC/ddI arm removed from the study

10. A5175 Standard of Care Issues Influence of pharmaceutical industry on study designInfluence of pharmaceutical industry on study design –Study is dependent on pharmaceutical companies for donation of ARVs –One sponsor will not support study unless the ZDV/3TC/ddI arm is included –Scientific objectives of ARV research in developing countries is being influenced by pharmaceutical company marketing concerns –Pharma-independent sources of ARVs are needed for clinical trials in resource-limited settings