Project Summary The AIDS Clinical Trials Group (ACTG) has been at the forefront of clinical research to advance HIV therapeutics and improve the health of people living with HIV/AIDS for 30 years. Rigorous scientific research conducted by the ACTG has laid the cornerstones for current HIV treatment guidelines. In this application for the competitive renewal of the ACTG we propose a transformative research agenda that draws on an international consortium of leading clinical and laboratory HIV investigators in collaboration with a world-class Statistics and Data Management Center to design and conduct innovative interventional clinical trials that will significantly reduce the global burden of disease due to HIV, TB and hepatitis B. The Leadership and Operations Center (LOC) provides scientific leadership and fiscal and organizational management of the ACTG. The ACTG Executive Committee (AEC) will serve as the overarching governing body of the network. The AEC is guided by an Executive Management Committee that includes the Network Chairs, Chief Quality Officer and the Chairs of the Laboratory and Statistical and Data Management Centers. Transformative Science Groups will oversee the development and execution of the ACTG research agenda, which will be coordinated and prioritized by the Scientific Agenda Steering Committee (SASC). Protocol development, implementation, training and network evaluation will be facilitated by the Network Clinical Core at Social & Scientific Systems, Inc. The LOC financial management group (Admin Core) at the University of California, Los Angeles will oversee resource management and protocol fund distribution at the direction of the AEC. The LOC will assure the engagement of Community in all aspects of the ACTG, and will coordinate communication between all three components of the network. Specific aims of this proposal include: 1) Identify interventions to reduce HIV reservoirs and control HIV replication in the absence of ART; 2) Test novel and durable interventions targeting HIV infection; 3) Improve the treatment and prevention of drug sensitive and drug resistant tuberculosis; 4) Prevent or improve the treatment of HIV-related non-infectious co-morbidities and evaluate strategies to cure hepatitis B virus infection in people with and without HIV.