In response to RFA AI-98-013, this application is part of the competitive renewal application for the AIDS Clinical Trials Group (ACTG). The Beth Israel (BI) AIDS Clinical Trials Unit (ACTU) has been a member of the ACTG network since 1987 as a subunit of the Mount Sinai ACTU, and proposes in the new grant cycle to be established as an independent main unit. Building on 15 years of experience and accomplishments in HlV-related clinical research, the focus of BI investigators encompasses several of the highest priorities of the ACTG scientific agenda, including adherence, antiretroviral toxicities, metabolic complications, and optimizing the care of HlV-infected women through an understanding of the influence of gender on these outcomes. This proposal aims to further the scientific goals of the ACTG research agenda committees by contributing to the design and implementation of novel studies that will provide optimal therapy for HIV-I infection and its complications, and explore the pathogenesis of HIV-1 infection and its complications, including bi- directional relationships between HIV and specific opportunistic pathogens. The BI site also has the demonstrated capability to further the goals of the ACTG by recruiting, enrolling, and retaining in long term follow up a demographically diverse population of subjects at all stages of HIV-1 infection in Phase I-IV clinical trials for the treatment of HIV-1 infection and its related complications. Based on extensive experience with the study of antiretroviral agents, tuberculosis (TB), and adherence to TB treatment, they will develop novel models to promote adherence to highly active antiretroviral therapy (HAART) and will assess the safety/tolerance and antiviral activity of a multi-drug antiretroviral combination regimen. The BI unit also proposes to validate an immunologic """"""""third marker"""""""" or additional markers for use, together with RNA and CD4, as a composite surrogate for clinical and virologic endpoints in treatment trials of immune-based therapeutic interventions. Studies of HlV-related complications will focus on: (1) microbial and immunologic measures that define opportunistic infection risk and protection; (2) metabolic and nutritional complications; (3) the role of cytokines as markers of disease progression and antiretroviral drug efficacy; (4) effects of HAART on restoration of pathogen-specific immune functions; (5) effects of protease inhibitors in HIV-infected women; and (6) sensory polyneuropathy, HIV-associated dementia, and reservoirs of viral infection in the CNS, including CSF antiretroviral pharmacokinetics.
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