In response to R.F.A. AI-98-013, this application is part of the competitive renewal application for the AIDS Clinical Trials Group (ACTG). The Beth Israel (BI) AIDS ClinicalTrials Unit (ACTU) has been a member of the ACTG network since 1987 as a subunitof the Mount Sinai ACTU, and proposes in the new grant cycle to be established as an independent main unit. Buildingon 15 years of experience and accomplishmentsin HIV-related clinical research, the focus of BI investigators encompasses several of the highest prioritiesof the ACTG scientific agenda, including adherence, antiretroviral toxicities, metabolic complications, and optimizingthe care of HIV-infected women throughan understanding of the influence of gender on these outcomes. This proposal aims to further the scientific goals of the ACTG research agenda committees by (1) contributing to the design and implementation of novel studies that will (a): provide optimal therapy for HIV-1 infection and its complications; and (b): explore the pathogenesis of HIV-1 infection and its complications, including bidirectional relationships between HIV and specific opportunisticpathogens. The BI site also has the demonstrated capability to further the goals of the ACTG by (2) recruiting, enrolling,and retainingin long term follow up a demographically diverse populationof 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, we will develop novel models to promote adherence to highly active antiretroviraltherapy (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 HIV-related complications will focus on: (1) microbial and immunologic measures that defineopportunistic infection risk and protection; (2) metabolic and nutritionalcomplications; (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 inhibitorsin HIV-infected women; and (6) sensory polyneuropathy, HIV-associated dementia,and reservoirs of viral infection tn the CNS, including CSF antiretroviralpharmacokinetics.
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