Exploratory human trials of rectal microbicides

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This proposal will address the critical issues pertinent to the development of reverse transcriptase (RT) antiretroviral rectal microbicides The proposed studies will use the RT inhibitor UC-781 as a candidate rectal microbicide and Biosyn Inc., will be the private sector leader of the project. The first aim of this proposal will be to define the optimal preclinical safety assessment of an RT rectal microbicide with the necessary Investigational New Drug Application (IND) studies, followed by studies in HIV seronegative subjects with subsequent evaluation in HIV seropositive subjects. Although the studies proposed in this project focus on the RT class of microbicide it is anticipated that the methodological approaches developed in this proposal could be used to evaluate other classes of microbicide for safety and preliminary efficacy. There are four specific goals in Aim 1: (1) To conduct the necessary preclinical animal studies, to file an IND, to allow human studies involving rectal administration of UC-781 gel, (2) To determine the sensitivity and specificity of a broad range of immunological, molecular and histopathological parameters in assessing potential microbicide toxicity, (3) To evaluate the intestinal explant / infection system as a means of generating early ex vivo/in vitro evidence of rectal microbicide efficacy in resisting HIV infection, and (4) To characterize the effect of anal coital activity on the distribution and bioavailabilty of UC-781 gel. The second aim of the study is to characterize the virological sequelae of rectal administration of UC-781 gel in subjects with HIV-1 infection. More specifically, studies will be conducted to determine the kinetic changes in plasma, mucosal, and rectal secretion HIV-1 viral load after rectal administration ofUC-781 gel. In addition, baseline and post treatment mucosal and plasma viral isolates will be genotyped to determine whether exposure to UC-781 gel is associated with evolution of viral mutations and whether these changes are restricted to the rectal mucosal compartment or can be detected in the plasma compartment. Completion of these studies will provide the necessary data to optimize the future conduct of rectal microbicide Phasel trials, provide specific information on the virological responses to RT microbicides in HIV positive subjects, and compliment the preclinical/discovery phase of rectal microbicide drug development begun in Project 1 of this U-19 Grant.