The rectal compartment is highly vulnerable to HIV infection and there is an urgent need to develop microbicides that have been specifically designed for use in the rectal compartment. These products need to be highly effective, minimize the risk of development of HIV resistance, and be protective against both wild type and resistant HIV. As a consequence, the ultimate goal of Project 3 (Exploratory Human Trials of Combination Rectal Microbicides) will be to develop a combination antiretroviral rectal specific microbicide that is most likely to have this desired product profile. Towards this end, Project 3 will undertake a series of innovative pre-Phase 1 clinical studies of the three rectal specific microbicides developed by Core C (Formulation Development Core). These formulations will include UC781, tenofovir and a combination product containing tenofovir and UC781. The design of these studies builds upon experience generated from a previous IP/CP grant (U19 A060614;Anton, PI) that characterized the rectal safety and pharmacokinetic (PK) profile of vaginal formulations of tenofovir and UC781. The design of all three pre-Phase 1 studies is identical. Following screening and collection of baseline samples, participants will receive a single dose of the specific rectal microbicide formulation. They will then undergo detailed assessment of mucosal safety, multicompartmental PK, product distribution, and the ability of rectal tissue explants to resist ex vivo I in vitro challenge with HIV. These data will provide a unique profile of the candidate microbicide and facilitate assessment of product suitability for further clinical development. However, all the products will still require formal Phase 1 safety assessment within a clinical trials network such as the Microbicide Trials Network (MTN). The studies will be conducted at three research sites with recognized excellence in rectal microbicide development (UCLA, Magee Women's Research Institute (MWRI) and Johns Hopkins University (JHU)). Project 3 Aim 1 will be to optimize and cross validate study endpoint assays across the trial sites.
Aims 2, 3 and 4 will be to conduct the pre-Phase 1 trials of UC781, tenofovir, and the combination (UC781 and tenofovir) respectively. The studies will not have a placebo group nor contain any dose-escalation component. The selected doses are those currently used in vaginal microbicide (VM) studies. These three trials will enable the assessment of mucosal toxicity and efficacy, permit correlations within the domains of dose, toxicity, efficacy and distribution and, finally, permit direct comparison to already completed VM trials using the same doses of antiretroviral products.

Public Health Relevance

In the absence of a safe and effective HIV vaccine, there is an urgent need to develop new approaches to HIV prevention including microbicides. The exquisite vulnerability of the rectal mucosa to HIV infection, the persistent, if not increasing, HIV epidemic in men who have sex with men, and recent epidemiological data demonstrating clinically significant levels of unprotected anal intercourse in women all define a critical need to develop rectal specific microbicides to compliment ongoing efforts in vaginal microbicide development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082637-04
Application #
8381365
Study Section
Special Emphasis Panel (ZAI1-BP-A)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$827,581
Indirect Cost
$241,970
Name
Magee-Women's Research Institute and Foundation
Department
Type
DUNS #
119132785
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Hiruy, Hiwot; Fuchs, Edward J; Marzinke, Mark A et al. (2015) A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02). AIDS Res Hum Retroviruses 31:1098-108
Hladik, Florian; Burgener, Adam; Ballweber, Lamar et al. (2015) Mucosal effects of tenofovir 1% gel. Elife 4:
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McGowan, Ian; Dezzutti, Charlene (2014) Rectal microbicide development. Curr Top Microbiol Immunol 383:117-36
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Chateau, Morgan L; Denton, Paul W; Swanson, Michael D et al. (2013) Rectal transmission of transmitted/founder HIV-1 is efficiently prevented by topical 1% tenofovir in BLT humanized mice. PLoS One 8:e60024
Chateau, Morgan; Swanson, Michael D; Garcia, J Victor (2013) Inefficient vaginal transmission of tenofovir-resistant HIV-1. J Virol 87:1274-7

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