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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BP-A)
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Magee-Women's Research Institute and Foundation
United States
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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
Mcgowan, Ian; Cranston, Ross D; Duffill, Kathryn et al. (2015) A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study). PLoS One 10:e0125363
Hladik, Florian; Burgener, Adam; Ballweber, Lamar et al. (2015) Mucosal effects of tenofovir 1% gel. Elife 4:
Wahl, Angela; Victor Garcia, J (2014) The use of BLT humanized mice to investigate the immune reconstitution of the gastrointestinal tract. J Immunol Methods 410:28-33
McGowan, Ian (2014) The development of rectal microbicides for HIV prevention. Expert Opin Drug Deliv 11:69-82
Dezzutti, Charlene S; Russo, Julie; Wang, Lin et al. (2014) Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation. PLoS One 9:e102585
McGowan, Ian; Dezzutti, Charlene (2014) Rectal microbicide development. Curr Top Microbiol Immunol 383:117-36
Rohan, Lisa C; Yang, Haitao; Wang, Lin (2013) Rectal pre-exposure prophylaxis (PrEP). Antiviral Res 100 Suppl:S17-24
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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