In the face of the existing HIV-1 epidemic, an effective mix of prevention modalities are needed to begin to reduce the incidence of HIV-1. This includes the used of topical microbicides. These are products that would be used to prevent the sexual transmission of HIV-1;including receptive anal intercourse. Project 1, Nonclinical Strategies for Refining Combination Rectal Formulations, of this U19 will strive to ensure that a safe and effective rectal microbicide will be developed. To date, the Phase 2b trials of """"""""first generation"""""""" microbicide products, nonoxynol-9, SAVVY, cellulose sulfate, and Carraguard, have either failed to show effectiveness or showed harm and were halted early. This has lead the way to using """"""""second generation"""""""" microbicide products that encompass the antiretroviral (ARV) drugs, UC781 and tenofovir. We have developed an innovative testing algorithm to evaluate safety and effectiveness of ARV rectal microbicide (RM) formulations that will be developed by this U19 (Core C). This includes the use of a polarized colorectal explant culture system which to date has generated results that has been reflective of nonhuman primate and human Phase 1 clinical safety data as well as predictive of nonhuman primate and human Phase 2b clinical effectiveness data. It is of interest to determine if these RM formulations are effective indepentent of coitus as well as in the presence of semen. Finally, in anticipation of developing combinations of microbicides that will have multiple mechanisms of action to improve preventative effectiveness, molecules that block or prevent the fusion of HIV-1 with the target cell will be tested for antagonism or synergy with the ARV drugs. The ultimate goal of this work will be to ensure that what is developed in this U19 for RM will be safe and have the potential to be highly effective when tested in a clinical trial.

Public Health Relevance

HIV-1 infection is a devistating disease that is mostly spread through sexual activity. Because of the high likelihood that a couple will participate in anal sex without a condom, we need to prevent possible HIV-1 infection through the rectum. To do this, rectal microbicides (products that kill HIV-1) are being developed to use just before or just after anal sex.

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 #
8381361
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
$239,299
Indirect Cost
$67,695
Name
Magee-Women's Research Institute and Foundation
Department
Type
DUNS #
119132785
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Richardson-Harman, Nicola; Parody, Robert; Anton, Peter et al. (2017) Analytical Advances in the Ex Vivo Challenge Efficacy Assay. AIDS Res Hum Retroviruses 33:395-403
Chiu, Wai Kan; Brand, Rhonda M; Camp, Danielle et al. (2017) The Safety of Multiple Flexible Sigmoidoscopies with Mucosal Biopsies in Healthy Clinical Trial Participants. AIDS Res Hum Retroviruses 33:820-826
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

Showing the most recent 10 out of 24 publications