Research efforts to develop topical microbicides for intravaginal use for the prevention of sexually transmitted infections (STI) including HIV have been ongoing for over a decade. In the past year an estimated 4.3 million people became newly infected with HIV. Women now represent almost half of all adults living with HIV/AIDS. The need for a female controlled STI preventive product is well understood. Preclinical safety and efficacy testing of topical microbicide products must be performed prior to human use to assess the product's effects on the vaginal ecosystem and to assess potential anti-HIV activity. We have developed a useful model to evaluate the safety of topical microbicide products after vaginal use in the pigtailed macaque. We have used this model to study the effects of single and repeated applications of microbicides on vaginal microflora and epithelium. We have conducted preclinical safety and pharmacokinetic studies of vaginal gel formulations containing UC781 ( 1% and 0.1%) and tenofovir (1%) in this macaque model. In addition, we have the ability to image (MRI) product dispersal and transport in the female reproductive tract. In this proposed cooperative agreement, a novel delivery system for topical microbicides, vaginal films, will be compared to vaginal gel formulations. We will use our macaque model to assess safety, dispersal and pharmacokinetic characteristics of various film formulations containing UC781 and/or tenofovir, and compare these findings to those compiled for gel formulations. Finally, we will assess the efficacy of each of the developed film products using a macaque model for RT-SHIV infection. These studies will in part guide the optimization of a combination topical microbicide delivery system.

Public Health Relevance

An effective topical microbicide product is desperately needed to mitigate the ongoing HIV pandemic. These macaque studies will provide data integral to the optimization of product safety, delivery and efficacy, with an end goal of providing a combination topical microbicide product poised for advancement to clinical trials.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082639-05
Application #
8660268
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Magee-Women's Research Institute and Foundation
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
Moncla, Bernard J; Chappell, Catherine A; Debo, Brian M et al. (2016) The Effects of Hormones and Vaginal Microflora on the Glycome of the Female Genital Tract: Cervical-Vaginal Fluid. PLoS One 11:e0158687
Bunge, Katherine E; Dezzutti, Charlene S; Rohan, Lisa C et al. (2016) A Phase 1 Trial to Assess the Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics of a Novel Dapivirine Vaginal Film. J Acquir Immune Defic Syndr 71:498-505
Zhou, Tian; Hu, Minlu; Pearlman, Andrew et al. (2016) Expression, regulation, and function of drug transporters in cervicovaginal tissues of a mouse model used for microbicide testing. Biochem Pharmacol 116:162-75
Fan, Maria D; Kramzer, Lindsay F; Hillier, Sharon L et al. (2016) Preferred Physical Characteristics of Vaginal Film Microbicides for HIV Prevention in Pittsburgh Women. Arch Sex Behav :
Coleman, Jenell S; Fuchs, Edward; Aung, Wutyi S et al. (2016) Feasibility of radiolabeled small molecule permeability as a quantitative measure of microbicide candidate toxicity. Contraception 93:331-6
Moncla, Bernard J; Chappell, Catherine A; Mahal, Lara K et al. (2015) Impact of bacterial vaginosis, as assessed by nugent criteria and hormonal status on glycosidases and lectin binding in cervicovaginal lavage samples. PLoS One 10:e0127091
Kramzer, Lindsay F; Cohen, Jessica; Schubert, Jesse et al. (2015) Assessing the potential of the Woman's Condom for vaginal drug delivery. Contraception 92:254-60
Hu, Minlu; Patel, Sravan Kumar; Zhou, Tian et al. (2015) Drug transporters in tissues and cells relevant to sexual transmission of HIV: Implications for drug delivery. J Control Release 219:681-96
Wang, Linlin; Koppolu, Sujeethraj; Chappell, Catherine et al. (2015) Studying the effects of reproductive hormones and bacterial vaginosis on the glycome of lavage samples from the cervicovaginal cavity. PLoS One 10:e0127021
Chappell, Catherine A; Isaacs, Charles E; Xu, Weimin et al. (2015) The effect of menopause on the innate antiviral activity of cervicovaginal lavage. Am J Obstet Gynecol 213:204.e1-6

Showing the most recent 10 out of 24 publications