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.
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.
|Akil, Ayman; Agashe, Hrushikesh; Dezzutti, Charlene S et al. (2015) Formulation and characterization of polymeric films containing combinations of antiretrovirals (ARVs) for HIV prevention. Pharm Res 32:458-68|
|Rinehart, Matthew; Grab, Sheila; Rohan, Lisa et al. (2014) Analysis of vaginal microbicide film hydration kinetics by quantitative imaging refractometry. PLoS One 9:e95005|
|Zhou, Tian; Hu, Minlu; Pearlman, Andrew et al. (2014) Expression and localization of p-glycoprotein, multidrug resistance protein 4, and breast cancer resistance protein in the female lower genital tract of human and pigtailed macaque. AIDS Res Hum Retroviruses 30:1106-16|
|Akil, Ayman; Devlin, Brid; Cost, Marilyn et al. (2014) Increased Dapivirine tissue accumulation through vaginal film codelivery of dapivirine and Tenofovir. Mol Pharm 11:1533-41|
|Chappell, Catherine A; Rohan, Lisa C; Moncla, Bernard J et al. (2014) The effects of reproductive hormones on the physical properties of cervicovaginal fluid. Am J Obstet Gynecol 211:226.e1-7|
|Parsons, Teresa L; Emory, Joshua F; Seserko, Lauren A et al. (2014) Dual quantification of dapivirine and maraviroc in cervicovaginal secretions from ophthalmic tear strips and polyester-based swabs via liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. J Pharm Biomed Anal 98:407-16|
|Dezzutti, Charlene S; Uranker, Kevin; Bunge, Katherine E et al. (2013) HIV-1 infection of female genital tract tissue for use in prevention studies. J Acquir Immune Defic Syndr 63:548-54|
|Zhou, Tian; Hu, Minlu; Cost, Marilyn et al. (2013) Short communication: expression of transporters and metabolizing enzymes in the female lower genital tract: implications for microbicide research. AIDS Res Hum Retroviruses 29:1496-503|
|Isaacs, Charles E; Xu, Weimin (2013) Theaflavin-3,3'-digallate and lactic acid combinations reduce herpes simplex virus infectivity. Antimicrob Agents Chemother 57:3806-14|
|Rinehart, Matthew T; Drake, Tyler K; Robles, Francisco E et al. (2011) Time-resolved imaging refractometry of microbicidal films using quantitative phase microscopy. J Biomed Opt 16:120510|