The growing HIV pandemic and its increasing burden on women highlights the urgent need for novel safe and effective preventative strategies such as topical microbicides. We hypothesize that a truly safe and effective microbicide will require sustained, local delivery of a combination of drugs that target different steps in the HIV life cycle and a delivery system that addresses the challenges related to adherence. A safe microbicide should not interfere with host defenses nor increase the risk of selecting for drug resistant viruses. Achieving this goal requires more stringent pre-clinical and clinical evaluation of microbicides, focusing on their interactions with the genital tract mucosal environment. The goal of this iterative Program is to develop a combination microbicide delivered via intravaginal ring (IVR) to prevent the sexual transmission of HIV. This will be accomplished either through IVR formulation of a dual-active single agent, a pyrimidinedione, which is both a potent reverse transcriptase and entry inhibitor, or by combining two distinct antiretroviral (ARV) drugs. We will address the importance of the biological synergy between HIV and HSV by also combining acyclovir with ARV drugs to provide local sustained suppression of HSV. The safety of the microbicides and formulations will be explored using novel assays designed to assess their impact on the epithelial barrier and mucosal immunity. Exploratory clinical studies to evaluate the genital tract mucosal environment of Rwandan women will be conducted as defining the healthy genital tract environment will provide crucial information for establishing clinical biomarkers of microbicide safety. Pilot studies to examine the safety and tolerability of three different polyurethane rings will be conducted to identify the optimal composition for formulation of microbicide rings. Results of this study will guide the IVR formulation of our lead drugs, which will be advanced for further safety and regulatory studies including macaque PK and safety studies. A pre-Phase I clinical study is proposed to evaluate PK and safety of our lead IVR formulated microbicide and to determine if the released drug retains its antiviral activity using a spiking strategy.

Public Health Relevance

These studies will provide crucial information for advancement of safe and effective IVR combination microbicides to prevent HIV and to suppress HSV. These studies will also address critical gaps in microbicide science focusing on the development of sustained delivery systems and safety biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI076980-04
Application #
8307887
Study Section
Special Emphasis Panel (ZAI1-BP-A (J1))
Program Officer
Turpin, Jim A
Project Start
2009-09-10
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$2,695,644
Indirect Cost
$885,979
Name
Albert Einstein College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Nixon, Briana; Jandl, Thomas; Teller, Ryan S et al. (2014) Vaginally delivered tenofovir disoproxil fumarate provides greater protection than tenofovir against genital herpes in a murine model of efficacy and safety. Antimicrob Agents Chemother 58:1153-60
Srinivasan, Priya; Dinh, Chuong; Zhang, Jining et al. (2014) Pharmacokinetic evaluation of tenofovir disoproxil fumarate released from an intravaginal ring in pigtailed macaques after 6 months of continuous use. J Med Primatol 43:364-9
Teller, Ryan S; Rastogi, Rachna; Johnson, Todd J et al. (2014) Intravaginal flux controlled pump for sustained release of macromolecules. Pharm Res 31:2344-53
Herold, Betsy C; Dezzutti, Charlene S; Richardson, Barbra A et al. (2014) Antiviral activity of genital tract secretions after oral or topical tenofovir pre-exposure prophylaxis for HIV-1. J Acquir Immune Defic Syndr 66:65-73
Smith, James M; Rastogi, Rachna; Teller, Ryan S et al. (2013) Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges. Proc Natl Acad Sci U S A 110:16145-50
Nixon, Briana; Stefanidou, Martha; Mesquita, Pedro M M et al. (2013) Griffithsin protects mice from genital herpes by preventing cell-to-cell spread. J Virol 87:6257-69
Mesquita, Pedro M M; Srinivasan, Priya; Johnson, Todd J et al. (2013) Novel preclinical models of topical PrEP pharmacodynamics provide rationale for combination of drugs with complementary properties. Retrovirology 10:113
Herold, Betsy C; Keller, Marla J; Shi, Qiuhu et al. (2013) Plasma and mucosal HIV viral loads are associated with genital tract inflammation in HIV-infected women. J Acquir Immune Defic Syndr 63:485-93
Johnson, Todd J; Srinivasan, Priya; Albright, Theodore H et al. (2012) Safe and sustained vaginal delivery of pyrimidinedione HIV-1 inhibitors from polyurethane intravaginal rings. Antimicrob Agents Chemother 56:1291-9
Kiser, Patrick F; Johnson, Todd J; Clark, Justin T (2012) State of the art in intravaginal ring technology for topical prophylaxis of HIV infection. AIDS Rev 14:62-77

Showing the most recent 10 out of 14 publications