A safe and effective topical HIV prevention strategy will likely require sustained delivery of a combination of potent drugs that target distinct steps in the HIV life cycle as well as a delivery system that overcomes the behavioral challenges of adherence. This competitive revision to our U19 addresses this public health imperative. Results obtained in studies funded by this U19, coupled with advances in the microbicide field, strongly support the rapid advancement of a polyurethane intravaginal ring (IVR) to deliver the combination of tenofovir disoproxil fumarate (TDF) and maraviroc (MVC). Both drugs are highly potent, safe, act by different mechanisms to inhibit HIV infection, and are additive an/or synergistic for both R5 and X4 laboratory and clinical isolates. Moreover, both are approved as oral therapeutic agents, thus greatly simplifying the regulatory pathway required for clinical studies. TDF replaced tenofovir (TFV) for oral antiretroviral therapy because of enhanced bioavailability and more potent anti-HIV activity. The improved efficacy is explained by more rapid intracellular uptake of TDF, resulting in an increased intracellular accumulation of TFV diphosphate, the pharmacologically active metabolite. The lower dose of drug needed has important implications with respect to the cost of developing an affordable IVR microbicide. In addition, the more hydrophobic nature of TDF provides distinct advantages for co-formulation with MVC in a single device. We hypothesize that greater protection will be achieved by replacing TFV with TDF and by combining TDF with MVC. We also hypothesize that sustained IVR delivery will overcome the significant adherence issue associated with coitally-dependent or daily gel application. We predict that a TDF-MVC IVR combination will prove to be highly effective, safe, and reduce the risk of selecting for resistant viruses. An additional advantage is that TDF may provide significant protection against HSV-2 infection. We propose to expand our program and complete all necessary preclinical and regulatory work to enable us to conduct a pre-Phase I safety and pharmacokinetic study with a TDF ring, which will incorporate novel biomarkers of efficacy and safety.
The overall goal of this iterative program is to advance the combination of tenofovir disoproxil fumarate and maraviroc delivered by intravaginal ring into the clinic to prevent the sexual transmission of HIV. The proposed studies will also address critical gaps in microbicide science focusing on the development of more predictive biomarkers of microbicide pharmacodynamices, efficacy and safety. Project 3 - Clinical Study to Measure Pharmacokinetics, Pharmacodynamics and Safety of a TDF Ring Project Leader - Marla J Keller, MD (Description as provided by applicant) The ultimate goal of this Program is to develop an intravaginal ring (IVR) for sustained delivery of a combination microbicide that will be safe and effective in preventing the sexual transmission of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). A safe and effective microbicide will likely require sustained, local delivery of a combination of antiretroviral drugs that target different steps in the HIV life cycle and a delivery system that overcomes the challenges related to adherence. This will be accomplished through IVR formulation of the reverse transcriptase inhibitor, tenofovir disoproxil fumarate (TDF), combined with the entry inhibitor, maraviroc (MVC). The rationale for pursuing this combination is based on the recent promising results of CAPRISA 004 in which significant protection against HIV-1 and HSV-2 was observed with 1% TFV gel. Ongoing work in Projects 1 and 2 demonstrate potential advantages of a TDF compared to a TFV IVR, including more potent activity against HIV and HSV, greater tissue permeability, and the successful development of a polyurethane (PU) IVR formulation of TDF. An exploratory pre-Phase I study is proposed in this new Project to rigorously measure the pharmacokinetics (PK), pharmacodynamics (PD) and safety of TDF following ring delivery in healthy women. The primary outcomes to be measured are PK of TDF release into the genital tract and adverse events. PD will be evaluated by measuring the antiviral activity (HIV and HSV) in genital tract secretions (luminal) and tissue following IVR delivery of TDF. Ectocervical tissu will be challenged ex vivo with virus to assess drug bioavailability and activity. The impact of PU IVRs on the mucosal immune environment will be assessed by quantifying immune cell populations in the genital tract and concentrations of inflammatory, anti-inflammatory and soluble mucosal immune mediators in genital tract secretions. Advanced molecular microbiological tools will be employed including broad range 16S rRNA gene PCR with pyrosequencing to define the bacterial communities, and fluorescence in situ hybridization to determine if rings alter the epithelium and lead to vaginal biofilm formation. Results will inform the design of a Phase I trial of a TDF-MVC combination IVR.
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