PROJECT 4 Non-vaccine biomedical prevention (nBP) strategies based on oral and topical vaginal administration of antiretroviral (ARV) agents have been shown to reduce the risk of HIV infection in a significant proportion of individuals. Intravaginal ring (IVR) formulations provide sustained, coitally independent drug release and may improve adherence. These factors will contribute significantly to the pharmacokinetics (PK) and efficacy of IVR formulations used clinically, and their evaluation will require enhanced behavior assessments. We have developed a sustained release IVR formulation of the FDA-approved drugs emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The goal of Project 4 is to evaluate this lead candidate TDF-FTC combination IVR in healthy women in a (pre-Phase 1) Exploratory Clinical Trial to determine PK, safety, and ex vivo efficacy. Measures of adherence and acceptability also will be developed.
In Aim 1, a (pre-Phase I) Exploratory Clinical Trial will be performed using lead candidate TDF-FTC (n = 12) and placebo (n = 6) IVRs for 7 days (9 women) and 28 days (9 women). Samples will be collected for: multi-compartment drug concentration measurements (Project 1);traditional and novel safety assessments using colposcopy, optical coherence tomography (OCT) for sensitive, non-invasive measurement of vaginal epithelial disruption and thinning, culture-independent analysis of vaginal microbiota and high resolution imaging of associated biofilms, and adverse event monitoring (Project 2);and ex vivo surrogate efficacy evaluation (Project 3).
In Aim 2, objective measures of IVR adherence and acceptability will be developed and implemented. Based on responses from the 7-day study, refined and expanded instruments will be developed for use in the 28-day study, including cognitive interviews, quantitative adherence data collected via daily phone check-ins, and surveys.
In Aim 3, a pilot study will be performed in 6 women using a novel, unmedicated adherence IVR that measures and stores temperature data to determine if the device is inserted or removed. These assessments will be made in the clinic and home settings, with measures of safety, acceptability, and adherence obtained. At the completion of the proposed efforts, the FTC-TDF IVR candidate will have undergone preliminary clinical evaluation and methods and capacity to manufacture clinical lots at CMOs under cGMP will have been established (Project 5) in anticipation of post-IPCP-MBP Phase I clinical trials.