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1 | INTRODUCTION Preexposure prophylaxis (PrEP) with oral Truvada[R] (emtricitabine 200 mg/tenofovir [TFV] disoproxil fumarate 300 mg) reduces HIV acquisition in women with high adherence to the daily medication [1]. [...], Introduction: Fast-dissolving vaginal film formulations release antiretroviral drugs directly into vaginal fluid and may be as efficient at drug delivery yet more acceptable to women than gels. In this Phase 1 vaginal film study, the safety, acceptability, pharmacokinetics and pharmacodynamics of two doses of tenofovir (TFV) film and TFV 1% gel were compared to corresponding placebo formulations. Methods: Seventy-eight healthy HIV negative women were randomized to self-insert daily vaginal film (10 mg TFV, 40 mg TFV or placebo) or 4 mL of vaginal gel (TFV 1% [40 mg] or placebo) for seven days. Grade 2 and higher adverse events (AEs) related to study product were compared across study arms using Fisher&apos;s exact test. Plasma TFV concentrations were measured before and 2 hours after last product use. Paired cervical and vaginal tissue biopsies obtained 2 hours after the last dose were measured to determine tenofovir diphosphate (TFV-DP) concentrations and exposed to HIV in an ex vivo challenge assay. Acceptability was assessed through questionnaire. Results: There was only one grade 2 or higher related AE, the primary endpoint; it occurred in the placebo gel arm. AEs occurred in 90% of participants; the majority (91%) were grade 1. AEs were similar across study arms. TFV concentrations in plasma and TFV-DP concentrations in cervical and vaginal tissues were comparable between 40 mg TFV film and the TFV gel groups. There was a significant relationship between reduced viral replication and TFV-DP concentrations in cervical tissues. Film users were less likely to report product leakage than gel users (66% vs. 100%, p < 0.001). Conclusions: Films were safe and well tolerated. Furthermore, films delivered TFV to mucosal tissues at concentrations similar to gel and were sufficient to block HIV infection of genital tissue ex vivo. Keywords: tenofovir; microbicide; vaginal film; vaginal gel; prevention

Introduction Since the identification of HIV as the causative agent of acquired immunodeficiency syndrome (AIDS), advances have been made in the treatment and care of HIV-infected persons with drug cocktails [...], Introduction: Preclinical testing plays an integral role in the development of HIV prevention modalities. Several models are used including humanized mice, non-human primates and human mucosal tissue cultures. Discussion: Pharmaceutical development traditionally uses preclinical models to evaluate product safety. The HIV prevention field has extended this paradigm to include models of efficacy, encompassing humanized mice, non-human primates (typically Asian macaques) and human mucosal tissue (such as cervical and colorectal). As our understanding of the biology of HIV transmission improves and includes the influence of human behaviour/biology and co-pathogens, these models have evolved as well to address more complex questions. These three models have demonstrated the effectiveness of systemic (oral) and topical use of antiretroviral drugs. Importantly, pharmacokinetic/pharmacodynamic relationships are being developed and linked to information gathered from human clinical trials. The models are incorporating co-pathogens (bacterial and viral) and the effects of coitus (mucosal fluids) on drug distribution and efficacy. Humanized mice are being tailored in their immune reconstitution to better represent humans. Importantly, human mucosal tissue cultures are now being used in early clinical trials to provide information on product efficacy to more accurately characterize efficacious products to advance to larger clinical trials. While all of these models have made advancements in product development, each has limitations and the data need to be interpreted by keeping these limitations in mind. Conclusions: Development and refinement of each of these models has been an iterative process and linkages to data generated among each of them and from human clinical trials are needed to determine their reliability. Preclinical testing has evolved from simply identifying products that demonstrate efficacy prior to clinical trials to defining essential pharmacokinetic/ pharmacodynamic relationships under a variety of conditions and has the potential to improve product selection prior to the initiation of large-scale human clinical trials. The goal is to provide researchers with ample information to make conversant decisions that guide optimized and efficient product development. Keywords: HIV prevention; pre-exposure prophylaxis; microbicide; humanized mouse; non-human primate; macaque; mucosal tissue; ex vivo challenge.