The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.

Objective: The purpose of this study was to evaluate differences in vaginal immune cell populations, vaginal tissue gene expression, anti-microbial activity of the cervicovaginal (CV) fluid lavage (CVL), vaginal flora and p24 antigen production from CV tissues after ex vivo HIV infection between the follicular (FOL) and luteal (LUT) phases of the menstrual cycle. Methods: CV tissue biopsies, CV secretions and blood samples were obtained as part of two longitudinal clinical trials of healthy women (CONRAD D11-119 and A12-124 studies). Participants (n = 39) were HIV seronegative women not using exogenous hormone supplementation, with normal menstrual cycles, who were screened to exclude sexually transmitted and reproductive tract infections. Results: Serum levels of estradiol and progesterone were significantly higher in the LUT versus the FOL phase of the menstrual cycle. Controlling for race, reported contraceptive use/sexual practices, and clinical trial, we found no differences in vaginal tissue immune cell populations and activation status, transcriptomes, inhibition of HIV, herpes simplex virus type 2 (HSV2) and Escherichia coli (E. coli) by the CVL, vaginal pH or Nugent score or production of p24 antigen after ex vivo infection by HIV-1BaL between CV samples obtained in the FOL versus the LUT phase of the menstrual cycle. There were no significant correlations between serum estradiol and progesterone levels and CV endpoints. Conclusion: The hypothesis that the LUT phase of the menstrual cycle represents a more vulnerable stage for mucosal infection with HIV was not supported by data from samples obtained from the lower genital tract (ectocervix and vagina) from these two clinical trials. Key Words: Follicular, Luteal, Menstrual Cycle, HIV acquisition, mucosa

While vitamin D insufficiency is known to impact a multitude of health outcomes, including HIV-1, little is known about the role of vitamin D-mediated immune regulation in the female reproductive tract (FRT). We performed a pilot clinical study of 20 women with circulating 25(OH)D levels <62.5 nmol/L. Participants were randomized into either weekly or daily high-dose oral vitamin D supplementation groups. In addition to serum vitamin D levels, genital mucosal endpoints, including soluble mediators, immune cell populations, gene expression, and ex vivo HIV-1 infection, were assessed. While systemic vitamin D levels showed a significant increase following supplementation, these changes translated into modest effects on the cervicovaginal factors studied. Paradoxically, post-supplementation vitamin D levels were decreased in cervicovaginal fluids. Given the strong correlation between vitamin D status and HIV-1 infection and the widespread nature of vitamin D deficiency, further understanding of the role of vitamin D immunoregulation in the female reproductive tract is important.