The use of microbicidal agents for the prevention of HIV-1 transmission and
consequent infection is emerging as a promising strategy for controlling this global
epidemic. Sexual HIV-1 transmission in resource-limited regions is driven by gender
inequalities imposing a particular burden on women and girls. Topical microbicide
administration directly to the vagina could play an important role in HIV-1 prevention
efforts, as this female-controlled approach leads to high local levels of anti-HIV-1
compounds, while resulting in low systemic exposure. After twenty years of clinical
investigation, however, this dosing route has had limited success. In this chapter, we
thoroughly review the current state of vaginal microbicide research for HIV-1
prevention. The vaginal route of HIV-1 infection is discussed along with an overview of
the classes of microbicides currently under investigation, including: broad-spectrum
(i.e., non-specific), specific (e.g., antiretroviral drugs), and biological (peptides,
proteins, and bacteria) agents. Dosage forms (tablets/suppositories, films, gels, and
intravaginal rings) are discussed along with the merits and challenges associated with
each modality. An anatomical, histological, and physiological description of the vaginal
mucosa links the applied and fundamental sections of the chapter. An introduction to
the interplay between hormone regulation and the vaginal mucosa is provided,
accompanied by a discussion of potential biomarkers of inflammation that may be used
to evaluate microbicide safety. Host expression of membrane transporters and
metabolizing enzymes is reviewed in detail, as both can influence local drug
distribution and, hence, pharmacodynamic outcomes in HIV-1 prevention. The vaginal
microbiome, and its interactions with the host, are likely to play a pivotal role in topical
HIV-1 prophylaxis is discussed. Finally, ex vivo and animal models for evaluating
candidate product efficacy are critically reviewed and the current state of clinical
vaginal product evaluation is discussed.
Keywords: HIV prevention, intravaginal ring, microbicides, Pre-exposure
prophylaxis (PrEP), topical dosing, vaginal epithelial cell culture model, vaginal
gel, vaginal microbiome, vaginal mucosa.