Globally, human immunodeficiency virus (HIV) remains a major public health crisis, with approximately 1.8 million new infections annually, and almost 38 million people living with HIV in 2018 [1
]. New HIV infections are declining annually, but not rapidly enough to meet the 90-90-90 target (90% diagnosed, 90% on treatment, and 90% virally suppressed) by 2020, set by The Joint United Nations Programme on HIV and AIDS (UNAIDS) to end the acquired immune deficiency syndrome (AIDS) epidemic [2
]. In order to meet current targets geared toward reducing new HIV infections to fewer than 500,000 globally by 2020, one of the highest priorities in the HIV prevention field is to develop stable, safe, effective and acceptable products which can successfully reduce HIV sexual transmission [3
Oral pre-exposure prophylaxis (PrEP), specifically daily tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (Truvada®
), is highly effective when taken consistently [4
]; however, adherence has proven challenging, especially in younger populations [7
]. Recently, the 1-month dapivirine (DPV) intravaginal ring (IVR) was also proven to reduce HIV incidence. Protection was observed in women over 21 years, but not in younger women where adherence was lower [6
]. The tenofovir (TFV) 1% gel, a 4-mL vaginal gel packaged in pre-filled applicators, demonstrated initial success in the CAPRISA 004 trial [10
]; however, subsequent Phase IIb/III trials of the gel were unable to confirm effectiveness by intention-to-treat analysis in either daily [7
] or pericoital (one dose before plus one dose after sex) [11
] dosing regimens likely due to inconsistent and insufficient gel use in young, at-risk women. In an effort to minimize user dependency and thus potentially improve adherence, the development landscape in HIV prevention has recently pivoted to focusing on long-acting (LA) parenteral PrEP products, such as the cabotegravir injectable (CAB LA) currently in Phase III trials and several implant systems in preclinical development [12
]. Although long acting parenterals have distinct benefits, they require health care provider delivery and training, have injection site and potential systemic side effects, and cannot be easily removed should safety concerns arise, all of which present potential new barriers affecting end-user uptake and continued use [15
]. For users who desire an on-demand HIV prevention option that they can self-administer—easily, quickly, painlessly and discreetly—the development of user-friendly, topical dosage forms remains a global imperative.
Delivering drugs via the vagina and rectum has several unique advantages, including increased local absorption of drug substances due to large surface area and rich blood supply and enhanced bioavailability, with potential for reduced systemic side effects [16
]. When considering developing a product for the prevention of sexual transmission of HIV acquisition, delivering antiretrovirals (ARVs) topically provides a direct, first-line defense against HIV infection via genital/rectal mucosa. Therefore, topical dosage forms represent a promising delivery method. Dosage forms such as tablets/inserts, capsules, creams, suppositories, pessaries, foams, gels, films, rings, and douches have been pursued for vaginal and/or rectal delivery of drugs to improve sexual and reproductive health [18
]. In this review, we will focus on topical (vaginal and rectal) inserts as a particularly promising and malleable delivery system for HIV prevention. Specifically, we will highlight the 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, and future directions and the potential impact of this dosage form on the HIV prevention landscape.