Background/Objectives: The prevention of sexual HIV-1 acquisition in women and girls in sub-Saharan Africa remains an important public health priority. Expanding the existing biomedical product portfolio to include long-acting vaginal products, such as intravaginal rings (IVRs), is expected to appeal to end users and drive adoption. Methods: We formulated two different triple-combination antiretroviral IVRs, both delivering the acid salt tenofovir (TFV), disoproxil fumarate (TDF), and the free base emtricitabine (FTC), with one delivering elvitegravir (EVG) as the free acid and the other as the sodium salt. The devices were evaluated for pharmacokinetics and local safety in two established preclinical models, sheep and pig-tailed macaques. Results: The IVRs were safe and maintained cervicovaginal fluid (CVF) drug concentrations that were above our efficacy targets derived from prior humanized mouse studies. All three agents were uniformly distributed vaginally, as evidenced by CVF and vaginal tissue measurements. Elevated drug concentrations were observed in macaque vaginal tissue samples collected three days after IVR removal, suggesting a possible forgiveness window. TFV and FTC concentrations in rectal tissue and fluid suggested potential for dual-compartment HIV-1 protection, although the vaginal-to-rectal drug transport mechanism appeared to differ across both species. The humanized mouse vaginal HIV-1 efficacy model was used to empirically compare combination effects when TDF, FTC, and EVG were co-administered, and TDF-EVG was identified as a promising combination to be developed further for IVR delivery in parallel with the triple combination.

Intravaginal rings (IVRs) are attractive user-controlled delivery systems that can achieve sustained release of compounds for several weeks. We modeled in macaques a three-dimensional (3D)–printed IVR delivering the investigational nucleoside reverse transcriptase translocator inhibitor islatravir (ISL). Three IVRs with 15, 30, or 60 milligrams of ISL were used in 30-day pharmacokinetic and safety studies followed by 90-day studies to identify a dose that maintains the concentration of the active intracellular metabolite islatravir triphosphate (ISL-TP) above protective benchmarks. IVRs were safe and delivered ISL in a dose-dependent manner. In a challenge study involving 12 weekly low-dose vaginal exposures to SHIV162p3, six macaques treated with 60-milligram ISL IVRs for 90 days remained seronegative and SHIV RNA negative, while two untreated controls were infected. These data provide initial preclinical evidence that a 90-day extended-release ISL IVR is safe and offers complete protection in a stringent challenge model, warranting further clinical investigation.