Significance Topical prevention of HIV is designed to pharmacologically interrupt sexual transmission at the genital mucosa. Attempts at preventing transmission in women using vaginal gels have yielded disappointing results in part because of poor rates of adherence. Controlled topical drug delivery using intravaginal ring technology should improve efficacy and adherence by providing sustained mucosal delivery of antiretrovirals. In this paper, we describe a reservoir intravaginal ring that delivers tenofovir disoproxil fumarate (TDF) for 1 month. The ring protected pigtailed macaques from weekly vaginal simian–human immunodeficiency virus challenges for 4 mo. The sterilizing performance of this drug delivery system supports the concept that an intravaginal ring delivering TDF could be an effective tool for prevention of HIV sexual transmission in women.

Preexposure prophylaxis (PrEP) using FDA-approved antiretroviral (ARV) drugs is emerging as a promising strategy for the prevention of sexual HIV infection. There is growing consensus that a combination of ARV agents, analogous to highly active antiretroviral therapy (HAART), likely is essential for optimally effective PrEP (1, 2). Oral administration of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) (Truvada; Gilead Sciences, Inc.) is the first regimen approved by the FDA to reduce the risk of HIV infection in uninfected individuals (http://www.fda.gov/NewsEvents/Newsroom /PressAnnouncements/ucm312210.htm). Three recent clinical trials demonstrated that oral ARV regimens using the combination of TDF and FTC can be effective in susceptible men, women, and partners of HIV-infected individuals (3-5). However, the relative risk reduction in these trials varied widely (from 44 to 75%), and a study in which women used a daily oral TDF-FTC regimen was stopped early due to futility. A critical factor driving success in these trials appears to involve sustaining high levels of adherence to frequent dosing (6).It is well established across different delivery methods that adherence to therapy is inversely related to the dosing period (7-10). Controlled topical delivery of ARV drugs using intravaginal rings (IVRs) is thought to improve adherence (11) and to provide sustained mucosal levels independent of coitus and daily dosing (12). The delivery of two or more ARV drugs from conventional IVR designs involves significant technological and manufacturing hurdles. To meet these challenges, we have developed a novel IVR technology, the pod-IVR (13), that enables rapid development of devices capable of delivering multiple agents over a wide range of target delivery rates and aqueous solubilities (14-16). We recently published the design and 28-day pharmacokinetic (PK) evaluation in sheep of a five-drug pod-IVR as a proof-of-concept, advanced multipurpose prevention technology (MPT), combining three ARV drugs from different mechanistic classes (tenofovir [TFV], nevirapine, and saquinavir) with a proven estrogen-progestogen contraceptive for prevention of HIV infection and unintended pregnancy (17).Here we present the first report of an IVR delivering TDF and FTC, as well as the first report of a triple-combination IVR delivering TDF, FTC, and maraviroc (MVC) (an entry inhibitor/antagonist of chemokine receptor 5 [CCR5]). Preliminary local safety and pharmacokinetic (PK) findings for these devices were determined in pig-tailed macaques, which are considered by many to represent the most relevant animal model for HIV vaginal PrEP studies (15,18,19). Steady-state drug levels for all three ARV agents in vaginal fluids were sustained over the 28-day study period, with corresponding vaginal tissue concentrations suggesting putative efficacy in preventing HIV infection.

Preclinical HIV prevention models use either a single high-dose viral challenge in depot medroxyprogesterone acetate (DMPA)-treated macaques or repeated viral challenges in cycling macaques. We tested the efficacy of an intravaginal tenofovir disoproxil fumarate (TDF) ring in a model combining repeated 30 mg injections of DMPA every 6 weeks with vaginal viral challenges weekly for 12 weeks. Twelve macaques were randomized to TDF or placebo rings. All placebo macaques became infected after a median of 2 exposures, whereas only one TDF macaque became infected at the eighth exposure (p=0.0012). The TDF ring provides durable protection in a stringent challenge model.

Topical preexposure prophylaxis (PrEP) against HIV has been marginally successful in recent clinical trials with low adherence rates being a primary factor for failure. Controlled, sustained release of antiretroviral (ARV) drugs may help overcome these low adherence rates if the product is protective for extended periods of time. The oral combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is currently the only FDA-approved ARV drug for HIV PrEP. A novel pod-intravaginal ring (IVR) delivering TDF and FTC at independently controlled rates was evaluated for efficacy at preventing SHIV162p3 infection in a rigorous, repeat low-dose vaginal exposure model using normally cycling female pigtailed macaques. Six macaques received pod-IVRs containing TDF (65 mg) and FTC (68 mg) every two weeks, and weekly vaginal exposures to 50 TCID50 of SHIV162p3 began one week after the first pod-IVR insertion. All pod-IVR-treated macaques were fully protected throughout the study (P = 0.0002, Log-rank test), whereas all control animals became infected with a median of 4 exposures to infection. The topical, sustained release of TDF and FTC from the pod-IVR maintained protective drug levels in macaques over four months of virus exposures. This novel and versatile delivery system has the capacity to deliver and maintain protective levels of multiple drugs and the protection observed here warrants clinical evaluation of this pod-IVR design.