Novel multipurpose pod-intravaginal ring for the prevention of HIV, HSV, and unintended pregnancy: Pharmacokinetic evaluation in a macaque model

Abstract

Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35–0.40; ACV 0.56–0.70; EE 0.03–0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL-1 prior to IVR insertion and 0.075 ± 0.064 ng mL-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women’s sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.

Antiretroviral agents in pre-exposure prophylaxis: emerging and advanced trends in HIV prevention

“…This technology is able to increase adherence towards HIV PrEP and provide protection against HIV, HSV as well as unexpected pregnancy. Hence, it could be a potential prevention method to safeguard women's reproductive and sexual health . Other than that the polymeric nanoparticle is a potential delivery tool for DPV in terms of a prophylactic anti‐HIV vaginal microbicide .…”

Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides

“…Interestingly, despite the very limited anti HSV-2 activity of tenofovir [ 16 ], in the CAPRISA 004 study, TFV PrEP reduced occurrence of HSV-2 infection by 50%, possibly enhancing the overall observed efficacy against HIV-1. Thus, multipurpose combinations of different compounds with antiviral and antiretroviral activity are intensively investigated, sometimes also associated with unintended pregnancy prevention compounds [ 23 – 28 ]. Compounds acting on both viruses such as the rhodanine derivatives described in this paper, represent effective agents to be used in candidate PrEP approaches without the need of dual-agents preparations.…”

Impact of ring size and drug loading on the pharmacokinetics of a combination dapivirine-darunavir vaginal ring in cynomolgus macaques

“…Non-human primate models have played an important role in the development of our understanding of the complex mechanisms of HIV infection and in the testing of new vaccine and vaginal microbicide strategies (Bernard-Stoecklin et al, 2014;Dezzutti, 2015;Henning et al, 2015;Hessell and Haigwood, 2015;Veazey et al, 2012). Three macaque speciesthe rhesus macaque (Macaca mulatta), the pig-tailed macaque (Macaca nemestrina) and the cynomolgus macaque (Macaca fascicularis)are widely used in vaginal ring pharmacokinetic and viral challenge studies (Fetherston et al, 2013b;Hsu et al, 2014;Malcolm et al, 2012b;Moss et al, 2014Moss et al, , 2012Murphy et al, 2014;Singer et al, 2012;Smith et al, 2017) as these species are susceptible to the closely related simian (SIV) and simian/human chimera (SHIV) immunodeficiency viruses that produce pathologies similar to that seen with HIV-1 infection in humans (Dezzutti, 2015;Pereira et al, 2012). Since there are differences in size/weight between these macaque species, vaginal rings should ideally be customised for optimal fit (Promadej-Lanier et al, 2009).…”