Sustained Release of Potent Antiviral Prodrugs for HIV Prevention - ABSTRACT Important progress in curbing the progression of the HIV epidemic has been achieved, but new HIV infection rates are outpacing the targets set by global health organizations: in 2019, an estimated 1.7 million people became newly HIV infected worldwide. New HIV pre-exposure prophylaxis (PrEP) strategies are needed urgently to overcome this alarming prevention gap. Adherence to daily dosing regimens has been a critical impediment to success in previous HIV PrEP clinical trials with antiretroviral (ARV) drugs in susceptible, uninfected individuals. This challenge can be mitigated with sustained release, or long-acting, ARV formulations that reduce dosing frequency to intervals of once per month or longer and target the heterogeneous populations most at risk from contracting HIV. An injectable sustained release nanoparticle formulation of the ARV drug cabotegravir recently has been approved by the US FDA for HIV PrEP, but this technology suffers from a number of drawbacks: a high initial concentration burst; the particles cannot be removed following injection should there be an adverse reaction; pharmacokinetic (PK) tail-phase where sub- therapeutic systemic drug concentrations can persist for over 1 year after the last injection. Subdermal implants with a duration of use of six months or longer are being developed for HIV PrEP using a single agent; however, effective strategies likely will require two ARV drugs. This biomedical challenge is exacerbated by the scarcity of safe, efficacious FDA-approved available agents with sufficient potency to enable a feasible implant size and a period of use of six months, or longer. The proposed efforts build on our previous successful accomplishments in developing sustained release drug delivery biomedical technologies and will test the central hypothesis that an innovative subdermal implant system delivering two, new potent ARV agents will demonstrate initial feasibility in terms of drug biophysicochemical properties and expected duration of use. In Aim 1, we will design, synthesize, and screen a library of novel prodrugs based on established, FDA-approved agents from different mechanistic classes. Lead candidates will be selected rationally using a decision tree based on clearly defined, quantitative rules. In Aim 2, promising prodrug candidates will be formulated for sustained delivery using our next-generation subdermal implant system, and these efforts will be guided by user preference research conducted in South Africa to fine-tune modifiable device attributes. In Aim 3, we will conduct PK and safety studies in mice and sheep, followed by efficacy studies in humanized mice to determine if the devices can safely prevent vaginal and rectal HIV infection. The project builds on an established collaboration of highly experienced investigators and will advance our scientific knowledge on the many, interrelated aspects of systemic, sustained drug delivery for HIV prevention.
