Systemic Sustained Release Delivery of Antiretroviral Agents for HIV Prevention

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ABSTRACT New HIV infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. In 2017, an estimated 1.8 million people became newly HIV infected globally. New HIV pre-exposure prophylaxis (PrEP) strategies are needed urgently to overcome this alarming prevention gap. Adherence to daily dosing regimens has emerged as a critical factor driving the clinical success of HIV-1 PrEP 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, ideally to intervals of once per month or longer, and target the heterogeneous populations most at risk from contracting HIV. Several ARV drugs are undergoing clinical evaluation as injectable sustained release formulations, but suffer from a number of drawbacks: a high initial concentration burst; the particles cannot be removed following injection should there be an adverse reaction; the approach requires specific ARV physiochemical characteristics, dramatically limiting the range of candidate drugs. Multiple large-scale clinical trials have shown that PrEP using oral preparations of the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir (TFV) can prevent HIV-1 infection in a significant proportion of individuals. A long-acting TFV formulation for systemic dosing would add a much-needed NRTI to the portfolio of sustained release PrEP options. Under previous NIH support we have developed a subdermal implant delivering the highly potent prodrug TFV alafenamide (TAF). We have evaluated the pharmacokinetics (PKs) and safety of prototype implants delivering TAF over a wide range of release rates in mice, beagle dogs, and sheep. The devices were safe in the target dosing window and allowed us to simulate a human dose for HIV-1 PrEP. The proposed efforts build on these important accomplishments and will test the central hypothesis that a one-year TAF implant with practical physical dimensions can safely prevent sexual HIV-1 infection. In Aim 1, we will design the next generation TAF implant to maximize drug loading and control of drug release using scalable processes and acceptable biomedical materials. We will conduct PK studies in rats and sheep to help select lead candidates for extensive safety assessment in sheep under Aim 2. Here, the implant materials and excipients will be evaluated to maximize local tolerance in vivo, including using innovative targeted proteomic/metabolomic and non-invasive imaging methods. In Aim 3, HIV-1 (SHIV) prevention efficacy studies will be carried out in rhesus macaques using repeat low dose rectal, vaginal, and penile exposure models. The PK-pharmacodynamic relationships will be investigated in exploratory models. The project will advance our scientific knowledge on the pharmacologic properties of sustained release systemic TAF and its metabolites compared with oral formulations in the context of HIV-1 prevention.