Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis

Abstract

Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries.

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

“…20 µg/kg/day, they report a mean TFV-DP level of 533 fmol/10 6 PBMCs. (23) Gundawarna et al delivered controlled doses of 920 µg/day in beagle dogs with a corresponding dose of 85 µg/kg/day. (20) We delivered a lower dose of 130 µg/day in rhesus, or 10 µg/kg/day, and obtained lower median TFV-DP levels than Chua et al ., yet we still observed unacceptable histopathology and inflammation around the active implants and not the placebos at a 10 µg/kg/day TAF dose ( Table 1 ).…”

“…A third implant was presented by Johnson et al, and was a reservoir formed from extruded poly(caprolactone) filled with TAF and castor oil excipient; release rates of 0.15 – 0.91 mg/day were demonstrated in vitro (22). The fourth implant, presented by Chua and Gratonni, consisted of a refillable titanium device that delivered TAF and FTC through silicon nanochannels (23). This refillable implant demonstrated the sustained release of TAF of ∼ 0.2 mg/day (∼ 20 µg/kg/day) for 83 days in rhesus macaques (23).…”

“…The fourth implant, presented by Chua and Gratonni, consisted of a refillable titanium device that delivered TAF and FTC through silicon nanochannels (23). This refillable implant demonstrated the sustained release of TAF of ∼ 0.2 mg/day (∼ 20 µg/kg/day) for 83 days in rhesus macaques (23). They rapidly achieved TFV-DP benchmark levels in macaque peripheral blood mononuclear cells (PBMCs) with means of 72 fmol/10 6 PBMCs early in the pharmacokinetic (PK) study to 533 fmol/10 6 PBMCs to day 70.…”

“…None of the studies have reported placebo-controlled histopathology, but all authors have suggested that the implants are safe. (20, 23, 24)…”

“…In the normal foreign body response, the implant is walled off at its site of implantation by a fibrin-containing capsule (25). Focal toxicity can result in inflammation and necrosis, potentially leading to skin disruption and potential infection (23, 26). Ultimately, any process that disrupts the multistage wound healing response can result in a non-biocompatible drug delivery implant.…”