Antiretroviral drugs such tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), are effective as HIV preventive, pre-exposure prophylaxis (PrEP). Unfortunately, poor patient adherence has rendered treatment less effective. TDF success motivated development of tenofovir alafenamide (TAF), which is more potent with reduced side effects. However, patient adherence remains a concern. To address this, we developed a novel transcutaneously refillable nanochannel system (nDS) for the delivery of TAF and FTC for HIV PrEP. We hypothesized that the nDS implant could deliver sustained doses of TAF and FTC as PrEP to prevent infection from SHIV challenge in non-human primates long term.
We microfabricated silicon nanochannel membrane with channels as small as 2.5 nm in compliance with FDA requirement for implantable devices. nDS implants achieved constant release therapeutics in small and large animal models for over 6 months. In this study, nDS was tailored for the controlled delivery of TAF and FTC (received in kind from Gilead). Ti implants were designed for transcutaneous refilling to extend the duration of treatment. Implants loaded with TAF and FTC were tested in vitro for 3 months to assess release rates and drug stability. PK studies were then performed in vivo in three rhesus macaques with implants subcutaneously inserted in the dorsum and transcutaneous refilling tested at day 70. Plasma and biopsy samples were collected at different timepoints and TFVpp and FTCtp concentration quantified in PBMCs.
The implant demonstrated sustained release of both TAF and FTC for over 83 days. Both TAF and FTC maintained bioactivity over the duration of the study. PK data (figure 1) showed that nDS achieved sustained preventative levels of TFVpp above 70 fmol/million PBMCs over 83 days. For FTCtp levels of approximately 1.5 pmol/million PBMCs were sustained for 28 days followed by a decrease in PBMC levels due to a decline of FTC in the implant reservoir. Transcutaneous refilling proved successful with FTCtp levels again reaching above 1.5 pmol/million PBMCs. Implants were well tolerated by the animals and surrounding tissues.
nDS achieved sustained delivery of TAF and FTC at approximately 2 and 100 mg/day, respectively, compatible with HIV PrEP. Successful transcutaneous refilling was achieved. Current studies supported by NIH and Gilead are examining the potential of nDS as a breakthrough delivery system addressing the current limitation of HIV PrEP.