Antiretroviral drugs are predominantly administered orally for both therapy and pre-exposure prophylaxis (PrEP). Despite ease of administration, oral delivery is prone to patient non-adherence exacerbated for some drugs by pill fatigue and gastrointestinal intolerance. By decreasing frequency of administration, long-acting injectable (LAI) medications are effective strategies to circumvent these issues. We report here a preclinical assessment of LAI semi-solid prodrug nanoparticle (SSPN) formulations of novel emtricitabine (FTC) prodrugs to prevent HIV infection.
SSPNs of FTC carbamate/carbonate prodrugs were generated using a proprietary emulsion-templated freeze-drying technology. 2 lead formulations were tested for their ability to prevent HIV infection in NSG-cmah[sup]-/-[/sup] mice humanised by CD34+ cell transplantation. Animals received 140 mg/kg FTC equivalent (SSPN 9 or 10) via 2 intramuscular injections vs an untreated control (n= 7-6 per group). At days 7 and 14 mice were challenged intraperitoneally with a 103 TCID50 dose of HIVADA. Animals were sacrificed at 28 days post infection. Plasma samples were taken for determination of viral load (VL). Tissue samples were collected for viral RNA and proteins detection via RT-PCR and immunohistology.
Mice treated with SSPN 9 and 10 demonstrated undetectable VL (700 copies/mL detection limit), and HIV RNA remained undetectable 28 days post infection in plasma, spleen, lung and liver in all animals for the 7 challenge. Following 14-day challenge, mice treated with SSPN 9 demonstrated undetectable HIV in plasma and all tissues. Mice treated with SSPN 10 demonstrated 2 mice had detectable plasma VL (4.77 x 103 copies/mL) and 3 mice showed presence of HIV RNA in plasma and proteins in spleen, lung and liver in day 28. HIV was detectable in all untreated animals.
The data presented here demonstrate both formulations were 100% effective at preventing HIV infection 7 days post LAI administration. Following 14 days SSPN9 prevented HIV infection in 100% of mice while SSPN 10 prevented infection in 50% of mice. These data indicate great potential for delivering FTC via LAI and the approach may support LAI development for PrEP. Further studies will aim to optimise formulations to produce exposure beyond 14 days and to assess applications in therapy as part of a combination.