A subcutaneous implant that releases islatravir provides long-lasting protection against vaginal SHIV infection in macaques

Abstract

Pre-exposure prophylaxis (PrEP) is crucial for curbing the global HIV epidemic. While daily oral drug regimens serve as the cornerstone of HIV PrEP, inconsistent adherence has highlighted the necessity for long-acting drug delivery systems to enhance user uptake and retention. In this study, we developed a ε-polycaprolactone (PCL) implant designed for sustained release of islatravir (ISL), a potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) utilized in HIV treatment. In pig-tailed macaques, implantation of two ISL implants in the inner arms resulted in persistent ISL concentrations in plasma (median = 3.9 nM [range = 1.2-6.7]) and ISL-triphosphate (ISL-TP) levels in peripheral blood mononuclear cells (PBMCs) (median = 192.4 fmol/106 PBMCs [range = 28.4-362.1]). After removal of one implant, median plasma ISL levels decreased approximately 2.7-fold (1.4 nM [range = 0.4-2.0]). These levels were similar to those observed in humans receiving daily oral ISL dosing of 0.25 mg/day, which is considered safe and effective (1.3 nM). Median ISL-TP levels also showed a decrease of about 2.5-fold (76.3 fmol/106 PBMCs [range = 18.4-148.8]) but remained above the established PrEP protection threshold for up to 8 months. In efficacy studies with repeated vaginal challenges to SHIVSF162P3, placebo controls were infected after a median of two SHIV exposures. After a cumulative total of 144 SHIV exposures, five of six macaques with ISL implants remained protected, resulting in an estimated efficacy of 96.8 % (CI = 74.9-99.6 %). The ISL implants were well-tolerated in macaques and showed no signs of ISL-induced lymphopenia over the 8-month dosing period. These findings support the clinical development of the PCL implant as a safe and effective long-acting drug delivery of ISL or other NRTTIs for long-acting HIV PrEP in women.