Background:
Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, is in development for long-acting pre-exposure prophylaxis (LA PrEP) as a monthly pill and subdermal implant. ISL is on clinical hold after lymphopenia was observed in clinical trials. Here we investigated in macaques ISL implants with varied release rates and assessed safety, pharmacokinetics, and vaginal efficacy for LA PrEP.
Methods:
Biodegradable polycaprolactone implants loaded with 86 mg or 45 mg of ISL and in vitro release rates of 705 µg/d (ISL-705) or 83 µg/d (ISL-83), respectively, were implanted subcutaneously in the arms of female pigtailed macaques. Macaques received one ISL-705 implant (n=6) or two ISL-83 implants (1/arm) for a cumulative release of 176 µg/d (n=6). Implant-site reactions were graded weekly using a modified Draize scale (range: 0-5). Plasma ISL was measured weekly by LC/MS-MS. Macaques with two ISL-83 implants were exposed vaginally to SHIV162p3 twice-weekly at weeks 5-11 post-implantation (12 total challenges). Infection outcome was compared with 6 untreated animals (2 real-time and 4 historical controls). Blood was collected at each challenge to monitor plasma ISL and SHIV RNA.
Results:
ISL-705 and ISL-83 implants reached steady-state by day 21 with median [range] plasma ISL levels of 25.4 [23.0- 28.4] and 5.2 [2.3-6.6] nM, respectively. All macaques with ISL-705 implants had adverse implant-site reactions (Draize score 1-3) that persisted for 8 weeks, at which point the implants were removed. In contrast, no implant-site reactions were observed in animals with two ISL-83 implants (n=12 implants) over the 12-week study period (144 observations). Macaques with two ISL-83 implants (176 µg/d) remained uninfected during a cumulative of 72 SHIV exposures, while the 6 controls were infected after a median of 2.5 challenges [range 1-5] resulting in 100% efficacy. Median [range] plasma ISL levels during SHIV challenges were 4.0 nM [1.2-7.0].
Conclusions:
We show that release rates from ISL-705 implants may impact local toxicity. In contrast, we identified ISL-eluting implants (ISL-83) with a cumulative in vitro release rate of 176 µg/d that did not result in implant-site reactions and fully protected macaques against repeated vaginal SHIV exposures. We also defined clinically relevant plasma concentrations of 1-7 nM that were associated with complete vaginal protection. These data will inform the selection of safe and effective biodegradable ISL implants for HIV LA-PrEP in women.