Safety and efficacy of a biodegradable implant releasing tenofovir alafenamide for vaginal protection in a macaque model

Abstract

Objectives: To advance the initiative of ending the global epidemic, long-lasting HIV protection is needed through sustained release of antiretroviral drugs for months to years. We investigated in macaques the safety and efficacy of biodegradable polycaprolactone implants releasing tenofovir alafenamide for HIV pre-exposure prophylaxis (PrEP).

Methods: Implants were administered subcutaneously in the arm using a contraceptive trocar. Efficacy against vaginal simian-HIV (SHIV) infection was investigated in six pigtailed macaques that received two tenofovir alafenamide implants (0.35 mg/day), one in each arm, for a total release rate of tenofovir alafenamide at 0.7 mg/day. Macaques were exposed to SHIV twice weekly for 6 weeks. Statistical analyses were used to compare outcome with eight untreated controls. Histological assessments were performed on skin biopsies collected near implantation sites.

Results: Median (range) tenofovir diphosphate level in PBMCs was 1519 (1068-1898) fmol/106 cells. All macaques with tenofovir alafenamide implants were protected against vaginal SHIV infection. In contrast, 7/8 controls were infected after a median of 4 SHIV exposures (P = 0.0047). Histological assessment of tissues near tenofovir alafenamide implant sites showed inflammation and necrosis in 5/6 animals, which were not evident by visual inspection.

Conclusions: We demonstrated complete protection against vaginal SHIV infection with two implants releasing a total of 0.7 mg of tenofovir alafenamide per day. We also identified tenofovir diphosphate concentrations in PBMCs associated with complete vaginal protection. Consistent with previous findings, we observed adverse local toxicity and necrosis near the tenofovir alafenamide implant site. Improved tenofovir alafenamide implants that are safe and maintain high efficacy have the potential to provide long-lasting protection against vaginal HIV infection.

Figure 1.

Protection of macaques against vaginal SHIV infection by tenofovir alafenamide (TAF) implants. (a) Study design. Six female pigtailed macaques received two TAF implants (placed in opposite arms), each releasing TAF at 0.35 mg/day (0.7 mg/day in total) 1 week prior to the challenge period. Animals were exposed vaginally to SHIV_162P3 twice weekly for six consecutive weeks or a total of 12 challenges. Implants were removed 8 weeks post implantation. Infection outcome was compared with two real-time and six historical controls. (b) Survival analysis representing the cumulative percentage of uninfected macaques in the TAF-treated (n = 6) and untreated (n = 8) groups. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Tenofovir diphosphate (TFV-DP) concentrations in PBMCs. TFV-DP levels were measured weekly during virus challenges and after implant removal at Week 8. Solid circles and bars represent medians and ranges, respectively. The horizontal dotted line denotes the concentrations of TFV-DP associated with steady-state levels with daily oral tenofovir alafenamide (TAF) in humans.

Figure 3.

(a) Heatmap of local skin reactions at implant site. Local skin reactions observed during the 8 week study period were scored using a Draize scale: 0 (none) to 4 (severe). Visual assessments of the tenofovir alafenamide (TAF) implant site in the left (LT) and right (RT) arm are indicated for each animal. (b) Histological observations of implantation sites. Panels show a representative H&E stain of skin biopsies collected near the implantation site from an animal with a placebo or TAF implant. Left panel: skin biopsies surrounding the placebo PCL implants show normal and unremarkable tissue. Central and right panels: tissue surrounding the TAF implant show moderate to marked inflammation and subcutaneous fibrosis (A, B and C). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.