Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.
RTI International, Research Triangle Park, NC, USA.
J Antimicrob Chemother. 2022 Oct 28;77(11):2964-2971. doi: 10.1093/jac/dkac252.
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).
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.
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.
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.
为推进终结全球艾滋病流行倡议，需要通过持续数月至数年释放抗逆转录病毒药物来实现长效的艾滋病毒保护。我们在食蟹猴中研究了可生物降解的聚己内酯植入物持续释放替诺福韦艾拉酚胺用于艾滋病毒暴露前预防（PrEP）的安全性和有效性。
使用避孕穿刺器将植入物皮下植入手臂。六只长尾猕猴接受了两个替诺福韦艾拉酚胺植入物（每天 0.35mg），每个手臂一个，总替诺福韦艾拉酚胺释放率为每天 0.7mg，用于研究其对阴道猴免疫缺陷病毒（SHIV）感染的疗效。猕猴每周接受两次阴道 SHIV 暴露共 6 周。采用统计分析比较了 8 只未治疗对照的结果。在靠近植入部位采集皮肤活检进行组织学评估。
PBMC 中替诺福韦二磷酸的中位数（范围）为 1519（1068-1898）fmol/106 细胞。所有接受替诺福韦艾拉酚胺植入物的猕猴均免受阴道 SHIV 感染。相比之下，8 只对照中有 7 只在中位 4 次 SHIV 暴露后感染（P=0.0047）。对替诺福韦艾拉酚胺植入部位附近组织的组织学评估显示，6 只动物中有 5 只出现炎症和坏死，而肉眼观察并未发现这些变化。
我们证明了通过每天释放总共 0.7mg 的替诺福韦艾拉酚胺的两个植入物可完全预防阴道 SHIV 感染。我们还确定了与完全阴道保护相关的 PBMC 中替诺福韦二磷酸浓度。与之前的发现一致，我们观察到替诺福韦艾拉酚胺植入部位附近出现局部毒性和坏死。具有长效保护阴道免受 HIV 感染潜力的改良替诺福韦艾拉酚胺植入物需要具有安全性和高疗效。
