Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Nat Commun. 2023 Feb 9;14(1):708. doi: 10.1038/s41467-023-36330-5.
Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.
用于 HIV 暴露前预防 (PrEP) 的超长效给药平台可能会提高依从性并最大限度地发挥公共卫生效益。我们报告了一种可注射、可生物降解和可移除的原位形成植入物 (ISFI)，可通过皮下给药，能将整合酶抑制剂卡替拉韦（CAB）释放到超过 6 个月的保护基准以上。CAB ISFI 在雌性小鼠和雌性食蟹猴中耐受良好，没有毒性或慢性炎症的迹象。在食蟹猴中，CAB 的中位血浆浓度在 3 周内超过既定的 PrEP 保护基准，并能完全防止重复直肠 SHIV 挑战。在 2 只猕猴中，在第 12 周通过小切口取出植入物，导致 CAB 血浆水平在 72 小时内下降 7 至 48 倍。通过建模来转化 CAB ISFI 的剂量，表明在给药后超过 5 个月，3 毫升注射量将超过人类的保护基准。我们的研究结果支持将 CAB ISFI 用于人类的超长效 PrEP 的临床推进。
