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Abstract
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.
In this study, the authors developed an ultra-long-acting injectable, biodegradable, and removable in-situ forming implant delivering cabotegravir (CAB ISFI). CAB ISFI was well tolerated and protected against multiple rectal SHIV challenges in female macaques.
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1 University of North Carolina at Chapel Hill, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000 0001 2248 3208)
2 Centers for Disease Control and Prevention, Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Atlanta, USA (GRID:grid.416738.f) (ISNI:0000 0001 2163 0069)
3 University of North Carolina at Chapel Hill, Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000 0001 2248 3208)
4 North Carolina State University and The University of North Carolina at Chapel Hill, Joint Department of Biomedical Engineering, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208)
5 National Center for Emerging and Zoonotic Infection Diseases, Centers for Disease Control and Prevention, Comparative Medicine Branch, Division of Scientific Resources, Atlanta, USA (GRID:grid.416738.f) (ISNI:0000 0001 2163 0069)
6 Centers for Disease Control and Prevention, Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infection Diseases, Atlanta, USA (GRID:grid.416738.f) (ISNI:0000 0001 2163 0069)
7 University of North Carolina at Chapel Hill, Department of Psychology and Neuroscience, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000 0001 2248 3208)
8 University of North Carolina School of Medicine, Pathology Services Core, Lineberger Comprehensive Cancer Center, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208)
9 University of North Carolina at Chapel Hill, International Center for the Advancement of Translational Science, Division of Infectious Diseases, Center for AIDS Research, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208)
10 University of North Carolina at Chapel Hill, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000 0001 2248 3208); North Carolina State University and The University of North Carolina at Chapel Hill, Joint Department of Biomedical Engineering, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208)