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.

Details

Title
Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
Author
Young, Isabella C. 1 ; Massud, Ivana 2 ; Cottrell, Mackenzie L. 3 ; Shrivastava, Roopali 4 ; Maturavongsadit, Panita 4 ; Prasher, Alka 4 ; Wong-Sam, Andres 2   VIAFID ORCID Logo  ; Dinh, Chuong 2 ; Edwards, Tiancheng 2 ; Mrotz, Victoria 5 ; Mitchell, James 2 ; Seixas, Josilene Nascimento 6 ; Pallerla, Aryani 7 ; Thorson, Allison 4 ; Schauer, Amanda 3 ; Sykes, Craig 3 ; De la Cruz, Gabriela 8 ; Montgomery, Stephanie A. 8   VIAFID ORCID Logo  ; Kashuba, Angela D. M. 3 ; Heneine, Walid 2 ; Dobard, Charles W. 2   VIAFID ORCID Logo  ; Kovarova, Martina 9 ; Garcia, J. Victor 9   VIAFID ORCID Logo  ; Garcίa-Lerma, J. Gerardo 2   VIAFID ORCID Logo  ; Benhabbour, S. Rahima 10   VIAFID ORCID Logo 

 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) 
 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) 
 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) 
 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) 
 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) 
 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) 
 University of North Carolina at Chapel Hill, Department of Psychology and Neuroscience, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000 0001 2248 3208) 
 University of North Carolina School of Medicine, Pathology Services Core, Lineberger Comprehensive Cancer Center, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
 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) 
Pages
708
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2774722855
Copyright
© The Author(s) 2023. corrected publication 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.