Nature Communications (Feb 2023)
Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
- Isabella C. Young,
- Ivana Massud,
- Mackenzie L. Cottrell,
- Roopali Shrivastava,
- Panita Maturavongsadit,
- Alka Prasher,
- Andres Wong-Sam,
- Chuong Dinh,
- Tiancheng Edwards,
- Victoria Mrotz,
- James Mitchell,
- Josilene Nascimento Seixas,
- Aryani Pallerla,
- Allison Thorson,
- Amanda Schauer,
- Craig Sykes,
- Gabriela De la Cruz,
- Stephanie A. Montgomery,
- Angela D. M. Kashuba,
- Walid Heneine,
- Charles W. Dobard,
- Martina Kovarova,
- J. Victor Garcia,
- J. Gerardo Garcίa-Lerma,
- S. Rahima Benhabbour
Affiliations
- Isabella C. Young
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Ivana Massud
- Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention
- Mackenzie L. Cottrell
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Roopali Shrivastava
- Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill
- Panita Maturavongsadit
- Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill
- Alka Prasher
- Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill
- Andres Wong-Sam
- Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention
- Chuong Dinh
- Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention
- Tiancheng Edwards
- Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention
- Victoria Mrotz
- Comparative Medicine Branch, Division of Scientific Resources, National Center for Emerging and Zoonotic Infection Diseases, Centers for Disease Control and Prevention
- James Mitchell
- Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention
- Josilene Nascimento Seixas
- Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infection Diseases, Centers for Disease Control and Prevention
- Aryani Pallerla
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill
- Allison Thorson
- Joint Department of Biomedical Engineering, North Carolina State University and The University of North Carolina at Chapel Hill
- Amanda Schauer
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Craig Sykes
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Gabriela De la Cruz
- Pathology Services Core, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine
- Stephanie A. Montgomery
- Pathology Services Core, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine
- Angela D. M. Kashuba
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Walid Heneine
- Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention
- Charles W. Dobard
- Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention
- Martina Kovarova
- International Center for the Advancement of Translational Science, Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill
- J. Victor Garcia
- International Center for the Advancement of Translational Science, Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill
- J. Gerardo Garcίa-Lerma
- Laboratory Branch, Division of HIV Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention
- S. Rahima Benhabbour
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- DOI
- https://doi.org/10.1038/s41467-023-36330-5
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 15
Abstract
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.
