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 Cruz, Stephanie A. Montgomery, Angela D. M. Kashuba, Walid Heneine, Charles W. Dobard, Martina Kovarova, J. Victor Garcia, J. Gerardo Garcίa-Lerma () and S. Rahima Benhabbour ()
Additional contact information
Isabella C. Young: University of North Carolina at Chapel Hill
Ivana Massud: Centers for Disease Control and Prevention
Mackenzie L. Cottrell: University of North Carolina at Chapel Hill
Roopali Shrivastava: North Carolina State University and The University of North Carolina at Chapel Hill
Panita Maturavongsadit: North Carolina State University and The University of North Carolina at Chapel Hill
Alka Prasher: North Carolina State University and The University of North Carolina at Chapel Hill
Andres Wong-Sam: Centers for Disease Control and Prevention
Chuong Dinh: Centers for Disease Control and Prevention
Tiancheng Edwards: Centers for Disease Control and Prevention
Victoria Mrotz: National Center for Emerging and Zoonotic Infection Diseases, Centers for Disease Control and Prevention
James Mitchell: Centers for Disease Control and Prevention
Josilene Nascimento Seixas: Centers for Disease Control and Prevention
Aryani Pallerla: University of North Carolina at Chapel Hill
Allison Thorson: North Carolina State University and The University of North Carolina at Chapel Hill
Amanda Schauer: University of North Carolina at Chapel Hill
Craig Sykes: University of North Carolina at Chapel Hill
Gabriela Cruz: University of North Carolina School of Medicine
Stephanie A. Montgomery: University of North Carolina School of Medicine
Angela D. M. Kashuba: University of North Carolina at Chapel Hill
Walid Heneine: Centers for Disease Control and Prevention
Charles W. Dobard: Centers for Disease Control and Prevention
Martina Kovarova: University of North Carolina at Chapel Hill
J. Victor Garcia: University of North Carolina at Chapel Hill
J. Gerardo Garcίa-Lerma: Centers for Disease Control and Prevention
S. Rahima Benhabbour: University of North Carolina at Chapel Hill

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-36330-5

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