Cabotegravir long-acting (CAB LA) is an investigational HIV integrase inhibitor that is currently in clinical development as a PrEP agent. In pre-clinical proof-of-concept studies in macaques, CAB LA was highly effective against rectal, vaginal, and intravenous infection with simian HIV (SHIV). Penile transmission accounts for nearly one-half of all HIV infections globally, and whether CAB LA can also protect against this important route has not been adequately addressed primarily due to the lack of a validated in vivo model of penile transmission. Here we used a novel macaque model of repeated penile SHIV exposures to investigate the efficacy of CAB LA against penile infection.
Rhesus macaques (n=22) were exposed once a week (up to 12 weeks) to low doses of SHIV162p3 administered into the foreskin pouch (200 TCID50) and urethra (16 TCID50). Of these, 6 received CAB LA (50 mg/kg) and 10 received no drug. CAB LA was administered intramuscularly every 4 weeks to sustain plasma drug levels above 4 times the protein-adjusted IC90 (4xPA-IC90) to model plasma concentrations in humans treated with CAB (600 mg) every 8 weeks. For model validation, an additional group of 6 macaques received oral FTC/TDF (20/22 mg/kg) 24h before and 2h after each penile SHIV exposure. Infection was monitored weekly by PCR amplification of SHIV RNA in plasma. Plasma CAB levels were measured weekly by HPLC.
All 10 controls were infected after a median of 3 penile SHIV exposures (range=1-12). In contrast, 5 of 6 animals that received CAB LA were SHIV negative during 12 penile challenges and remain aviremic 5 weeks after the last challenge (estimated efficacy of 94%, p=0.0003). Plasma CAB concentrations during the challenge period (median = 2,175 ng/ml, range = 303-5,025) remained above the 4xPA-IC90 (664 ng/ml) in all 5 protected animals. Plasma CAB levels in the breakthrough infection fell below the 4xPA-IC90 at weeks 4, 8, and the week prior to detecting SHIV RNA in plasma (week 12). Consistent with clinical efficacy in men, oral FTC/TDF was highly protective with 5 of 6 animals uninfected after 12 SHIV challenges (estimated efficacy of 94%, p=0.0007).
Monthly injections of CAB LA was as effective as oral FTC/TDF in a macaque model of penile SHIV infection that mimics high-risk HIV exposures in men. The high efficacy by CAB LA was related to high plasma drug concentrations that remained above 4xPA-IC90. These data support advancement of CAB LA as a PrEP candidate for men.