Long-acting lenacapavir acts as an effective preexposure prophylaxis in a rectal SHIV challenge macaque model

• Published in: The Journal of clinical investigation Vol. 133; no. 16; pp. 1 - 9
• Main Authors: Bekerman, Elena, Yant, Stephen R, VanderVeen, Laurie, Hansen, Derek, Lu, Bing, Rowe, William, Wang, Kelly, Callebaut, Christian
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.08.2023
• Subjects: Acquired immune deficiency syndrome; AIDS; AIDS/HIV; Analysis; Animals; Antiretroviral agents; Antiviral activity; Antiviral agents; Biological products industry; Biomedical research; Disease prevention; Dosage and administration; Drug dosages; Drug therapy; Health aspects; Highly active antiretroviral therapy; HIV; HIV (Viruses); HIV infection; Human immunodeficiency virus; Infection; Infections; Inoculum; Macaques; Medical research; Medicine, Experimental; Pharmacokinetics; Plasma; Plasma levels; Plasma physics; Prevention; Prophylaxis; Rectum; Scientific equipment and supplies industry; Serology; Sexually transmitted diseases; Titration; United States; Drug therapy; AIDS/HIV; Pharmacology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI167818

Long-acting antiretroviral agents for preexposure prophylaxis (PrEP) represent a promising new alternative to daily oral regimens for HIV prevention. Lenacapavir (LEN) is a first-in-class long-acting capsid inhibitor approved for the treatment of HIV-1 infection. Here, we assessed the efficacy of LEN for PrEP using a single high-dose simian-human immunodeficiency virus (SHIV) rectal challenge macaque model. In vitro, LEN showed potent antiviral activity against SHIV, as it did for HIV-1. In macaques, a single subcutaneous administration of LEN demonstrated dose proportional increases in and durability of drug plasma levels. A high-dose SHIV inoculum for the PrEP efficacy evaluation was identified via virus titration in untreated macaques. LEN-treated macaques were challenged with high-dose SHIV 7 weeks after drug administration, and the majority remained protected from infection, as confirmed by plasma PCR, cell-associated proviral DNA, and serology testing. Complete protection and superiority to the untreated group was observed among animals whose LEN plasma exposure exceeded its model-adjusted clinical efficacy target at the time of challenge. All infected animals had subprotective LEN concentrations and showed no emergent resistance. These data demonstrate effective SHIV prophylaxis in a stringent macaque model at clinically relevant LEN exposures and support the clinical evaluation of LEN for HIV PrEP in humans.