Long-acting lenacapavir acts as an effective preexposure prophylaxis in a rectal SHIV challenge macaque model
Elena Bekerman, … , Kelly Wang, Christian Callebaut
Elena Bekerman, … , Kelly Wang, Christian Callebaut
Published June 29, 2023
Citation Information: J Clin Invest. 2023;133(16):e167818. https://doi.org/10.1172/JCI167818.
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Research Article AIDS/HIV

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

Abstract

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.

Authors

Elena Bekerman, Stephen R. Yant, Laurie VanderVeen, Derek Hansen, Bing Lu, William Rowe, Kelly Wang, Christian Callebaut

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Figure 4

Animal infection status relative to LEN exposure at the time of challenge.

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Animal infection status relative to LEN exposure at the time of challeng...
(A) Plasma levels of LEN measured by mass spectrometry among SHIV-challenged animals at the time of challenge versus final infection status. Symbols represent plasma LEN concentration derived from an average of 3 biological assay replicates for individual study animals and are color-coded by the corresponding LEN-dosing groups. The horizontal bars represent group averages. The P value comparing exposures among infected versus uninfected animals, computed via an unpaired t test with Welch’s correction, is shown. The lower dotted line represents the rhesus paEC95 for LEN (8.8 nM), while the higher dotted line represents the rhesus-adjusted clinical target Ctrough concentration for LEN (70 nM). (B) Infection rates among the different study animal subgroups. Bars represent the number of infected (red) or uninfected (gray) study animals that were not treated, the total number of animals dosed with LEN or dosed with LEN and split into subsets with exposures below or above the adjusted LEN target concentration. P values, computed via Fisher’s exact test, are shown.