Long-acting lenacapavir acts as an effective preexposure prophylaxis in a rectal SHIV challenge macaque model
Elena Bekerman, Stephen R. Yant, Laurie VanderVeen, Derek Hansen, Bing Lu, William Rowe, Kelly Wang, Christian Callebaut
Elena Bekerman, Stephen R. Yant, Laurie VanderVeen, Derek Hansen, Bing Lu, William Rowe, Kelly Wang, Christian Callebaut
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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 3

Study design, SHIV infectivity, seroconversion status, and capsid resistance profile after single challenge of LEN-treated macaques.

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Study design, SHIV infectivity, seroconversion status, and capsid resist...
(A) Study design. Rhesus macaques of Indian origin were treated with a single subcutaneous administration of LEN at the specified dose level on week 0 and challenged with a high-dose of SHIV on week 7. (B) Plasma SHIV viral loads measured by gag RT-qPCR among LEN-treated rhesus macaques after a single challenge with 100 TCID50 SHIV (plotted on the left y axis) versus plasma LEN exposure (plotted on the right y axis). Animals dosed with 20, 50, and 75 mg/kg LEN are represented by the top, middle, and bottom rows, respectively. Each symbol represents an average of 3 assay replicates. Dotted lines represent the assay limit of detection (LOD, 62 copies per mL). Asterisks indicate the timing of ART initiation among the 3 viremic animals. (C) The timing of p27 antibody detection (i.e., seroconversion) measured via serum ELISA and depicted by the gray shaded regions on corresponding plasma viral load curves (only animals with detectable signal shown of 11 assayed). Capsid-encoding gene sequencing results are noted above the viral load curves as applicable. WT, WT sequence; SF, sequence failure. (D) SHIV intact proviral DNA counts from PBMCs determined by intact proviral DNA assay among 11 SHIV-challenged rhesus macaques at the indicated time points. Each symbol represents an average of 12 technical replicates in a single experiment. Red symbols represent animals that were viremic by qPCR and seropositive by p27 serum ELISA. Dotted line represents the assay limit of detection (2 copies per million PBMCs).