Lenacapavir (LEN) is a first-in-class, multistage inhibitor of HIV-1 capsid function in clinical development that was recently approved in the European Union for use in adults with multidrug-resistant HIV-1 infection. LEN is highly potent against HIV-1 in vitro and maintains wild-type activity across HIV-1 isolates with resistance to all existing drug classes. In clinical trials, LEN has shown high levels of efficacy in people with HIV-1 who are treatment-naïve or treatment-experienced. However, a comprehensive characterization of the antiviral activity of LEN against HIV-2 is lacking. Herein, we studied the activity of LEN against a panel of HIV-2 isolates with or without resistance to existing drug classes.
The activity of LEN against HIV-1 and HIV-2 isolates from antiretroviral-naïve individuals was directly compared in two different assays: single-cycle infections of MAGIC-5A indicator cells and multicycle infections of an immortalized T cell line (CEM-NKR-CCR5-Luc). Drug-resistant HIV-2 variants with mutations in reverse transcriptase (RT) and integrase (IN) were tested for resistance to LEN in the single-cycle assay.
In the single-cycle assay, LEN inhibited HIV-1 with a mean 50% inhibitory concentration (IC50) of 210 pM (range = 140–310 pM; n = 10 isolates). In comparison, the mean IC50 value for HIV-2 was 2.3 nM (range = 1.1–3.2 nM; n = 12 isolates), indicating an 11-fold decrease in the activity of LEN against HIV-2 compared with HIV-1. In the multicycle assay, a comparable difference in LEN activity between HIV-1 and HIV-2 was also noted, with mean IC50 values of 110 pM for HIV-1 (range = 67–196 pM; n = 4 isolates) and 1.8 nM for HIV-2 (range = 1.0–3.2 nM; n = 6 isolates). The presence of drug resistance mutations in HIV-2 RT and IN had no effect on LEN activity (fold-change in LEN IC50 = 0.73–1.2 relative to wild-type HIV-2ROD9).
In our study, LEN was active against HIV-2 isolates with low-nanomolar activity, but was 11- to 16-fold less potent against HIV-2 in comparison to HIV-1, regardless of the presence of drug resistance mutations in HIV-2 RT or IN. As a result of this difference in potency, treating people with HIV-2 with a LEN-based regimen would require careful monitoring to assess virologic and immunologic responsiveness. These data provide information on the potential clinical utility of LEN in people with HIV-2 for whom treatment options are limited.