Lenacapavir may be beneficial for individuals infected with HIV-2

Lenacapavir may inhibit the replication of HIV-2 isolates and drug-resistant HIV-2 variants, according to results of a study published in The Journal of Infectious Diseases.

The clinical course of HIV-2 infection is distinct from that of HIV-1 infection. Most patients infected with HIV-2 have low or undetectable viral RNA loads and experience a prolonged asymptomatic period. However, without antiretroviral therapy (ART), people living with HIV-2 eventually progress to AIDS.

As there is a scarcity of research into the potential use of lenacapavir in the setting of HIV-2 infection, researchers conducted a drug susceptibility study to evaluate the in vitro activity of lenacapavir against HIV-2 isolates sourced from ART-naive individuals. Cells infected with HIV-2 isolates and drug-resistant HIV-2 variants were challenged with lenacapavir, and those infected with HIV-1 or simian immunodeficiency virus (SIV) were used as comparators.

In a single-cycle assay, there was an 11-fold decrease in the susceptibility of HIV-2 isolates to lenacapavir (mean 50% inhibitory concentration [IC₅₀], 2.2 [range, 1.1-3.2] picomolar [pM]) relative to HIV-1 isolates (mean IC₅₀, 200 [range, 140-310] nanomolar [nM]). The SIV isolates were also less susceptible to lenacapavir (mean IC₅₀, 0.81 [range, 0.63-1.0 nM]) relative to HIV-1 isolates. Overall, susceptibility differed significantly between HIV-1 and HIV-2 isolates, HIV-1 and SIV isolates, and HIV-2 and SIV isolates (all P ≤.0001).

The mean Hill slopes for the dose-response curves were 2.1 for HIV-1, 2.9 for HIV-2, and 2.2 for SIV, indicating a significant difference in Hill slope between HIV-1 and HIV-2 (P ≤.01) but not between HIV-1 and SIV or HIV-2 and SIV.

In an analysis of lenacapavir activity via multicycle 6-day infection assay, the mean IC₅₀ for HIV-2 was 2.4 (range, 0.94-5.4) nM, which was 14-fold higher than that of HIV-1 (mean IC₅₀, 170 [range, 70-340] pM; P ≤.0001). The mean IC₅₀ for both HIV-1 and HIV-2 isolates significantly differed from that of SIV isolates (mean range, 1.2-1.6 nM; all P ≤.0001).

Further analysis of HIV-2 variants showed that the mean IC₅₀ for the I54M+I84V+L90M variant was 1.9-fold higher relative to HIV-2 wild-type isolates (P ≤.01). No other tested HIV-2 variants differed significantly from wild-type isolates.

The researchers noted that mean IC₅₀ values for the I54M+I84V+L90M variant were in range with those observed in HIV-2 isolates collected from ART-naive individuals. The I54M+I84V+L90M variant was also fully susceptible to lenacapavir in the multicycle experiment.

According to the researchers, “[G]iven the limitation of therapeutic options for HIV-2 patients, it is encouraging that our data suggest that lenacapavir could play a role…”

Disclosures: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

By Jessica Nye, PhD

References:

Smith RA, Raugi DN, Nixon RS, et al; on behalf of the University of Washington-Senegal HIV-2 Study Group. Antiviral activity of lenacapavir against HIV-2 isolates and drug-resistant HIV-2 mutants. J Infect Dis. Published online December 7, 2023. doi:10.1093/infdis/jiad562