Background:
Lenacapavir (LEN) is a first-in-class, long-acting HIV-1 capsid inhibitor approved for treatment of HIV-1 infection in adults with multidrug resistance. Teropavimab (TAB) & zinlirvimab (ZAB) are long-acting broadly neutralizing antibodies (bNAbs), targeting the CD4-binding site & V3 loop of gp120, respectively. In a phase 1b study (NCT04811040), LEN+TAB+ZAB maintained virologic suppression (VS) for 6 months in 18/20 participants with HIV with high-level sensitivity to both bNAbs. We evaluated safety & efficacy of LEN+TAB+ZAB for maintenance of VS in a cohort of participants who met viral sensitivity criteria to either TAB or ZAB.
Methods:
Virologically suppressed adults with HIV on antiretroviral therapy (ART; HIV-1 RNA <50 copies/mL for ≥18 months), with high-level sensitivity to TAB or ZAB but not both by HIV proviral DNA phenotype (PhenoSense monoclonal antibody assay IC[sub]90[/sub] ≤2µg/mL), a CD4 nadir of ≥350 cells/µL, & CD4 ≥500 cells/µL at baseline were randomized 1:1 to one of two active treatment groups: LEN (927 mg subcutaneously after oral loading) + TAB (30 mg/kg intravenously [IV]) + ZAB (Group 1, 10 mg/kg IV; Group 2, 30 mg/kg IV). The primary endpoint was incidence of treatment-emergent serious adverse events at Week 26; secondary endpoints included virologic outcomes (VS or ≥50 copies/mL) at Week 26 by FDA Snapshot analysis.
Results:
Eleven participants were randomized & treated (Group 1, n=5; Group 2, n=6). Age range was 28–63 years; 3/11 were female; 4/11 were Black; & median CD4 count was 916 cells/µL. There was 1 serious adverse event of soft tissue infection not related to study treatment. No adverse events led to study drug. Safety outcomes were similar between groups. One participant restarted baseline ART due to a protocol violation (chronic hepatitis B infection) & was excluded from the efficacy analysis. At Week 26, 8/10 participants maintained VS (Group 1, 2/4; Group 2, 6/6). Of the two participants in Group 1 who had virologic rebound, one had sensitivity to TAB & was diagnosed with acute COVID-19 at the time of rebound, & one had sensitivity to ZAB & rebounded at Week 26; both had HIV RNA <100 copies/mL.
Conclusions:
The long-acting combination of LEN+TAB+ZAB was well tolerated, with a favorable safety profile. All participants in the higher ZAB dose group maintained VS for 6 months, which suggests that more inclusive sensitivity criteria may be appropriate for treatment studies of LEN+TAB+ZAB when higher bNAb levels are maintained.