Background:
Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, and lenacapavir (LEN), a capsid inhibitor, have potent anti-HIV-1 activity and pharmacokinetic profiles permitting once-weekly (QW) oral dosing. We investigated efficacy and safety of ISL+LEN in virologically suppressed people with HIV-1.
Methods:
In this Phase 2, randomized, open-label, active-controlled study (NCT05052996), virologically suppressed adults on bictegravir/emtricitabine/tenofovir alafenamide fumarate (B/F/TAF) were randomized to either oral ISL 2 mg + LEN 300 mg QW or to continue daily B/F/TAF. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA ≥ 50 copies/mL (FDA-defined Snapshot algorithm) at Week 24 (W24). Safety parameters, including CD4+ T-cell and absolute lymphocyte counts (ALC) and adverse events (AEs), were also evaluated.
Results:
A total of 104 participants were randomized and dosed (52/group); median age (range) was 40 (26–76) years, and 19 (18.3%) were female at birth. One (1.9%) participant in the ISL+LEN group (whose baseline HIV RNA was 251 copies/mL) had HIV-1 RNA > 50 copies/mL at W24, then suppressed on ISL+LEN (64 copies/mL at W24, < 50 copies/mL at W30); no participant in the B/F/TAF group had HIV RNA > 50 copies/mL at W24. Forty-nine (94.2%) and 48 (92.3%) participants maintained viral suppression in the ISL+LEN and B/F/TAF groups at W24, respectively; 2 (3.8%) and 4 (7.7%) participants had no data at W24 due to discontinuation or missing visits. No between-group differences were seen in changes in CD4+ T-cell counts or ALC at W24 (Table). AEs occurred in 39 participants (75.0%) on ISL+LEN and 38 (73.1%) on B/F/TAF. The most common AEs in ISL+LEN participants included diarrhea (n=7; 13.5%), upper respiratory infection (n=6; 11.5%), and arthralgia, pain in extremity, and fatigue (each n=3; 5.8%). No grade 3 or 4 AEs related to study drug were reported. Two participants discontinued ISL+LEN due to AEs unrelated to drug (large intestine perforation/renal colic; hepatitis B).
Conclusions:
In this Phase 2 study, the first QW oral ARV regimen of ISL+LEN maintained viral suppression at W24 and was well tolerated. The ISL 2 mg dose showed no clinically significant decreases in CD4+ T-cell counts or ALCs as were seen previously with higher daily, weekly, and monthly doses of ISL.
