Authors: Amy Colson, Gordon Crofoot, Peter J. Ruane, Moti Ramgopal, Alexandra W. Dretler, Ronald G. Nahass, Gary Sinclair, Mezgebe Berhe, Chris Deaton, Angela S. Liu, Eva Mortensen, Martin S. Rhee, Elizabeth G. Rhee, Jared Baeten, Joseph J. Eron
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.