Background
Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, and lenacapavir (LEN), an approved capsid inhibitor, have potent anti-HIV-1 activities and pharmacokinetic profiles enabling once-weekly (QW) oral dosing. GS-US-563-6041 (NCT05052996) is a Phase 2, open-label study evaluating QW ISL+LEN in virologically suppressed people with HIV-1 (PWH). All participants maintained virologic suppression (VS; HIV-1 RNA <50 copies/mL [c/mL]) at study week (W) 96 or at discontinuation. Here, we report HIV-1 resistance analyses through W96.
Methods
Participants were randomized to receive either ISL (2 mg QW from Day [D] 1) + LEN (600 mg D1 and D2 loading dose; then 300 mg QW) orally or remained on once-daily oral bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) until W48. At W48, participants were offered to enter an extension phase to either remain on ISL+LEN or switch from B/F/TAF to ISL+LEN. Proviral DNA sequencing of HIV-1 protease, reverse transcriptase (RT), and integrase was performed at screening; historical genotypes were collected if available. Participants with documented primary nucleoside RT inhibitor (NRTI) or non-NRTI (NNRTI) resistance were not eligible for study enrollment. Resistance analyses were conducted for participants with HIV-1 RNA ≥200 c/mL at the time of confirmed virologic failure (defined as 2 consecutive visits with HIV-1 RNA ≥50 c/mL) or at study discontinuation.
Results
Of participants randomized and dosed (n=52 per arm), most had subtype B HIV-1 (91/104, 87.5%). Five participants who enrolled based on historical genotype were found to have baseline (N)NRTI resistance-associated mutations (RAMs) on proviral genotype analysis post-randomization: 3 in the ISL+LEN arm and 2 in the B/F/TAF to ISL+LEN arm. All 5 maintained VS through study W96 including 2 participants with pre-existing M184I/V (ISL+LEN arm, n=1; B/F/TAF to ISL+LEN arm, n=1). Two ISL+LEN arm participants without baseline N(N)RTI RAMs met criteria for resistance analysis. Both resuppressed on ISL+LEN with no treatment-emergent resistance detected. No participants in the B/F/TAF to ISL+LEN arm met criteria for resistance testing.
Conclusions
No treatment-emergent resistance was detected with ISL+LEN through study W96, consistent with the high rates of VS observed. These findings support ongoing Phase 3 studies of the QW fixed dose combination ISL/LEN regimen for virologically suppressed PWH (NCT06630286, NCT06630299).