Background
Lenacapavir (LEN) and broadly neutralizing antibodies, teropavimab (TAB) and zinlirvimab (ZAB), have pharmacokinetic profiles supporting twice-yearly dosing. In a Phase 2 study (NCT05729568), twice-yearly LEN, TAB, and ZAB maintained a high rate (89%) of virological suppression (HIV-1 RNA <50 copies/mL) at Week (W) 52. We describe resistance analyses through W52.
Methods
Virologically suppressed participants with HIV-1 highly susceptible to TAB and ZAB (90% inhibitory concentration [IC90] ≤2 µg/mL) were randomized 2:1 to receive twice-yearly subcutaneous LEN 927 mg (plus oral loading) and intravenous TAB 2550 mg and ZAB 2550 mg, or to stay on their oral stable baseline regimen (SBR). Genotypic and phenotypic drug susceptibility analyses were performed at screening for all participants, and post-baseline for those meeting virologic failure criteria (HIV-1 RNA ≥50 copies/mL, subsequently confirmed and ≥200 copies/mL, or ≥200 copies/mL at study drug discontinuation/last visit). Longitudinal single genome sequencing of plasma HIV-1 was conducted to assess HIV-1 clonality.
Results
Of 80 participants (LEN, TAB, and ZAB, n=53; SBR, n=27), most had subtype B HIV-1 (75/80, 93.8%). Baseline IC90 values for LEN, TAB, and ZAB participants ranged from 0.05–1.71 µg/mL for TAB and 0.01–1.99 µg/mL for ZAB. Three participants in the LEN, TAB, and ZAB group (5.7%) and no SBR participants met resistance analysis criteria. Of the three LEN, TAB, and ZAB participants (Pt), Pt1 developed LEN resistance (Q67H) and resistance to ZAB (IC90 >50 µg/mL) at W24, with low plasma LEN concentrations; Pt2 had loss of ZAB susceptibility at W50 without LEN resistance or change in TAB susceptibility, with low exposure to TAB and ZAB; and Pt3 had persistent low-level viremia after restarting oral antiretroviral therapy (ART), with no resistance, and identical HIV-1 RNA sequences detected over time, suggesting proviral expression from an expanded clone. Pt1 and Pt2 had rapid HIV-1 RNA suppression after switching to oral ART. Pt3 resuppressed 180 days following initiation of oral ART.
Conclusions
Emergent resistance was infrequent in virologically suppressed participants who received LEN, TAB, and ZAB through 52 weeks of treatment. Loss of ZAB susceptibility was observed in 2 participants (3.8%), one of whom also had emergent LEN-associated resistance. These findings support ongoing evaluation of LEN, TAB, and ZAB as the first potential twice-yearly HIV-1 combination treatment regimen.