Final efficacy and safety of twice-yearly subcutaneous lenacapavir in treatment-naive people with HIV

OBJECTIVE: To assess final efficacy (through Week [W] 132), safety, and emergent resistance with lenacapavir-based combination regimens in the CALIBRATE study. DESIGN: CALIBRATE was a Phase 2, randomized, open-label study (NCT04143594). METHODS: Treatment-naive PWH were randomized (2 : 2:2 : 1) to four treatment groups (TG): TG1 and TG2 received twice-yearly subcutaneous lenacapavir plus oral daily emtricitabine/tenofovir alafenamide (F/TAF); TG3 received oral daily lenacapavir plus F/TAF; and TG4 received oral daily bictegravir/F/TAF. At W28, TG1 switched to lenacapavir plus TAF and TG2 switched to lenacapavir plus bictegravir. At W80, TG4 completed the study and TG1-3 continued assigned treatments. RESULTS: Overall, 182 participants received at least one dose of study drug (TG1-4, respectively: n = 52, n = 53, n = 52, n = 25). Virologic suppression (HIV-1 RNA <50 copies/ml) at W80 by FDA snapshot: 87, 75, 87, and 92% in TG1-4, respectively. When excluding missing data, virologic suppression at W132 across TG1-3 was 98-100%. Mean (95% CI) increase from baseline to W80 in CD4 cells/μl was consistent across TG1-4: 275 (214; 337), 262 (203; 320), 245 (174; 315), and 248 (155; 340), respectively. No serious treatment-related adverse events occurred. Two participants in TG1 and three in TG2 discontinued study drug due to adverse events. Injection-site reactions were mostly mild to moderate. LEN resistance-associated mutations emerged in four participants. CONCLUSION: Lenacapavir-containing combinations achieved and maintained high rates of virologic suppression in treatment-naive participants through W132; lenacapavir was well tolerated. These data support future development of lenacapavir-containing regimens for HIV-1 treatment.