Background:
Lenacapavir (LEN), a long-acting HIV-1 capsid inhibitor, is approved for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) with multidrug resistance (MDR) in combination with other antiretrovirals (ARVs). LEN is highly potent with no overlapping resistance with other ARVs. In CAPELLA, LEN in combination with an optimized background regimen (OBR) led to high virologic suppression: 78% (n=56/72; week [W] 52). We assessed LEN efficacy in participants whose OBR had no fully active ARVs.
Methods:
The Phase 2/3 CAPELLA study enrolled HTE PWH with MDR. Eligible participants had resistance to ≥2 ARVs in ≥3 of the 4 main ARV classes (NRTI, NNRTI, PI, INSTI). After oral loading, SC LEN was administered every 6 months. OBRs were selected by the clinicians; other investigational drugs were permitted. OBR overall susceptibility score was the sum of susceptibility scores for each OBR ARV; 0 (no susceptibility), 0.5 (partial susceptibility) and 1 (full susceptibility). Efficacy data (HIV-1 RNA copies/mL; FDA Snapshot algorithm) were assessed at W26, 52, and 104. LEN and OBR ARV resistance analyses were done at virologic failure (virologic rebound ≥50 copies/mL or <1 log10 decline vs baseline).
Results:
Of the enrolled 72 participants, 12 (17%) had no fully active ARVs in their OBR; 6/12 and 1/12 had 1 or 2 partially active (score 0.5 each) ARVs, respectively. Median (range) number of OBR ARVs was 4 (2–6). Overall, OBR comprised NRTI (9 participants), INSTI (8), PI (7) or NNRTI (6); 5, 2, and 2 participants were on a CD4 post-attachment inhibitor (ibalizumab), CCR5 inhibitor (maraviroc), or attachment inhibitor (fostemsavir), respectively. Treatment outcomes: 8 participants had HIV-1 RNA <50 copies/mL at all 3 visits (W26, 52, and 104), including 1 participant with LEN resistance (R; M66I) at W10 and an OBR change at W25. 1 participant with missing W104 data was suppressed at a later visit; 1 participant not suppressed at W26 developed LEN-R (M66I) but was suppressed at W52 and 104 (OBR changed at W25); and 2 participants had HIV-1 RNA ≥50 copies/mL throughout, but with a stable, low level viral load (1 with <600 copies/mL, OBR changed at W30; 1 with <3000 copies/mL despite emerging LEN-R at W4 [M66M/I]). None of the 12 participants discontinued the study drug.
Conclusions:
In HTE PWH with MDR on an OBR with no fully active ARVs, LEN led to sustained virologic suppression over 104 weeks for most participants. LEN is an important option for treating HTE PWH with MDR.