Abstract Body

Background:

Broadly neutralizing antibodies (bNAbs) hold promise for antiretroviral therapy (ART). ACTG A5357 is a phase II, single-arm clinical trial, investigating the combination of VRC07-523LS, a bNAb targeting the HIV-1 CD4-binding site, and long-acting cabotegravir (LA CAB) for maintenance ART

Methods:

Participants are adults with HIV, virally suppressed for >2 years, a current CD4 count ≥350 cells/mm3, and susceptibility to VRC07-523LS (IC50 0.25 µg/mL and a Maximum Percent Inhibition (MPI) >98% on the Monogram PhenoSense mAb Assay using screening PBMCs). In Step 1, participants received 4 or 5 weeks of oral CAB and two NRTIs. Those still suppressed entered Step 2 and received intravenous VRC07-523LS (40 mg/kg) Q8 weeks plus intramuscular LA CAB (600mg load followed by 400mg Q4 weeks). At the end of 48 weeks on Step 2 or premature treatment discontinuation, participants returned to a standard of care regimen for 48 weeks in Step 3. The primary outcomes were: 1) grade 3 adverse event (AE) or treatment discontinuation related to VRC07-523LS and LA CAB; and 2) virologic failure (VF) defined as confirmed viral load (VL) ≥200 c/mL at or prior to week 44 of Step 2. Efficacy analyses were as-treated; participants with VL<200 c/mL at the treatment discontinuation were censored.

Results:

Analysis included complete Step1/2 follow-up for 74 participants: 26% cis-female, 51% White (non-Hispanic), median age 54. At baseline, 96% had VL <50 c/mL, median CD4 count 720 cells/mm3. Median IC50 was 0.076 μg/mL, median MPI 99.9%. Seventy-one (96%) participants initiated Step 2 treatment; 61 (86%) completed Step 2 treatment and 10 (14%) prematurely discontinued the regimen (5 VFs, 1 death, and 4 participant/physician request). Twelve (16.9%) participants met the primary safety endpoint: 11 (15%) had grade ≥3 AEs (mostly chills, myalgia, fatigue) and one discontinued therapy due to a grade 1 infusion-related reaction. The only death was unrelated to study treatment. The five VFs (Table) include two of the three participants with VL 51-200 c/mL at week 4. The cumulative probability of VF at or prior to week 44 of Step 2 treatment was 7.3% (95% CI 3.2-16.0%). The integrase R263K mutation was seen in a participant at VF. Pharmacokinetics and anti-idiotype antibodies results are expected in late 2023

Conclusions:

The parenteral maintenance ART regimen of VRC07-523LS plus LA CAB was safe. Most participants maintained viral suppression. Observed potential vulnerabilities should inform future bNAb based ART strategies.