ART blocks infection of new cells but has no impact on cells already infected with latent or active proviruses. Broadly neutralizing monoclonal antibodies (bnMAb) may promote clearance of viremia and virus-expressing cells through antibody-dependent mechanisms. We evaluated whether the CD4-binding site bnMAb VRC01 affects HIV persistence in chronically-infected individuals on ART.
A5342 was a phase 1, randomized, double-blind, placebo-controlled, parallel arm study. Participants with ART-suppressed viremia (<40 copies/ml) were randomized to Arm A: 2 infusions of VRC01 (40 mg/kg) at entry and week 3 and 2 infusions of placebo (saline) at weeks 6 and 9; or Arm B: 2 infusions of placebo at entry and week 3 and 2 infusions of VRC01 at weeks 6 and 9. Primary outcomes were safety and change in cell-associated HIV RNA/DNA ratio (CAR/CAD) from baseline (BL) to week 6. Plasma viremia (single copy HIV RNA assay [SCA]) and PMA/ionomycin-stimulated virus production (HIV RNA copies/ml) from CD4+T-cells were also assessed. Changes from pre- to post-VRC01 (Arm A: entry to week 6; Arm B: week 6 to week 12) time points across both arms were evaluated.
40 participants were randomized; 20 per arm. Median age was 52 y; median CD4+ T-cell count was 696 /mm3. No treatment-related adverse events ≥grade 3 were reported during study follow up. No significant difference between VRC01 and placebo was observed for change in CAR/CAD ratio from BL to week 6 (median fold change: 1.12 vs. 0.83, p=0.16, 95% CI (0.75, 2.42)), or from pre-to post-VRC01 time points with both arms combined (1.24, 95% CI (0.83, 1.69), p=0.29; Table). At entry, 22/40 (55%) participants had SCA ≥1 copy/ml. At week 6, there was no difference in the proportion with SCA ≥1 copy/ml between the arms (42% vs. 37%, p=1.0). There were also no significant differences between arms from BL to week 6, or from pre- to post-VRC01 time points with both arms combined in PMA/ionomycin stimulated virus production (all p>0.05).
In individuals with chronic ART-suppressed HIV infection, VRC01 infusions were safe and well tolerated but did not affect plasma viremia, cellular HIV RNA/DNA levels, or stimulated virus production from CD4+T-cells. Potential mechanisms being evaluated to explain the lack of response include viral resistance to VRC01, poor penetration of VRC01 to sites of virus expression, or inherent inability of VRC01 to clear virus particles or virus-expressing cells.