Abstract Body

Background:

Vesatolimod (VES) is a well-tolerated toll-like receptor 7 agonist that was associated with a modest delay in time-to-HIV-rebound (TTHR) during analytical treatment interruption (ATI) in HIV viremic controllers. This analysis evaluated VES exposure in relation to pharmacodynamic (PD) biomarkers and TTHR, as well as the associations among VES pharmacokinetics (PK)/PD, PD biomarkers and TTHR.

Methods:

25 HIV viremic controllers (pre-ART plasma viral load [pVL] 50-5000 copies/mL) on ART were randomized to receive VES (n=17) or placebo (n=8) biweekly for 20 weeks followed by ATI for up to 48 weeks. Whole blood samples were collected at pre-dose and 24h post first dose to evaluate interferon-stimulated genes (ISGs) with real-time QPCR method. Plasma samples were collected pre-dose* and at 0.5, 1, 2, 4*, 6*, 8, 10*, and 24*h after the first dose to evaluate VES PK and biomarkers*. Plasma protein levels were evaluated with multiplex or SIMOA method. Maximum fold change (FCmax) and area under the curve (AUC) of % baseline (AUEC0-24h) were used to analyze plasma proteins including PD cytokines VES PK (peak concentration [Cmax] or AUC0-24h) and plasma protein (FCmax or AUEC0-24h) correlations were analyzed using Spearman’s correlation. The relationships of VES PK and biomarkers (ISGs or plasma proteins) with viral outcomes (1st time of viral rebound to ≥200 c/mL or 1000 c/mL, duration of VL < 400 c/mL during ATI, or change from baseline in intact proviral HIV DNA [IPDA]) were analyzed with Spearman’s correlation and Cox proportional-hazards model.

Results:

Significant increases in VES PD biomarkers and several plasma proteins were observed after the first VES dose and were significantly correlated with VES PK (adj.p < 0.05), including ISGs (ISG15, OAS1, MX1), IFNa, IL-1RA, IP-10, CCL4, CCL8, MCP-1, CXCL9, and IL-8. Increased ISGs and CCL4 were associated with longer TTHR. Additionally, Factor VII, MMP3, BDNF, IL-2, and MMP9 were also associated with TTHR. There was no significant association between PK and viral outcomes.

Conclusions:

These data indicate that VES-mediated biological effects, particularly PD response, were associated with viral outcome in viremic controllers. Larger independent cohorts are needed to validate these findings and investigate the prognostic and functional significance of the biomarkers identified.

Figure 1. Higher Elevation in ISGs at 24h Post First VES Dose Was Associated with Longer Time-to-HIV-rebound