Background: HIV infection requires lifelong treatment due to persistent viral reservoirs. Vesatolimod (VES; GS-9620) is an investigational oral toll-like receptor (TLR) 7 agonist that has led to viral remission in preclinical S(H)IV models when combined with an anti-HIV antibody or CD8 vaccine. VES targets dendritic cells in gut associated lymphoid tissue (GALT) and the liver, resulting in a pre-systemic response with localized cytokine production and innate immune modulatory effects. We evaluated the activity of VES in people living with HIV (PLH).
Methods: Virologically-suppressed PLH were enrolled in a double-blind, placebo-controlled dose escalation study. Participants (n=48) were randomized (6:2) to receive VES or placebo every other week in sequential dose escalation cohorts. Multiple (6-10) doses of 1-12 mg were tested. Measurements collected included: plasma HIV-1 RNA, pharmacokinetic (PK), and pharmacodynamic (PD) parameters [interferon stimulated gene (ISG) mRNA expression, serum cytokines and cellular activation].
Results: The median (IQR) age of the participants (43 men, 5 women) was 47 (39, 54) years. The majority of individuals initiated antiretroviral therapy (ART) during chronic HIV-1 infection, with a median of 8.1 years on ART. VES was well-tolerated at all doses, with no study drug-related Grade (G) 3 or 4 adverse events (AEs), no related serious AEs, and no AEs leading to study drug discontinuation. Study drug-related AEs including mild, flu-like symptoms consistent with VES PD, resolving within one day and not occurring with each dose, were observed in 10/40 participants at ≥2 mg. VES plasma exposure increased with dose escalation. Individuals receiving VES ≥4 mg had dose-dependent induction in whole blood ISG mRNA at 24-48 hours post-dose, and changes in the serum cytokines/chemokines ITAC, IP-10 and IL-1RA. Consistent T cell and NK cell activation occurred at doses ≥8 mg. Transient increases in plasma HIV-1 RNA >20 copies/mL (range 21-2430 copies/mL) were observed at least once in 13/48 participants (blinded) after 1 to 3 oral doses at different dose levels.
Conclusions: VES is well-tolerated at doses of 1-12 mg and induced immune activation at higher doses. Clinical trials are in progress to evaluate the efficacy of VES, alone or in combination with other agents, to control viremia without ART.