Administration of a toll-like receptor (TLR) 7 agonist in combination with a therapeutic vaccine induces CD8+ T cell-mediated control of SIV in a non-human primate model. We hypothesized that among people living with HIV (PLH) who had evidence of a partially effective host response (viremic controllers), treatment with the investigational oral TLR7 agonist vesatolimod (VES; GS-9620) would lead to enhanced immune control post-ART.
We conducted a phase 1b, randomized, double-blind, placebo-controlled study in virologically suppressed PLH with historical chronic pre-ART plasma HIV-1 RNA of 50 to ≤5,000 c/mL. Participants were randomized 2:1 to receive 10 biweekly doses of VES 4-8 mg or placebo while continuing ART, followed by carefully monitored analytical treatment interruption (ATI). Viral rebound and safety were evaluated through at least 24 weeks (w) of ATI.
Twenty-five participants were randomized to VES (n=17) or placebo (n=8). The median age was 45 yrs (range 27-66 yrs) and 16% were women. The median pre-ART HIV-1 RNA 3.2 log10 c/mL (IQR 3, 3.3) and the median time on ART was 2.7 yrs (range 0.7-17.2 yrs). VES was well tolerated, with no drug-related discontinuations. Most common study-drug related AEs were lymphadenopathy, chills, and headache. Pharmacodynamic activity of VES was confirmed by increases in whole blood interferon stimulated gene mRNAs and plasma cytokine levels. During the ATI, the median (95% CI) times to viral rebound (>50 c/mL and >200 c/mL, respectively) were 4.1 w (2.9-5.9) and 5 w (3.9-6) for the VES group, and 3.9 w (2.0-4.1) and 4 w (2-4.4) for placebo (p=0.036; p=0.024; see Figure). Median (95% CI) plasma viral set-point change from pre-ART value was -0.34 (-0.60, 0.06) log10 c/mL for VES (p=0.035) and -0.28 (-0.75, 0.32) log10 c/mL for placebo (p=0.38). Four individuals in the VES group had no virologic rebound (>50 c/mL) for ≥6 w, with one participant rebounding at 15 w (and >200 c/mL at 31 w); this participant also had a 0.94 log10 c/mL decrease in viral set-point and completed the study after 48 w off ART with HIV-1 RNA 164-215 c/mL.
VES was well tolerated in HIV controllers at multiple doses up to 8 mg and was associated with a modest increase in time to viral rebound after ATI, potentially due to an augmented antiviral immune response. Trials evaluating the efficacy of VES in combination with other agents such as CD8-inducing vaccines and monoclonal antibodies are warranted.