Research ArticleHIV

The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy

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Science Translational Medicine  23 Jun 2021:
Vol. 13, Issue 599, eabg3071
DOI: 10.1126/scitranslmed.abg3071

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A TLR7 agonist for HIV control

Toll-like receptor 7 (TLR7) agonists, combined with other therapies, can help to control immunodeficiency viruses in nonhuman primates. SenGupta et al. evaluated the safety and efficacy of vesatolimod, an oral TLR7 agonist, in people with HIV who had exhibited partial control of their virus—so-called “controllers”—before receiving antiretroviral therapy (ART). Compared to placebo, vesatolimod was associated with an increase in interferon signaling and NK cell and T cell activation and a decay in the frequency of cells harboring intact HIV genomes. Vesatolimod also induced a modest increase in the time to virus rebound after ART was interrupted.

Abstract

Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1–infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound was analyzed using the Kaplan-Meier method. Vesatolimod was associated with induction of immune cell activation, decreases in intact proviral DNA during ART, and a modest increase in time to rebound after ART was interrupted. The delayed viral rebound was predicted by the lower intact proviral DNA at the end of vesatolimod treatment (13 days after the final dose). Inferred pathway analysis suggested increased dendritic cell and natural killer cell cross-talk and an increase in cytotoxicity potential after vesatolimod dosing. Larger clinical studies will be necessary to assess the efficacy of vesatolimod-based combination therapies aimed at long-term control of HIV infection.

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