Background. Resiquimod, an investigational immune response modifier and Toll-like receptor (TLR) 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 (Th1)—acquired immune response. In animal models, induction of Th1-specific responses modifies experimental herpes simplex virus (HSV) infection.

Methods. We conducted a randomized, double-blind, vehicle-controlled trial to assess the efficacy of resiquimod 0.01% gel for reducing human anogenital HSV-2 mucosal reactivation. Adults with genital HSV-2 applied resiquimod or vehicle topically to herpes lesions 2 times weekly for 3 weeks and then collected daily anogenital swabs for 60 days for HSV DNA polymerase chain reaction. Recurrences during the subsequent 7 months were treated with study gel. During the final treatment-free 60 days, participants again collected daily swabs to assess shedding.

Results. The median lesion and shedding rates were lower for resiquimod compared with vehicle recipients during the initial sampling period (10% vs. 16% [P = .03] and 10% vs. 17% [P = .08], respectively) and during the final sampling period (3% vs. 22% [P < .001] and 10% vs. 26% [P = .009], respectively). Resiquimod did not influence recurrence length.

Conclusions. These findings suggest that the immunological control of HSV-2 reactivation and lesion clearance may differ and that TLR7 and TLR8 agonists can reduce the frequency of mucosal HSV-2 reactivation.