Three phase III randomized controlled trials of topical resiquimod 0.01-percent gel to reduce anogenital herpes recurrences.

Resiquimod, a Toll-like receptor 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 acquired immune response. Animal and phase II human trials showed posttreatment efficacy in reducing recurrent herpes lesion days and/or time to first recurrence. Three phase III randomized, double-blind, vehicle-controlled trials of topical resiquimod to reduce anogenital herpes recurrences were conducted in healthy adults with ≥4 recurrences within the prior year. Participants applied resiquimod 0.01% gel or vehicle gel 2 times per week for 3 weeks to each recurrence for 12 months. Trials 1 and 2 had 2:1 resiquimod-vehicle randomization. Trial 3 had 1:1:1 randomization for resiquimod and 500 mg valacyclovir orally twice daily for 5 days (RESI-VAL), resiquimod and oral placebo (RESI-PLA), and vehicle and oral placebo (VEH-PLA). The median time to first recurrence was similar for resiquimod and vehicle (trial 1, 60 and 56 days, P=0.7; trial 2, 54 and 48 days, P=0.47; trial 3, 51 [RESI-VAL], 55 [RESI-PLA], and 44 [VEH-PLA] days, P=not significant [NS]). The median time to healing of initial treated recurrence was longer for resiquimod (trial 1, 18 compared to 10 days, P<0.001; trial 2, 19 compared to 13 days, P=0.16; trial 3, 14 [RESI-VAL], 16 [RESI-PLA], and 8 [VEH-PLA] days, P<0.001). In trials 1 and 2, moderate to severe erythema and erosion/ulceration at the application site were more common in resiquimod recipients. In conclusion, no posttreatment efficacy of resiquimod 0.01% gel was observed. Increased application site reactions and initial recurrence healing time are consistent with resiquimod-induced cytokine effects.