Herpes Simplex Virus: Rapidly Cleared Reactivation Episodes, Treatment with Topical Resiquimod, and Incidence and Clinical Management of Newly Diagnosed Symptomatic Disease

Abstract

Objectives: We sought to 1) characterize the frequency and duration of herpes simplex virus (HSV) oral and anogenital reactivation in both immunocompetent and HIV-infected adults, 2) determine whether topical resiquimod 0.01% gel, a toll-like receptor 7 and 8 agonist, has post-treatment efficacy in reducing time to first anogenital herpes recurrence, and 3) determine the incidence and clinical management of newly diagnosed symptomatic genital herpes in western Washington. Methods: 1) Twenty-five HSV-2 seropositive and 18 HSV-1 seropositive healthy adults collected anogenital and oral swabs, respectively, and 20 HSV-2 seropositive, HIV seropositive adults, including 9 (45%) who were also HSV-1 seropositive, collected both anogenital and oral swabs, 4 times a day for 60 days. Samples were positive for HSV if we detected >= 150 copies of HSV DNA/mL of specimen. 2) Three phase III randomized, double-blind, vehicle-controlled trials of topical resiquimod 0.01% gel to reduce anogenital herpes recurrences were conducted in healthy adults with >= 4 recurrences within the prior year. 3) Surveillance data collected in King and Pierce Counties, Washington ware used to identify persons >= 18 years of age with newly diagnosed symptomatic genital herpes; patients and their clinicians were interviewed. Results: 1) Among immunocompetent and HIV-infected participants respectively, 24% and 29% of anogenital and 21% and 35% of oral reactivations lasted <= 6 hours, while 49% and 53% of anogenital and 39% and 59% of oral reactivations lasted <= 12 hours. The median maximum level of HSV DNA detected in an episode increased with episode duration for both oral and anogenital episodes in both immunocompetent and HIV-infected participants. 2) Median time to first recurrence was similar for resiquimod and vehicle treated participants in all three trials, while median time to healing of initial treated recurrence was longer for resiquimod. In two of the three trials, moderate to severe erythema and erosion/ulceration at the application site were more common in resiquimod recipients. 3) Incidence of newly diagnosed symptomatic genital herpes decreased with age and was almost 3 times higher in women than men and in Blacks than Whites. Patients reported condom use was discussed in 75% of clinical encounters, suppressive therapy in 69%, and suppressive therapy to decrease transmission in 39%; 30% reported taking suppressive therapy. Both discussion of suppressive therapy and discussion of suppressive therapy for transmission prevention were associated with suppressive therapy use (p<0.001 for both), as was a lesion culture or PCR positive for HSV-2 as opposed to HSV-1 (p=0.016). Conclusions: 1) Rapidly cleared episodes of oral and anogenital HSV shedding occur in both immunocompetent and HIV-infected hosts, strongly suggesting that the peripheral mucosal immune system plays a critical role in clearing HSV reactivations and illuminating how frequent anogenital mucosal immune activation caused by HSV-2 could contribute to increased risk of HIV acquisition and transmission. 2) No post-treatment efficacy of resiquimod 0.01% gel was observed, while increased application site reactions and initial recurrence healing time are consistent with resiquimod-induced cytokine effects. 3) Although clinicians usually discuss condoms and suppressive therapy with patients diagnosed with genital herpes, only a minority discuss suppressive therapy to prevent transmission and only 30% of patients take suppressive therapy, suggesting that suppressive therapy may be an underutilized tool for HSV-2 transmission prevention.