Imiquimod 5-Percent Cream Does Not Alter the Natural History of Recurrent Herpes Genitalis: a Phase II, Randomized, Double-Blind, Placebo-Controlled Study

Abstract

Present strategies for control of herpes genitalis recurrences require multiple daily doses of antiviral medication. Imiquimod, an immune response modifier, induces alpha interferon and interleukin-12; application in the presence of local herpes antigens during a recurrence may augment herpes simplex virus (HSV)-specific cell-mediated immunity. To test this theory, we performed a randomized, double-blind, placebocontrolled study of imiquimod 5% cream to assess safety and efficacy for decreasing recurrences. Patients with six or more recurrences of herpes genitalis per year applied study cream (imiquimod or placebo) to lesions one, two, or three times per week for 3 weeks for each recurrence during a 16-week treatment period. This was followed by a 16-week observation period. Of 124 patients randomized to the study, 103 completed the treatment period and 93 completed the observation period. The median times to first genital herpes recurrence were 53 days for those receiving placebo (n ‫؍‬ 30) and 54, 60, and 64 days for those receiving imiquimod one time per week (n ‫؍‬ 34), two times per week (n ‫؍‬ 32), and three times per week (n ‫؍‬ 28), respectively. The median annualized recurrence rates during the treatment period were 3.8, 4.9, 3.2, and 3.1, respectively. There were no statistically significant differences in the time to first recurrence or in the annualized recurrence rate between the imiquimod and placebo groups in either the treatment or the observation period. A trend in increased rates of local adverse events at the application site and a delay in lesion healing with more frequent dosing suggested a pharmacologic effect. Although clinical efficacy has been observed for imiquimod in other conditions in which a TH1-type immune response may be beneficial, including other viral infections such as those caused by human papillomavirus, no apparent effect on the short-term natural history of herpes genitalis recurrences was observed.

Evaluation of Imiquimod 5% Cream to Modify the Natural History of Herpes Labialis: A Pilot Study

“…Thus, it appears that induction of these proinflammatory cytokines exacerbated the preexisting inflammation, leading to significant increases in local reactions rather than reducing acute lesion severity through possible antiviral effects. This is consistent with the limited time that HSV can be recovered from recurrences of HSV infection, the presumed role of inflammation in lesion progression, and the apparent beneficial effects of anti-inflammatory molecules, such as topical corticosteroids, on the disease [24][25][26] Qualitatively, the local adverse events were similar to those observed after application of imiquimod 5% cream in other diseases, such as external anogenital warts, basal cell carcinoma, and herpes genitalis [16][17][18]27]. The local adverse effects, however, appeared to be more severe after application to herpes labialis lesion(s) than they were after application to herpes genitalis lesion(s), possibly as a result of differences in local penetration due to anatomical differences in skin [27].…”

The potential of immunostimulatory CpG DNA for inducing immunity against genital herpes: opportunities and challenges

“…However, latency once established could not be reversed by imiquimod. In a recent clinical trial, application of imiquimod 5% cream to lesions of patients with recurrent herpes genitalis had no apparent effect on the short-term natural history of herpes genitalis recurrences (Schacker et al, 2002).…”

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

“…A topical formulation of imiquimod is licensed for the treatment of genital and perianal warts caused by human papillomavirus (90). Topical application of imiquimod and resiquimod showed contradictory results in clinical trials evaluating their efficacy in the treatment of herpes labialis (17) and genital herpes (11,37,92,104,145,194,203). The TLR-3 agonist poly(I:C) induced innate-immune-mediated protection against genital HSV-2 infection in mice when administered intravaginally but not when administered systemically (6).…”