Imiquimod is used topically for the treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on the face or scalp in immunocompetent adults; treatment of biopsy-confirmed, primary superficial basal cell carcinoma in immunocompetent adults; and treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by human papillomavirus (HPV). Imiquimod has not been evaluated in controlled clinical studies for the topical treatment of verruca vulgaris (common warts). Although imiquimod has been used topically for the treatment of molluscum contagiosum, safety and efficacy have not been established.
Imiquimod is used for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on the face or scalp in immunocompetent adults.
Safety and efficacy of topical imiquimod for the treatment of actinic keratosis have been evaluated in 2 double-blind, vehicle-controlled studies that included 436 adults with actinic keratosis (4-8 clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic lesions within a contiguous area no larger than 25 cm occurring on either the face or scalp). Patients were randomized to receive topical imiquimod 5% cream or vehicle placebo twice weekly for 16 weeks, and clinical response was evaluated 8 weeks after the last dose. Complete clearance was defined as no visible actinic keratosis lesions in the treatment area, with clearance of baseline lesions as well as any new or subclinical lesions that appeared during treatment. Complete clearance occurred in 44-46% of patients treated with imiquimod compared with 3-4% of patients treated with placebo. There was partial clearance of actinic keratosis lesions (clearance of at least 75% of baseline lesions) in 58-60% of those treated with imiquimod compared with 10-14% of those treated with placebo. During treatment, 48% of patients had an increase in the number of actinic keratosis lesions in the treatment area relative to baseline; this did not affect the response to treatment.
In one randomized, double-blind, vehicle-controlled study in adults with a histologic diagnosis of multiple actinic keratoses, topical imiquimod (3 times weekly for up to 12 weeks) resulted in clinical clearance of lesions in 84% and partial clearance of lesions in 8% of patients; clearance of lesions was histologically confirmed 2 weeks after the last application of imiquimod. There was no reduction in size or number of actinic keratosis lesions in patients who received placebo.
Basal Cell Carcinoma
Imiquimod is used for the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma in immunocompetent adults. Safety and efficacy of the drug have not been established for the treatment of any other type of basal cell carcinoma, including nodular and morpheaform (fibrosing or sclerosing) types.
Topical imiquimod should be used for the treatment of superficial basal cell carcinoma only when the diagnosis has been confirmed histologically, the tumor diameter is 2 cm or less, the tumor is located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), and surgical methods are medically less appropriate and patient follow-up can be reasonably assured. Safety and efficacy of imiquimod for the treatment of superficial basal cell carcinoma that occurs on the face, head, or anogenital area have not been established.
In 2 double-blind, vehicle-controlled studies in 364 adults with primary superficial basal cell carcinoma (biopsy-confirmed tumors with a minimum area of 0.5 cm and a maximum diameter of 2 cm), patients were randomized to receive topical imiquimod 5% cream or vehicle placebo 5 times weekly for 6 weeks. Efficacy was assessed 12 weeks after the last dose and a complete response was defined as the proportion of patients with clinical (visual) and histologic clearance of the superficial basal cell carcinoma lesion. At 12 weeks after treatment, 75% of those treated with imiquimod had clinical and histologic clearance compared with 2% of those treated with placebo. Long-term follow-up of those with no clinical evidence of superficial basal cell carcinoma 12 weeks after treatment indicate that 84% still had clinical clearance 1 year later and 79% still had clinical clearance 2 years later.
Human Papillomavirus Infections
External Genital and Perianal HPV Warts
Imiquimod is used for the topical treatment of external genital and perianal HPV warts. Safety and efficacy of topical imiquimod for the treatment of urethral, intravaginal, cervical, rectal, or anal HPV warts have not been established. Some clinicians suggest that use of the drug may be considered for the treatment of distal meatal HPV warts; however, data are limited. Imiquimod should not be used to treat subclinical genital HPV infection (without exophytic warts).
Regimens recommended by the US Centers for Disease Control and Prevention (CDC) and others for the treatment of external genital and perianal exophytic HPV warts are topical therapies for self-administration (imiquimod 5%, podofilox 0.5%); topical therapies that must be administered by a health-care provider (podophyllum resin 10-25%, trichloroacetic acid [TCA] 80-90%, bichloroacetic acid [BCA] 80-90%); or surgical techniques (cryotherapy, electrosurgery, surgical excision). Alternative regimens include intralesional interferon alfa or laser surgery. The CDC and others recommend that selection of therapy for the treatment of exophytic warts be guided by the preference of the patient, available resources, experience of the health-care provider, factors related to the warts (e.g., size, number, morphology, anatomic site involved), and factors related to the therapy (e.g., cost, convenience, adverse effects). There is some evidence that warts located on moist surfaces and/or in intertriginous areas appear to respond better to topical treatments (e.g., imiquimod, podofilox, podophyllum resin, TCA) than warts on drier surfaces; however, there is no clear evidence that any one therapy is superior to any other therapy and no single treatment is ideal for all patients or all warts. Overly aggressive treatment should be avoided and the risks versus benefits of the therapy selected should be evaluated throughout treatment; therapy should be changed if the desired response is not obtained.
The primary goal of treating exophytic genital and perianal HPV warts is the destruction or clearance of visible, symptomatic warts. Most patients have fewer than 10 genital warts with a total wart area of 0.5-1 cm, and treatment with recommended regimens generally can induce wart-free periods. Without treatment, exophytic genital and perianal HPV warts may spontaneously regress, remain unchanged, or increase in size or number becoming painful and a source of psychological trauma. No currently available therapy for exophytic genital and perianal warts, including imiquimod, has been shown to eradicate HPV (i.e., produce a virologic cure) or affect the natural history of HPV infection. In addition, while there is some evidence that exophytic warts play a role in transmission of HPV to sexual partners, it is unclear whether treating these warts has any effect on transmission of the virus. Existing data indicate that currently treatment regimens may reduce, but probably do not eradicate, infectivity. It is unclear whether reduction in viral DNA following treatment impacts future transmission of the virus. HPV apparently may establish one or more sites of latent infection following primary infection with the virus. Despite the use of therapies that effectively result in the destruction or clearance of exophytic HPV warts, latent or subclinical HPV infection can persist and recurrence of visible warts commonly occurs.
Exophytic genital and perianal warts generally are caused by HPV types 6 or 11. Other HPV types (e.g., types 16, 18, 31, 33, 35) sometimes are present in the anogenital region, may be present in visible warts, and have been strongly associated with vaginal, anal, and cervical intraepithelial dysplasia and squamous cell carcinoma. Individuals with visible genital warts often are infected simultaneously with multiple HPV types. Because HPV genital and perianal warts have a characteristic appearance, biopsy to confirm the diagnosis generally is necessary only if the diagnosis is uncertain, warts do not respond to standard therapies, the disease worsens during therapy, the patient is immunocompromised, and/or warts are pigmented, indurated, fixed, and ulcerated. Tests for detecting HPV DNA are widely available, but the clinical usefulness of these tests in the routine diagnosis or management of visible genital or perianal warts has not been determined.
Follow-up visits are not required for patients self-administering treatment but may be useful several weeks after initiation of therapy to determine the response to treatment and to monitor for and treat complications of therapy. If visible genital and perianal warts have cleared after treatment, follow-up examination is not mandatory; however, a follow-up evaluation 3 months after treatment may be beneficial since external genital warts can be difficult to identify. Earlier follow-up visits may benefit certain patients by providing the clinician the opportunity to document the absence of warts, monitor for and treat complications of therapy, and provide additional patient education and counseling. Patients should be cautioned to watch for recurrences and advised that such recurrences occur most frequently during the first 3 months. Examination of sexual partners is not necessary for the management of genital HPV warts because no data indicate that reinfection plays a role in recurrences and, in the absence of curative therapy, treatment to reduce transmission is not realistic. However, sexual partners of patients with genital HPV warts may benefit from examination to assess the presence of HPV warts or other sexually transmitted diseases and also may benefit from counseling about the implications of having a partner who has HPV warts. Women with genital HPV warts should be advised to undergo regular Papanicolaou (Pap) tests as recommended for women without genital warts.
Safety and efficacy of topical imiquimod for the treatment of external genital and perianal warts have been evaluated in several double-blind, placebo-controlled studies in otherwise healthy adults 18 years of age or older. In a phase III study in adults who had biopsy-confirmed external genital and/or perianal HPV warts, patients were randomized to receive imiquimod 5% cream, imiquimod 1% cream (not commercially available), or vehicle placebo 3 times weekly for up to 16 weeks. At the end of 16 weeks, results of the intent-to-treat analysis indicated that there was complete clearance of visible warts in 50% of those who received imiquimod 5% cream, 21% of those who received imiquimod 1% cream, and 11% of those who received vehicle placebo. Results of the treatment failures analysis indicated that complete clearance of visible warts occurred in 56% of those who received imiquimod 5% cream, 27% of those who received imiquimod 1% cream, and 14% of those who received vehicle placebo; there was a 50% or greater reduction in total wart area in 81, 41, or 31% of patients, respectively. Warts generally cleared within 8-12 weeks. The clearance rate was higher and the median time to complete wart clearance was shorter in females than in males; this difference may be due to differences in keratinization of wart tissue. Based on the treatment failures analysis, there was complete clearance of visible warts in 77% of females and 40% of males receiving imiquimod 5% cream. Of those patients who had complete clearance of warts during imiquimod therapy and who were available for a 12-week follow-up, 13% had a recurrence of at least one wart; there was no gender-related difference in recurrence rates.
Imiquimod 5% cream has been used for the topical treatment of external genital and perianal HPV warts in a limited number of adults with human immunodeficiency virus (HIV) infection; however, the response rate appears to be lower in these individuals than in those who are not HIV infected.
(See Cautions: Precautions and Contraindications.)In a phase I, double-blind, vehicle-controlled study in HIV-infected patients 18 years of age or older, results of the intent-to-treat analysis indicated that 11% of those who received imiquimod and 6% of those who received placebo had complete clearance of warts. In addition, adverse effects reported in this patient population (e.g., mild to moderate local reactions including erythema) were similar to those reported when the drug is used in otherwise healthy adults with HPV warts.
For the treatment of external HPV warts in HIV-infected adults and adolescents, the CDC, National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) generally recommend a patient-applied topical therapy (imiquimod 5%, podofilox 0.5%) for uncomplicated lesions and a topical therapy administered by a health-care provider (podophyllum resin 10-25%, TCA, BCA) or a surgical technique (cryotherapy, electrosurgery, surgical excision) for complex or multicentric lesions or those that are inaccessible to patient-applied treatments. Although topical agents (podofilox 0.5%, imiquimod 5%, podophyllum resin, TCA 80-90%) are recommended as alternatives for the treatment of HPV warts in HIV-infected children, the CDC, NIH, and IDSA state that topical therapy often is ineffective in these patients and use of a surgical technique (cryotherapy, electrosurgery) may be preferred.
Topical imiquimod has been effective when used in a limited number of adults and children for the treatment of molluscum contagiosum. However, safety and efficacy for treatment of molluscum contagiosum have not been established. Results of 2 randomized, double-blind, vehicle-controlled studies in 702 children 2-12 years of age with molluscum contagiosum indicate that topical imiquimod (3 times weekly for up to 16 weeks) is no more effective than placebo in these patients.
Molluscum contagiosum generally is a benign, cutaneous viral infection characterized by discrete, smooth-surfaced, pearly pink or white, papular skin lesions that may have a central umbilication. While these lesions may resolve spontaneously in immunocompetent individuals, they can become widespread as a result of scratching (especially in children) and the infection tends to be more severe in individuals who have eczema or are immunosuppressed, including those with HIV infection. Molluscum contagiosum can be transmitted through direct contact (e.g., skin-to-skin contact, sexual contact) and by fomites such as towels.