Imiquimod: An Immune Response Modifier

ABSTRACT

Imiquimod cream 5% (Aldara®, 3M Pharmaceuticals) was approved by the FDA February, 1997 for the treatment of external genital and perianal warts/condyloma acuminata in adults. Anogenital warts are very common, sexually transmitted, virally induced tumors that although benign themselves, have been associated with the development of squamous cell carcinoma, particularly cervical carcinoma.¹ 

Key Words: genital, perianal, warts, condyloma

Imiquimod is an immune response modifier. Studies have shown that it has potent immunomodulatory effects and stimulates human peripheral mononuclear cells to release interferon alpha, sub-types α1,α2, α5, α6, and α8. It also induces monocytes and macrophages to produce other cytokines including interleukins 1, 6, 8 and tumor necrosis factor α.² The clinical relevance of these findings is not fully understood.

Imiquimod’s advantages

• Low recurrence rate.
• Self-application.
• Limited systemic effects and only mild (rarely moderate) local inflammation.

Previously available treatments (e.g. cryotherapy, laser vaporization, electrocautery and excision) for anogenital warts are often painful and expensive. Local therapy with podophyllin, or podophyllotoxin or trichloracetic acids, requires multiple applications, is slow acting and often causes problems associated with local inflammation.¹ 5-Fluorouracil, although sometimes used for external anogenital warts, is not yet approved for this indication, has neither antiviral nor immunomodulatory effects, earlier formulations were irritating and intralesional injections are painful.^3,4 Unfortunately, recurrence often follows cessation of treatment following the use of these therapies.¹

Recent reports suggest that multiple injections of interferon alpha produce clearance rates of 36 – 62% and are well tolerated locally; however, such treatments are time-consuming, expensive and are associated with systemic side effects.^5,6

Efficacy

In early multicenter, double-blind, dose-ranging, vehicle controlled clinical trials, imiquimod 5% has proven effective in treating anogenital warts. In 311 patients, imiquimod 5% three times weekly completely cleared warts in 50% of patients, compared to 11% clearance in patients treated with the vehicle (p < 0.0001, intent-to-treat analysis). In a subsequent trial, daily application of the 5% cream completely cleared the warts of 52% of patients compared to 3% clearance of warts in patients using the vehicle alone (p < 0.0001, intent-totreat analysis). In these two trials, following cessation of treatment, wart recurrence rates were 13% and 19% respectively.⁷

Combination treatment, using this new topical immunomodulator, imiquimod, and ablative destructive therapy, is currently under study.⁸ Although results are not available, it seems logical to combine imiquimod with an ablative therapy so that imiquimod could induce an immune response which has the potential to affect the virus, eliminate residual lesions, and possibly reduce recurrence rates.

Side Effects

The trials discussed above revealed that erythema and increased skin irritation was the most common reaction and was severe in 4% of both male and female patients treated three times weekly.⁹ Other adverse events reported by more than 1% of patients include fatigue, fever, influenza like symptoms, headache, diarrhea, myalgia and fungal infections.⁹

Safety During Pregnancy & Lactation

There are no adequate and well controlled studies in pregnancy and it is not known whether topically applied imiquimod is excreted in breast milk.

Pharmacokinetics

Percutaneous absorption was minimal (less than 0.9%) following a single dose, topical application of 5 mg of imiquimod to the skin of six healthy volunteers.

Dosage and Administration of Imiquimod

Prior to retiring, a thin layer of the cream is applied to the wart area, rubbed in until cream is no longer visible, left on the skin overnight and then in the morning washed off with mild soap and water. Hands should be washed before and after being used to apply the cream. The anogenital warts should be treated three times per week. For those patients who respond, clearance of warts requires on average 8 weeks for female patients and 12 weeks for male patients.

Patient Information

• Local skin reactions are common but are usually mild to moderate in severity. Severe skin reactions should be reported to the physician promptly.
• Do not occlude the treatment area. Uncircumcised males treating warts under the foreskin should clean the area daily.
• The cream is for external use. Avoid contact with the eyes. Avoid sexual (genital, anal, oral) contact while the cream is on the skin.
• Imiquimod cream may weaken condoms and vaginal diaphragms and should not be used concurrently.

Clinical Assessment

Imiquimod has not yet been compared to any other treatment for anogenital warts. Podophyllin, the most frequently used topical treatment, is not a standardised preparation¹⁰, has an unknown shelf life¹⁰, contains potentially carcinogenic mutagens and has no known antiviral/immunomodulatory activity. Imiquimod has no mutagenic activity, is immunomodulatory/antiviral and would appear to be the drug of choice³ for multiple warts when cryotherapy is inappropriate and cost is not a problem.

Imiquimod’s place in therapy:

• Imiquimod provides a new and practical treatment option to previously available treatments.¹⁰
• First line therapy^{3, 8} for patients who do not demand immediate removal of warts — it takes as long as eight weeks and sometimes longer to achieve clearance of warts.
• Alternative therapy for persons who have failed another first line treatment and who have experienced recurrences of genital warts.
• A potential component of combination therapy for patients with large/multiple warts.⁸ The immune response engendered by imiquimod may affect the virus, eliminate residual lesions, and possibly reduce recurrence rates.
• Applying imiquimod three times per week costs the patient approximately US $100 per month for the cream.

Preliminary clinical data suggests that this new treatment approach utilizing imiquimod to treat external genital and perianal warts/condyloma can be justified on phamacoeconomic grounds.
Dr. Stephen Tyring, Galveston, Texas.

This review was prepared by Rodger Hall, Vancouver.

References

1. Edwards L, Ferenczy A, Eron L. Self-administered 5% imiquimod cream for external anogenital warts. Arch Dermatol. In press.
2. Megyeri K, Au WC, Rosztoczy I et al. Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. Molecular and Cellular Biology 1995; 15: 2207-2218.
3. Tyring SK. Personal communication. August 1997.
4. Krebs Hans-B. Treatment of genital condylomata with topical 5-fluorouracil. Dermatol Clin 1991; 9: 333-341.
5. Eron SJ, Judson F, Tucker S et al. Interferon therapy for condyloma acuminata. N Eng J Med 1986; 315: 1059-1064
6. Friedman-K ein AE, Eron LJ, Conant M et al. Natural interferon alfa for treatment of condyloma acuminata. JAMA. 1988; 259: 533-538.
7. Edwards L, Beutner K, Tyring S et al. Comparison of results from two vehicle controlled clinical trials evaluating topical imiquimod for the treatment of genital/perianal warts. Clinical Dermatology 2000, Vancouver, British Columbia, May 28-31, 1996.
8. Sauder DN. Personal communication. August 1997.
9. Physician Packet Insert.
10. Beutner KR. Personal communication. October, 1997.