Safety, Efficacy & Recurrence Rates of Imiquimod Cream 5% for Treatment of Anogenital Warts

M.L. Diamantis, BS¹; B.L. Bartlett, MD²; S.K. Tyring, MD, PhD³
1. The University of Texas Medical School at Houston, Houston, TX
2. Center for Clinical Studies, Houston, TX
3. The University of Texas Health Science Center at Houston and Center for Clinical Studies, Houston, TX

ABSTRACT

Imiquimod 5% cream (Aldara™, Graceway Pharmaceuticals) is an immune response modifier used for the topical treatment of anogenital warts in non-HIV-infected patients. Several randomized controlled trials have demonstrated that imiquimod 5% cream is a safe and efficacious treatment. Current data regarding efficacy shows that complete clearance of warts occurred in up to 50% of patients treated with imiquimod 5% cream applied once-daily, 3 times per week for up to 16 weeks. Recurrence rates ranged from up to 19% at 3 months to 23% at 6 months. Imiquimod 5% cream showed an acceptable safety profile; local inflammatory reactions were the most frequent adverse effects, with local erythema being the most common.

Key Words: anogenital warts, HPV, human papillomavirus, imiquimod

Imiquimod is an immune response modifier that was approved by the US FDA in 1997 for the topical treatment of anogenital warts in individuals 12 years old and older. An estimated 30%-50% of sexually active adults in the US are infected with human papillomavirus (HPV), and approximately 1%-2% of this same population have clinically evident genital warts.¹ This review will focus on studies that evaluate the safety, efficacy, and recurrence rates of imiquimod 5% cream in the treatment of anogenital warts in non-HIV-infected men and women. Local inflammatory reactions were the most frequent adverse effects, with local erythema being the most common. Overall, imiquimod 5% cream is a safe and efficacious treatment for anogenital warts.

Using Imiquimod

Imiquimod cream is supplied in individual packets. Each gram of the 5% cream contains 50mg of imiquimod in an off-white oil-in-water vanishing cream base.² The US Center for Disease Control recommends that imiquimod 5% cream be applied once daily at bedtime, 3 times per week for up to 16 weeks. The product should be washed off with mild soap and water 6-10 hours following application.^2-4 Many considerations exist when using imiquimod. Some of these are listed in Box 1. The US FDA provides a full list of considerations.³

Mechanism of Action

Imiquimod is a Toll-like receptor agonist that induces the production of local cytokines from predominantly T helper (Th) 1-type cells, thus stimulating both acquired and cellular immunity, which is important for fighting virus-infected and tumor cells.^5-7 Cytokines such as interferon (INF)-á, tumor necrosis factor (TNF)-á, interleukin (IL)-1, -6, -8, -10, and -12 stimulate tissue-specific apoptosis of virus-infected keratinocytes, thus leading to a viral load reduction of HPV types 6 and 11 with subsequent wart regression and normalization of keratinocyte proliferation.^5,6,8 Regression of warts after treatment with imiquimod is strongly associated with evidence of tissue production of INF-á, -â, and -ã and TNF-á as well as a decrease in the presence of HPV DNA and in the expression of mRNA for both early and late viral proteins.⁹

Safety

In all the randomized controlled trials (RCTs) examined, topical imiquimod 5% cream showed an acceptable safety profile. Local skin reactions are associated with a local inflammatory reaction including itching, erythema, burning, irritation, tenderness, ulceration, erosion, and pain.¹⁰ In several studies, local erythema was the most common reaction.^11-13 There were no differences in adverse systemic reactions or flu-like symptoms among treatment groups.^10,12,13 The optimal dosing regimen is 3 times per week. With more frequent applications (up to 3 times daily), wart clearance does not improve significantly and is associated with an increase in local adverse events, such as erythema, vesicle formation, ulceration, and excoriation.¹⁴ Imiquimod 5% cream is effective for up to 16 weeks of treatment for external anogenital warts and is well-tolerated for up to 32 weeks.¹¹ Imiquimod is contraindicated in individuals with a history of sensitivity reactions to any of its components and should be discontinued if hypersensitivity to any of its ingredients is noted. Overall, patient-applied imiquimod 5% cream is an effective treatment for external genital warts and has a favorable safety profile.

Efficacy and Recurrence

Several randomized controlled trials demonstrated that imiquimod 5% cream is an efficacious treatment for external anogenital warts when applied 3 times per week for up to 16 weeks. Complete clearance of warts occurred in up to 50% of patients treated with imiquimod 5% cream applied 3 times daily. At the end of 16 weeks, recurrence rates ranged from up to 19% after 3 months and 23% after 6 months.11 See Table 1 for comparisons. The recurrence rates of external genital warts were found to be similar at both 3- and 6-month follow-up, suggesting that after 3 months, the risk of developing recurrence is low.¹⁵

The studies that follow were chosen to evaluate imiquimod 5% cream for the treatment of anogenital warts because of sufficient data on efficacy, recurrence rates, and safety.^10-13 Studies that did not include this data were excluded. Several other studies focused on the treatment of anogenital or vulvar warts in the female population; however, the efficacy rates are generally higher for this population, ranging from 71%-77%.^12,16-18 To maintain continuity, this review focuses on comparing studies that include treatment of anogenital warts with imiquimod 5% cream in non-HIV-infected men and women.

Study	# Patients Receiving Imiquimod 5% Cream	Dosing Interval	Complete Clearance Rate	Length of Treatment	Recurrence Rates After Treatment
Beutner, Spruance et al.10	108	3 times/week	37%	8 weeks	19% at 10 weeks
Garland et al.11	943	3 times/week	47.8%	16 weeks	8.8% at 3 months 23% at 6 months
Edwards et al.12	109 / 311	3 times/week	50%	16 weeks	13% at 3 months
Beutner, Tyring et al.13	94 / 279	Once daily	52%	16 weeks	19% at 3 months
Table 1: Comparison of studies involving imiquimod 5% cream for treatment of anogenital warts

Beutner, Spruance et al.¹⁰

In a prospective, double-blind, placebo-controlled, clinical trial with 108 patients, imiquimod 5% cream was applied 3 times daily for up to 8 weeks. Complete wart clearance was achieved in 37% of the imiquimod-treated patients and 0% of the placebo group. Many patients experienced a partial response: an 80% or more reduction in baseline wart area was achieved in 62% of imiquimod-treated patients versus a 4% reduction in the placebo group. A 50% reduction in baseline wart area was noted in 76% of imiquimod-treated patients compared with 8% of the placebo group. For patients whose warts cleared completely, 19% experienced recurrences after a 10-week follow-up period. There were no differences in systemic reactions between treatment groups. Local inflammatory reactions were predominantly mild or moderate in severity and included itching (54%), erythema (33%), burning (31%), irritation (17%), tenderness (13%), ulceration (10%), erosion (10%), and pain (8%).

Garland et al.¹¹

In an open-label phase IIIB trial consisting of 943 patients in 20 countries, imiquimod 5% cream applied 3 times per week was found to be 47.8% effective for overall complete clearance after 16 weeks of treatment. Recurrence rates at the end of 3- and 6-month follow-up were 8.8% and 23%, respectively. The sustained clearance rates (patients who cleared during treatment and remained clear at the end of the follow-up period) after 3 and 6 months were 41.6% and 33%, respectively. The study also found that a greater proportion of female patients (75.5%) experienced complete clearance than did male patients (56.9%). At least 1 adverse event was reported in 42% of patients; the majority of reactions were mild to moderate in severity. Local erythema was the most common local skin reaction, occurring in 67% of patients.

Edwards et al.¹²

Another RCT consisting of 311 patients was randomized to 3 arms: imiquimod 5% cream, imiquimod 1% cream, or vehicle 3 times per week for a maximum of 16 weeks. Complete clearance of lesions was achieved in 50% of patients who received the imiquimod 5% cream, 21% of those who received imiquimod 1% cream, and 11% of those treated with the placebo. After a 3-month follow-up, the study found a recurrence rate of at least 1 wart in 13% of patients who receive imiquimod 5% cream. The majority of patients experienced no or mild local inflammatory reactions, with local erythema being the most common. Local adverse reactions, which were moderate or severe in intensity after being treated with imiquimod 5% cream, included erythema (40%), erosion (10%), excoriation (7%), edema (2%), and scabbing (5%).

Beutner, Tyring et al.¹³

In another prospective, multicenter, double-blind, RCT with 279 patients, 94 patients used imiquimod 5% cream once-daily for up to 16 weeks. Complete wart clearance was achieved in 52% of patients treated with imiquimod 5% cream, but 19% of these patients had a recurrence at a 3-month follow-up. These results are similar to those obtained with 3 applications per week. When patients were treated with 5% imiquimod cream vs. vehicle, local adverse reactions included erythema (66% vs. 9%), excoriation (21% vs. 4%), erosion (32% vs. 1%), edema (18% vs. 1%), scabbing (18%), induration (5%), ulceration (10%), and vesicles (3%).

Support for Comparable Efficacy in Clearance Rates After 3 Weeks

Garland et al.¹¹ found that a 1-month treatment course of imiquimod 5% cream applied 3 times weekly for women with external genital warts has comparable efficacy to a 4-month treatment with no statistically significant difference in complete clearance rates (i.e., 40% after 1 month and 51.6% after 4 months). The 1-month treatment had a lower incidence of local skin reactions, such as erythema, and no pain.¹⁸

Monotherapy Compared with Combination Therapy: Imiquimod + Surgery

Carrasco et al.¹⁹ showed that treatment with imiquimod 5% cream followed by excision of remaining warts resulted in a lower recurrence rate compared with surgery alone. This strategy represents a viable option for those with residual lesions and may provide long-term clearance of anogenital warts in patients for whom imiquimod monotherapy is insufficient.¹⁹

Conclusion

Patient-applied imiquimod 5% cream is a first-line topical treatment for anogenital warts that is both safe and efficacious, and yields complete and partial responses in the majority of patients. Various studies demonstrate complete clearance rates of up to 50% and partial responses manifest as a 50%-90% reduction in baseline wart area.^12-14 Recurrence rates range up to 19% at 3 months and 23% at 6 months. More studies are needed to compare the efficacy of combination therapies vs. monotherapy vs. other treatment modalities. Longer follow-up is also needed to evaluate recurrence rates after monotherapy, as well as in combination with other treatments for anogenital warts.

References

1. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 102(5A):3-8 (1997 May 5).
2. Chang YC, Madkan V, Cook-Norris R, et al. Current and potential uses of imiquimod. South Med J 98(9):914-20 (2005 Sep).
3. US FDA. Aldara (Imiquimod) Cream 5%. http://www.fda.gov/Cder/foi/label/2004/20723se1-015_aldara_lbl.pdf. Last accessed May 2009.
4. Scheinfeld N, Lehman DS. An evidence-based review of medical and surgical treatments of genital warts. Dermatol Online J 12(3):5 (2006 Mar).
5. Tyring SK, Arany II, Stanley MA, et al. Mechanism of action of imiquimod 5% cream in the treatment of anogenital warts. Prim Care Update Ob Gyns 5(4):151-2 (1998 Jul).
6. Berman B, Sullivan T, De Araujo T, et al. Expression of Fas-receptor on basal cell carcinomas after treatment with imiquimod 5% cream or vehicle. Br J Dermatol 149 (Suppl 66):59-61 (2003 Nov).
7. Schiller M, Metze D, Luger TA, et al. Immune response modifiers--mode of action. Exp Dermatol 15(5):331-41 (2006 May).
8. Lacarrubba F, Nasca MR, Micali G. Advances in the use of topical imiquimod to treat dermatologic disorders. Ther Clin Risk Manag 4(1):87-97 (2008 Feb).
9. Tyring SK, Arany I, Stanley MA, et al. A randomized, controlled, molecular study of condylomata acuminata clearance during treatment with imiquimod. J Infect Dis 178(2):551-5 (1998 Aug).
10. Beutner KR, Spruance SL, Hougham AJ, et al. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol 38(2 Pt 1):230-9 (1998 Feb).
11. Garland SM, Sellors JW, Wikstrom A, et al. Imiquimod 5% cream is a safe and effective self-applied treatment for anogenital warts--results of an open-label, multicentre Phase IIIB trial. Int J STD AIDS 12(11):722-9 (2001 Nov).
12. Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus. Arch Dermatol 134(1):25-30 (1998 Jan).
13. Beutner KR, Tyring SK, Trofatter KF, Jr., et al. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother 42(4):789-94 (1998 Apr).
14. Fife KH, Ferenczy A, Douglas JM, Jr., et al. Treatment of external genital warts in men using 5% imiquimod cream applied three times a week, once daily, twice daily, or three times a day. Sex Transm Dis 28(4):226-31 (2001 Apr).
15. Vexiau D, Decuypère L, Moyse D, et al. [Efficacy and safety of 5% imiquimod cream in external genital warts: a 6 month follow-up evaluation]. Ann Dermatol Venereol 132(11 Pt 1):845-51 (2005 Nov).
16. Haidopoulos D, Diakomanolis E, Rodolakis A, et al. Safety and efficacy of locally applied imiquimod cream 5% for the treatment of condylomata acuminata of the vulva. Arch Gynecol Obstet 270(4):240-3 (2004 Dec).
17. Buck HW, Fortier M, Knudsen J, et al. Imiquimod 5% cream in the treatment of anogenital warts in female patients. Int J Gynaecol Obstet 77(3):231-8 (2002 Jun).
18. Garland SM, Waddell R, Mindel A, et al. An open-label phase II pilot study investigating the optimal duration of imiquimod 5% cream for the treatment of external genital warts in women. Int J STD AIDS 17(7):448-52 (2006 Jul).
19. Carrasco D, vander Straten M, Tyring SK. Treatment of anogenital warts with imiquimod 5% cream followed by surgical excision of residual lesions. J Am Acad Dermatol 47(4 Suppl):S212-6 (2002 Oct).

In this issue:

1. Safety, Efficacy & Recurrence Rates of Imiquimod Cream 5% for Treatment of Anogenital Warts
2. Prevention of Infrared-A Radiation Mediated Detrimental Effects in Human Skin
3. Update on Drugs and Drug News - June 2009