Treatment of Anogenital Warts

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

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.

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.

Detailed Findings of This Study Can be Found Indexed by the US National Library of Medicine and PubMed

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.

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

Wart Treatment by Type of Wart

Treatment will depend in part on the location, the age of the patient, as well as the size and immune status of the individual. The treatment choice will depend in part on previous experience of the patient and the patient’s preference. Many of the treatments can be uncomfortable and therefore difficult to use in children.

Treatments can be either destructive as in the use of liquid nitrogen or most recently there is an immunological approach to boost the patient’s own immune system.

Common Warts

Liquid nitrogen cryotherapy is most commonly used in those who can tolerate the pain. Repeat treatments are frequently required. Excising or scraping off these warts is less desirable as it will scar. The use of pulse dye laser or very occasionally the Co2 laser can be used in resistant lesions. Cantharone can be used particularly in children as it is more easily tolerated. Other treatments involve the use of immune therapy. Substances such as DNCB involve painting the substance on the warts in order to develop an allergic reaction. This immune allergic reaction will be useful for destroying the wart.

Flat Warts

Flat warts frequently occur on the face and on the legs. Care needs to be taken not to use a treatment that will have a high risk of scarring. Very light liquid nitrogen cryotherapy can be used.

It is important that shaving is done very carefully or is stopped for a while as this is known to spread these warts. Treatments such as Aldara have been used. Topical treatments such as vitamin A acids (Tretinoin) can sometimes be of benefit. Efudex cream has also been used.

Plantar Warts

Plantar warts can be stubborn. Because of their location aggressive use of liquid nitrogen cryotherapy is difficult in that it can not only be painful but swelling and soreness can prevent walking for a number of days. Often paring the warts by thinning them down can be helpful. The use of salicylic acid preparations that are applied daily and cover the affected area will eat away at the surface of the wart allowing it to be pared down. This may make it more responsive to liquid nitrogen. The use of duct tape to soften the lesions in some individuals can be in itself curative. It appears that changing the water content and making the skin mushy enhances the patient’s ability to eradicate these warts. Treatments such as surgery and scraping of these warts is discouraged as scars can sometimes be painful on the weight-bearing parts of the foot. The pulse dye laser can be used once the wart has been thinned as it does not produce scarring. Occlusion combining these therapies with Aldara cream in some individuals is helpful.

Genital Warts

Genital warts are usually sexually transmitted. It is important that woman be checked to rule out any atypical changes on the cervix. Small warts can be treated with liquid nitrogen although this is uncomfortable. Podophyllin or podophyllotoxin can be applied every few days and this can be helpful.