Brian Berman, MD, PhD1,2 and Joel Wolf, BA3
1Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
2Center for Clinical and Cosmetic Research, Aventura, FL, USA
3University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Imiquimod 3.75% cream has recently been approved by both the U.S. Federal Drug Administration and Health Canada for the treatment of external genital warts. Herein, we provide an overview of external genital warts, review the phase 3 clinical trials leading to the approval of imiquimod 3.75% cream, and compare its efficacy and clinical use with imiquimod 5% cream. Moreover, therapeutic options have further expanded with the relatively recent introduction of sinecatechins 15% ointment, an extract of green tea leaves.
condylomata acuminata, external genital warts, human papilloma virus, HPV, imiquimod, sinecatechins, sexually transmitted infection, STI, topical immunotherapy
External Genital Warts
External genital warts (EGW) have been reported to affect approximately 1.4 million people in the US.1 More than a half a million new cases develop annually and 10% of all adults will have EGW in their lifetime.1 The etiology of EGW has been clearly linked to infection with non-oncogenic strains (types 6 and 11) of the human papilloma virus (HPV) transmitted through sexual contact.1
EGW commonly manifest on fully or partially keratinized skin, such as the penis, vulva, groin, perineum, and perianal areas.2 While EGW can be asymptomatic, patients can experience pruritus, dyspareunia, and burning in the anogenital region. EGW can obstruct the urethral orifice and vagina, and impede normal activity. Additionally, large warts can cause obstruction of the anus and rectum.3
Besides physical pain and discomfort, EGW can cause complicated psychological morbidity. Since the disease targets areas of the genitalia and carries the psychosocial stigma of being a sexually transmitted infection, patients can experience a range of emotions, including anger, shame, depression, and low self-worth as potential partners.4-6 Additionally, the disease can impact the sexual activity of affected individuals, either through actual physiologic pain (in cases of dyspareunia) or through abstinence due to either fear of transmitting to partners or embarrassment of the lesions.7 Finally, EGW induces anxiety over treatment efficacy6,8 and/or recurrences,6 as well as the lesion’s potential to develop into a malignancy.6 The health and economic burden of EGW is significant, e.g., average number of care days per episode was approximately 96 in 2004.9 From 1999 to 2008 the average yearly number of initial physician office visits increased from 240,000 to 385,000.10
Although EGW spontaneously regresses 30%2,3 of the time without treatment, there is no way to determine whether a specific lesion will regress, remain unchanged, or increase in size. Treatment should be offered to all patients with EGW resulting from unprotected sexual contact or ineffective prophylactic measures (e.g., condoms, abstinence, or HPV vaccine). Treatment options are available including surgical excision, destructive modalities (e.g., cryosurgery and laser ablation), and topically applied preparations. It is not uncommon for multiple modalities to be used (e.g., excision/destruction with imiquimod). It is outside the scope of this paper to present a cogent review of all therapies, the discussion will instead focus on topically applied imiquimod 3.75%, which received recent regulatory clearance for the treatment of EGW.
Topical Immunotherapy for EGW
Imiquimod 3.75% cream (Zyclara®) is US FDA approved for the treatment of external genital (EGW) and perianal warts – it is marketed in Canada under the trade name Vyloma™ for EGW and Zyclara® for actinic keratoses. Imiquimod, an imidazoquinoline heterocyclic amine, demonstrates antiviral and antitumor properties that are thought to stem, at least in part, from its ability to induce interferon-α as shown in animal studies.11 Specifically, it is an agonist of Toll-like receptor-7 (TLR-7), a member of a pathogen-recognition receptor family.12 Activation of TLR-7 ultimately enhances antigen-presenting cell activity, migration of Langerhans cells, and cytokine (IFN-α, TNF-α, and IL-1, 6, 8, 10, and 12) release.13 Upregulation of IFN-α, β, and γ and TNF-α has a strong association with EGW regression, as well as with a reduction in human papilloma virus DNA and mRNA.13,14
Elicitation of these immunobiologic changes by imiquimod is not just theoretical. Imiquimod 3.75% was challenged in a clinical study against a vehicle control.12 Study inclusion criteria required patients to be >12 years of age with 2 to 48 visually diagnosed lesions. The wart size was at least a 6 mm2, measured by the two longest axes. The location of the warts included the penis, scrotum, vulva, and inguinal, perineal, or perianal regions. Assessment of treatment was based on number of warts, with a cluster of warts considered as 1 lesion. At each visit, the number of warts was tallied with no differentiation as to whether the lesion was a new growth or an older lesion that had decreased in size. The study was conducted for a maximum of 8 weeks or until complete clearance occurred. The primary endpoint of the study was complete clearance by the end of the study. Secondarily, the researchers observed the sustained complete clearance for a 12-week period. This latter parameter demanded the sustained complete clearance in all areas. Of notable mention, it is very possible that new warts arising very close to the end of the study may not have received any treatment. Resultantly, such patients would have failed to meet the primary endpoint of the study.12
Overall, the imiquimod 3.75% cream achieved 27% and 29% significant complete clearance in two different studies, compared with 10% and 9% complete clearance in the respective controls. Females, who for the most part exhibited better response over males, showed a significant complete clearance of 37% in the active treatment group compared to females in the vehicle control group, who demonstrated 14% complete clearance. In treated males, 19% achieved complete clearance as opposed to 4% of males in the control group. After a 12-week observation period of patients who had achieved complete clearance, 85% treated with imiquimod 3.75% cream remained clear.12
A recent study comparing imiquimod 3.75% with placebo in female EGW patients found similar results.15 The study group had a mean wart count of 8.7 with the total mean area of 166.3 mm2. Patients receiving imiquimod treatment demonstrated superior clearance over placebo; the median time to clearance was 57 days for imiquimod 3.75% compared with 71 days for placebo. Some other interesting variables that may have contributed to a higher complete clearance rate for imiquimod therapy over placebo include non-white patients, ≤7 warts, total wart area ≤150 mm2, diagnosis at ≤6 months, and first episode vs. recurrence. The researchers also looked at the ≥75% clearance and found that again imiquimod 3.75% exhibited greater efficacy compared with placebo. However, the sustained clearance during a 12-week follow up was only 60.4% in imiquimod-treated patients vs. 100% in placebo.
How does Zyclara® differ from Aldara®?
Imiquimod 5% cream (Aldara®) has been FDA approved for the treatment of EGW since 1997. While imiquimod 5% is efficacious for EGW treatment, it is associated with localized adverse effects, including erythema, pruritus, burning, and pain. The standard treatment course requires dosing at 3 times weekly for up to 16 weeks, which may discourage adherence to the regimen.16 Tolerance of burning and itching for close to 4 months in the anogenital areas can be challenging for patients to endure. A compounding complication is the cumbersome number of treatment days per week, potentially contributing to unintentional noncompliance due to forgetfulness, missed dosing, and confusion as to how to proceed when therapy deviates from the prescribed regimen. Treatment complexity can frustrate patients and contribute to premature termination of therapy. This thought process is confirmed by Murphy and Coster, who have noted that long treatment duration and adverse affects have been associated with decreased compliance.17 In addition, they suggest linking treatment times with daily habits as one of the strategies to increase compliance,17 which can be quite difficult if the regimen is 3 times per week.
Development of imiquimod 3.75% focused in part on increasing tolerability and simplifying the treatment regime. Investigation of the 3.75% formulation was undertaken with the intention of reducing the incidence and severity of local skin reactions commonly associated with imiquimod 5%. The total treatment period for imiquimod 3.75% is 8 weeks11 as opposed to 16 weeks for imiquimod 5% cream.16 The significantly reduced treatment duration and simplified once-daily application offers a more intuitive dosing regimen that can enhance patient adherence.
Another favorable aspect of imiquimod 3.75% that may encourage treatment compliance is its improved tolerability profile as compared with the 5% formulation. In the phase 3 trials, pruritus only occurred in 3% of all imiquimod 3.75% treated patients and irritation was experienced by 6%.12 Burning was not listed as an independent parameter.12 Similarly, Baker et al. reported pruritus in 7.8% of treatment patients and irritation in 5.5%.15 To put these findings into perspective, in patients treated with imiquimod 5%, pruritus was reported by 32% of female patients and 22% of males; burning was experienced by 26% of female subjects and 9% of males.16 Therefore, imiquimod 3.75% not only shortens a course of therapy by half, but it also demonstrates increased tolerability and dosing simplicity, thereby encouraging treatment follow-through and optimizing outcomes.
Sinecatechins (Green Tea Extract)
It is appropriate to briefly mention sinecatechins 15% ointment (Veregen®), the first botanical drug product approved by the FDA for the treatment of external genital and perianal warts. It contains sinecatechins, including epigallocatechin gallate, derived from green tea leaves. Sinecatechins 15% ointment is applied 3 times a day for up to 16 weeks.18 Two randomized, double-blind, vehicle controlled studies of both men and women with EGW reported an overall clearance rate of 54.9%; after 6 weeks of therapy, statistically significant differences in clearance rates were observed in patients receiving active treatment.18 The 12-week sustained clearance was 93.5% of fully cleared patients. Interestingly, the comparator vehicle group showed a complete clearance rate of 35.4% and a sustained clearance rate of 94.2%.
Insights into the possible mechanism(s) of action of sinecatechins in treating EGW were recently presented.19 In vitro experiments indicated inhibition of matrix metalloproteinase 1, 2, 7, and 9, as well as 20S proteasome activity. In addition, significant suppression of human epidermal growth factor receptor (EGFR) kinase and partial inhibition of extracellular signal-regulated kinases ERK-1 and ERK-2 were also implicated. Furthermore, suppression of inflammatory mediators COX-1 and COX-2 and the lipoxygenase (LO) 12 and 15 proteins were detected. These pathways are involved in the pathogenesis of HPV infection and epidermal proliferation, thereby leading the author to reasonably conclude that these inhibitory activities confer immunostimulant, antiviral, and antitumor properties to sinecatechins that contribute to EGW clearance.19
In our opinion, imiquimod 3.75% (Zyclara®/Vyloma™) offers a more tolerable and simplified therapeutic option for EGW patients to adhere to therapy. In addition, the recent US regulatory approval of this agent in a pump dispenser further widens the dosing options (established forms consist of individual packets of Aldara® and generic 5% imiquimod cream), such a vehicle advance can facilitate ease of use, improve patient acceptability, and enhance compliance. A study determining the combined effectiveness of sequential cryotherapy followed by a course of imiquimod 3.75% is warranted, as in clinical practice many patients, if not most, are treated with both modalities.
- Hsueh PR. Human papillomavirus, genital warts, and vaccines. J Microbiol Immunol Infect. 2009 Apr;42(2):101-6.
- Wiley D, Masongsong E. Human papillomavirus: the burden of infection. Obstet Gynecol Surv. 2006 Jun;61(6 Suppl 1):S3-14.
- Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003 Sep;189(3 Suppl):S3-11.
- Clarke P, Ebel C, Catotti DN, et al. The psychosocial impact of human papillomavirus infection: implications for health care providers. Int J STD AIDS. 1996 May-Jun;7(3):197-200.
- Jeynes C, Chung MC, Challenor R. ‘Shame on you’–the psychosocial impact of genital warts. Int J STD AIDS. 2009 Aug;20(8):557-60.
- Sheppard S, White M, Walzman M. Genital warts: just a nuisance? Genitourin Med. 1995 Jun;71(3):194-5.
- Voog E, Lowhagen GB. Follow-up of men with genital papilloma virus infection. Psychosexual aspects. Acta Derm Venereol. 1992;72(3):185-6.
- Persson G, Dahlof LG, Krantz I. Physical and psychological effects of anogenital warts on female patients. Sex Transm Dis. 1993 Jan-Feb;20(1):10-3.
- Hoy T, Singhal PK, Willey VJ, et al. Assessing incidence and economic burden of genital warts with data from a US commercially insured population. Curr Med Res Opin. 2009 Oct;25(10):2343-51.
- Centers for Disease Control and Prevention. STD Surveillance 2008. Table 43. Selected STDs and complications – initial visits to physicians’ offices, National Disease and Therapeutic Index: United States, 1966-2008. Available at: http://www.cdc.gov/std/stats08/tables/43.htm. Accessed: February 28, 2012.
- 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. 1998 Jan;134(1):25-30.
- Zyclara® cream, 3.75% [prescribing information]. Graceway Pharmaceuticals, LLC. Bristol, TN, 2011.
- Scott M, Nakagawa M, Moscicki AB. Cell-mediated immune response to human papillomavirus infection. Clin Diagn Lab Immunol. 2001 Mar;8(2):209-20.
- Diamantis ML, Bartlett BL, Tyring SK. Safety, efficacy & recurrence rates of imiquimod cream 5% for treatment of anogenital warts. Skin Therapy Lett. 2009 Jun;14(5):1-3, 5.
- Baker DA, Ferris DG, Martens MG, et al. Imiquimod 3.75% cream applied daily to treat anogenital warts: combined results from women in two randomized, placebo-controlled studies. Infect Dis Obstet Gynecol. 2011;2011:806105.
- Aldara® cream, 5% [prescribing information]. Graceway Pharmaceuticals, LLC. Bristol, TN, 2010.
- Murphy J, Coster G. Issues in patient compliance. Drugs. 1997 Dec;54(6):797- 800.
- Tatti S, Stockfleth E, Beutner KR, et al. Polyphenon E: a new treatment for external anogenital warts. Br J Dermatol. 2010 Jan;162(1):176-84.
- Tyring SK. Sinecatechins: effects on HPV-induced enzymes involved in inflammatory mediator generation. J Clin Aesthet Dermatol. 2012 Jan; 5(1):19-26.