Clinical Management of External Genital Warts

Lyn Guenther, MD, FRCPC

¹Dermatrials Research Inc.
²Department of Medicine, McMaster University, Hamilton, ON, Canada

Introduction

External genital warts (EGW) is a common sexually transmitted infection (STI) affecting millions of individuals worldwide. It is likely the most frequent STI in both Canada and the US and is caused by infection with human papilloma virus (HPV) 6 and 11: importantly, these are non-oncogenic strains.¹ The lesions can be caused by HPV 6 (most commonly) or 11, both subtypes are rarely found together.² Patient and provider-applied therapies can be utilized concomitantly to effectively treat EGW. Recently, prophylactic strategies using HPV vaccines have been introduced with success, as has the introduction of a topical immunomodulator in a new formulation, all of which improve the therapeutic armamentarium, and ultimately, patient care.

Background

• The term EGW relates to the anatomic location of these lesions. The areas commonly involved include the penis, vulva, groin, perineum, perianal, suprapubic and even upper thighs and buttocks.³
• Most often EGW is painless and not bothersome. However, in certain individuals it can be quite symptomatic causing itching, pain during intercourse, stinging and burning. Larger lesions can cause obstruction of the meatus and the anus leading to restriction or complete blockage of normal excretionary functions.
• Women are more frequently affected than men, with the most common age groups being 20-24 years and 25-29 years in men.⁴
• Reports indicate that lesions are only noticed in 65% of cases. Males notice the lesions 79% of the time likely due to the anatomic visibility.⁵ Conversely, women only notice the lesions 52% of the time.⁵
• EGW are diagnosed by physicians in 16% of cases, more often in females and very infrequently in males.⁵ Likely, the clinician visit may have been regarding complaints of genital symptoms which lead to an unexpected diagnosis of EGW.⁵
• EGW carries a significant psychosocial impact. Often patients are embarrassed, angry and disgusted.^5,6 Anxiety not only results in sexual tension but also raises concerns regarding recurrence, cancer, and the effectiveness of treatment.^{7, 8}
• EGW diagnosis can often result in a change in lifestyle.⁵ Therefore, patients may have higher expectations from their physician to properly diagnose, counsel, manage and treat these lesions.

Treatment Options

• Patients should expect a treatment that provides favourable efficacy, safety, tolerability, low recurrence rates, minimal scaring and that can be self-applied in the privacy of their own home.
• According to Canadian STI Guidelines, therapies are broadly grouped as patient-applied or office-based treatments.⁹ Often, combinations of treatments are used.
  • Office-based cytodestructive therapies for EGW involve either chemical eradication or physical removal, specifically:
    • Cryotherapy (liquid nitrogen)
    • Surgical/ablative techniques (surgical excision, carbon dioxide laser, electocautery)
    • Trichloroacetic or bichloroacetic acid
    • Podophyllin resin
    • Podophyllotoxin (0.5%) – standardized concentration of purified podophyllin
• Patient-applied treatments are usually preferred and include podophylotoxin and imiquimod.
  • Immunomodulatory therapy with topical imiquimod:
    • Classified as an immune response modifier, imiquimod has antiviral effects functioning through TLR-7 agonism.¹⁰
    • It induces TH-1 type immune responses resulting in the expression of cytokines such as interferon-alpha and tumour necrosis factor-alpha.¹⁰
    • Due to its favourable efficacy, safety and tolerability profiles, as well as lowest recurrence rate, Canadian Consensus Guidelines on HPV 14 recommends the use of imiquimod prior to initiating more invasive strategies, such as destructive/ excision or laser therapies.⁹
• Imiquimod 5% cream (Aldara™):
  • Approved by Health Canada in 1999.
  • Officially indicated for the treatment of external genital and perianal warts in immunocompetent adults.
  • Applied 3 times weekly for up to 16 weeks to a specific treatment area.
  • In a Phase 3 clinical trial, 72% of women and 33% of men had complete clearance of baseline target warts (analyses did not include non-target or new warts).¹¹
  • Side effects include erythema (67%), erosion (32%), excoriation/flaking (25%), edema (16%).¹¹
• Imiquimod 3.75% cream (Vyloma™):
  • Approved by Health Canada in March 2011 for the topical treatment of EGW and perianal warts (whether present at the start of therapy or emerging during therapy) in immunocompetent adults.
  • Developed from its predecessor, imiquimod 5%, with the goal of encouraging treatment adherence by shortening treatment length, simplifying the dosing regimen, and improving tolerability.
  • Applied once-a-day for up to 8 weeks to the external genital/perianal warts, but should not exceed 8 weeks even in the event of missed doses or rest periods.¹²
  • Treatment is generally well tolerated and common side effects included pain, irritation and pruritus at the treatment site.¹³
  • Two randomized, placebo-controlled, double-blind studies of imiquimod 3.75% in 534 women (mean age 33.4 years) with 2-30 lesions (mean 7.9) in the vulvar (including mons), inguinal, perineum, and/or perianal areas, and with a minimum total wart area of 10 mm2 demonstrated good efficacy and safety.¹³
  • Imiquimod 3.75%, applied once daily for 8 weeks, achieved complete clearance in 36.6% of women versus 14.2% who applied placebo (p<0.001). A 63.5% decrease in wart count was seen in the imiquimod 3.75% group compared to a 10.7% decrease in the placebo arm (p<0.001). Discontinuation rates were 2.3% for the imiquimod 3.75% group versus 0.9% for placebo.
  • Of the patients who completely cleared, 70% (71/102) remained clear of recurred EGW at the end of the 12-week follow-up.¹²
  • Imiquimod 3.75% is pregnancy class C.
  • It is available in 250 mcg single dose sachets and in a pump containing 7.5 g of cream.¹²

Vaccines for EGW

Currently, 2 vaccines are available for the prevention of HPV infection:

• Quadrivalent (HPV types 6, 11, 16, 18) vaccine (Gardasil®):14
  • Prevents EGW caused by HPV 6, 11 and cervical cancer and other cancers caused by HPV 16, 18 including vulva and vaginal cancers, cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, and vaginal intraepithelial neoplasia.
  • Indicated in females aged 9-45 years.
  • Indicated in males aged 9-26 years.
• Bivalent (HPV types 16, 18) vaccine (Cervarix®):15,16
  • Prevents cervical cancer and other cancers caused by HPV 16, 18.
  • Adjuvant results in very high serum antibody levels against HPV, excellent subtype cross-protection.
  • Does not protect against EGW acquisition.
  • Indicated in females aged 10-25 years.

Conclusion

EGW is a global problem. In addition to its physical symptoms, patients also suffer associated psychosocial sequelae. Therefore, the effective and safe treatment of this STI is important for a host of reasons. Therapeutic strategies for EGW include officebased cytodestructive therapies and patient administered topical therapy with imiquimod. Further, effective vaccines have been developed and are now widely available. All of these approaches are associated with good outcomes, and aid the clinician in helping their patients effectively manage EGW.

References

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14. Gardasil product monograph. Kirkland, QC: Merck Canada Inc.; August 26, 2011.
15. Cervarix product monograph. Mississauga, ON: GlaxoSmithKline Inc.; July 12, 2010.
16. Hsueh PR. J Microbiol Immunol Infect. 2009;42(2):101-6.