Marni C. Wiseman, MD, FRCPC

Section of Dermatology, University of Manitoba, Faculty of Medicine, Winnipeg, MB
CancerCare Manitoba, Winnipeg, MB

Introduction

External genital warts (EGW) are a common infection caused primarily by human papillomavirus (HPV) types 6 and 11. EGW negatively impacts upon patient psychosocial function and is a co-factor for infection with other sexually transmitted infections (STI), by allowing an easier portal of entry into the skin. Both patient and provider-applied therapies can be utilized in tandem to effectively treat EGW. More recently, prophylactic strategies using vaccines have been instituted to prevent HPV acquisition and resultant disease. As well, the recent introduction of a new formulation topical immunomodulator has further widened the spectrum of available therapies.

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Pathogenesis

  • EGW is caused by human papillomavirus (HPV)
  • An HPV viron is small and non-enveloped; its protein coat (capsid) is composed of two structural proteins
  • The viral genome consists of single, supercoiled double-stranded circular DNA of approximately 8000 base pairs in size1
  • >200 types of HPV have been identified, approximately 40 infect the anogenital tract2
  • HPV infections are categorized as low risk or high risk based upon oncogenic potential3,4
  • High risk-types include HPV 16, 18
    • Responsible for 100% cases of cervical cancer and 80% cases of anogenital cancers
  • Low risk types include HPV 6, 114
    • Responsible for 95% EGW cases
    • HPV 6: 74.4%
    • HPV 11: 14.2 %
    • HPV 6 and 11: 3.7%
  • Low risk HPV types are also responsible for 10% of cervical intraepithelial neoplasia grade 1, 42% of related low-grade vulvar intraepithelial neoplasia, and 100% of recurrent respiratory papillomatosis

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Disease Overview

Epidemiology

  • The World Health Organization estimated 300 million cases worldwide of HPV infection without any detectable abnormality; 30 million cases worldwide of active EGW
  • Approximately 1 million new cases annually of EGW in the US5
  • Prevalence in Manitoba (2004): 165.2 per 100,000 for men; 128.4 per 100,000 for women6
  • Incidence in British Columbia (2004): 1.54 per 1000 males; 1.23 per 1000 females7
  • In Canada, the incidence of genital warts was estimated to be 107 per 100,000 person-years in 1999, increasing to 126 per 100,000 person-years in 2006.7
  • Incidence highest in women between the ages of 20-24 years (3.38 per 1000 women)
  • Incidence highest in men aged 25-29 years (3.03 per 1000 men)

Burden of Disease

  • Psychosocial impact8
    • Feelings of anger, disgust, embarrassment
    • Fear of cervical cancer
    • Concern over recurrence, transmission, and treatment
      efficacy
    • Change in lifestyle
  • Socioeconomic burden
    • 60% increase in office visits (US) in last decade9
    • $220 million in health care costs (US 2004, private insurance)10
    • A population-based study of EGW treatment in British Columbia confirmed its significant burden on the health care system:7
      • Between 1998 to 2006, 39,493 patients were diagnosed with EGW, with 43,586 episodes
      • Overall incidence was 1.26 per 1000 population, at an average cost of $190 per episode for treatment, which translates into about $1 million annually in direct medical costs.
      • The incidence and prevalence of EGW are comparable across Canada.

Natural History

  • EGW noted by patient in 65% of cases (52% females; 79% males)8
  • EGW noted at physician visit in 16% of cases (30% females; 1% males)8
  • Transmitted most commonly through sexual contact (i.e., genital-genital, oral-genital, genital-anal)
  • Infection may also rarely occur due to perinatal transmission (laryngeal papillomatosis) or fomites11
  • HPV gains access to basal epithelium via abrasions or microabrasions
  • Incubation (1-8 months)
  • Individual patient immune response results in active growth or host containment (6-9 months)
  • Clinical course of EGW include remission or persistent infection with recurrences
  • 30% spontaneously resolve within 4 months, 50% at 6 months12

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Treatment Options (Table 1)

  • Patients may prefer self-applied therapies for initial treatment
  • Combination therapy may be more effective than monotherapy
  • Inadequate responders may improve with transition to or addition of other therapies or modification of the existing approach
  • According to Canadian STI Guidelines13 therapies are broadly grouped as patient-applied or office-based treatments:
    • Office-based treatments
      • Podophyllin resin (when no other treatment is available)
      • Surgical excision
      • Cryotherapy
      • Bichloracetic acid or trichloroacetic acid
    • Patient-applied treatments
      • Podophyllotoxin
      • Imiquimod
  • Cytodestructive therapies involve the physical removal or chemical destruction of EGW:
    • 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
  • Immunomodulatory therapy with topical imiquimod
    • Immune response modifier
    • Antiviral and antitumor effects
    • TLR-7 agonist
    • Induces Th1-type immune response and the generation of cytokines such as IFN-alpha
    • Pregnancy Category C
    • Due to its favourable efficacy, safety, and tolerability profiles, as well as lowest recurrence rate, Canadian Consensus Guidelines on HPV14 recommends the use of imiquimod prior to initiating more invasive strategies, such as destructive/excision or laser therapies.
    • 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)15
      • Side-effects include erythema (67%), erosion (32%), excoriation/flaking (25%), edema (16%)15
    • Imiquimod 3.75% cream (Vyloma™)
      • Approved by Health Canada in March 2011 for the topical treatment of external genital warts and perianal warts (whether present at the start of therapy or emerging during therapy) in immunocompetent adults.
      • Developed with the goal to shorten treatment duration, simplify dosing regimen, and improve tolerability, thereby encouraging adherence.
      • Two recent identical, gender stratified, randomized, placebo-controlled clinical studies involving 981 patients >12 years of age with 2-30 lesions in the inguinal area, perineal region, perianal area, penile shaft/glans/foreskin, scrotum, or vulva demonstrated imiquimod 3.75% applied once-daily for up to 8 weeks was well tolerated and efficacious in the treatment of EGW (Table 2 and Figure 1).16,17
      • Efficacy was measured in terms of number of EGW (baseline and new).
      • In patients achieving complete clearance, almost 70% maintained clearance at 12 weeks post-treatment.17
      • Common side-effects included pain, irritation, and pruritus at the treatment site.

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Method Treatment Comments
Antiproliferative Therapies Podophyllum resin 10%-25%
  • Physician-administered
  • Removal of warts by destruction of infected tissue
  • Potential for systemic toxicity, especially if applied to large areas or in patients with renal insufficiency
  • Teratogenic (fetal death reported)
  • Antimitotic (causing tissue necrosis)
  • Local side-effects include erythema, edema, pain, burning, itching, severe necrosis, and scarring
  • Modest efficacy and potency; shelf-life unpredictable
Podophyllotoxin 0.5% solution or gel
  • Can be applied by the patient (twice-daily for 3 days, then off for 4 days; may repeat treatment cycle for up to 4 weeks); skin protectant, e.g., petroleum jelly, should be used on normal adjacent skin
  • Low cost, low toxicity
  • It does not contain any mutagenic substances, unlike those found in podophyllum resin
  • Potential systemic toxicity if applied to large area, limit use on EGW 3 times weekly for up to 4 consecutive weeks
Immunomodulatory Therapies Imiquimod cream
  • Self-administration may improve patient adherence
  • Enhances the cytotoxic immune reaction, usually seen as an inflammatory response
  • Low rate of recurrence due to reduction of the viral load and/or induction of HPVspecific cellular immune memory
  • Side-effects are mild to moderate and include local erythema and erosion at the site of application
Imiquimod 5%
  • For 5% imiquimod apply directly to the affected skin 3 times/week for up to 16 weeks; use on alternating days – leave on affected skin for 6-8 hours before washing off with soap and water
  • Reduce frequency of application or temporarily interrupt therapy if there is concern over the degree of inflammation
Imiquimod 3.75%
  • For 3.75% imiquimod apply daily at bedtime for up to 8 weeks
  • Reduces treatment duration; simplified once-daily dosing improves tolerability
Destruction/Excision Therapies
  • For more extensive disease
  • May require local or general anesthesia
  • Scaring and pigmentary changes common
 Topical trichloroacetic acid 85% (TCA) or bichloroacetic acid
  • Causes cellular destruction by chemical cautery
  • Most effective when treating small, moist lesions
  • Damage to surrounding tissue can be minimized by protection with petroleum jelly
  • If TCA is applied to nonaffected tissue, instruct patients to wash the area with liquid soap or baking soda
  • Can cause pain and ulceration
  • Inexpensive; safe in pregnancy
Local cryotherapy
  • Most common destructive mode; inexpensive
  • Involves freezing with liquid nitrogen
  • Offers ease of use with no systemic effects
  • Can cause pain, ulceration, and pigmentary changes
  • Safe for use during pregnancy
Electrodesiccation
  • Warts are burned off with a low-voltage electrical current
Excision by scissors, curette, or scalpel
  • Provides definitive clearance of abnormal tissue
  • Particularly suitable for larger exophytic warts
  • Local anesthesia is required
Ablative laser
  • CO2 laser therapy is usually reserved for extensive and/or treatment-resistant warts
  • May require a long time for recovery and is expensive
Combination Therapy
  • Can provide a better result over monotherapy
 Excision/destruction
+ imiquimod
  • Cryotherapy combined with imiquimod appears to be very commonly used
  • Initial therapy with imiquimod may reduce wart size and improve surgical outcomes
  • Initial treatment with imiquimod followed by excision of residual lesions may provide long-term clearance of EGWs, especially if prior monotherapy was insufficient
Excision/destruction
+ cidofovir
  • Due to cidofovir’s broad antiviral activity, it has been used successfully as a topical gel for refractory patients

Table 1: Overview of therapeutic options for external genital warts14-20

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Location Complete Clearance
(Per-protocol)		 Complete Clearance
(ITT)		 Partial (≥75%) Clearance
(Per-protocol)
Overall 33.8 28.3 45.9
Women overall 43.1 36.6 56.2
Vulva 51.0
Perineum 64.9
Perianal 78.5
Inguinal 45.0
Men overall* 22.7 18.6 33.6

Table 2: Overall and anatomic site-specific clearance rates, by gender, following treatment with imiquimod 3.75% cream16,17
* Anatomic site-specific clearance rates in men have not yet been published.
ITT = intent-to-treat; primary analysis includes all randomized subjects
Per-protocol = only data from adherent subjects are analyzed

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Figure 1: Change in wart count compared with baseline (left axis, circle) compared with local skin reaction (LSR) sum score (right axis, square) for imiquimod 3.75% in women. Modified from Baker et al.16

Prevention

Two vaccines available for the prevention of HPV acquisition:

  • Quadrivalent (HPV types 6, 11, 16, 18) vaccine (Gardasil®)21
    • Prevention of 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®)22,23
    • Adjuvant results in very high serum antibody levels against HPV, excellent subtype cross-protection
    • Excellent for prevention of cervical cancer and other cancers caused by HPV 16, 18
    • Does not protect against EGW acquisition
    • Indicated in females aged 10-25 years

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Conclusion

EGW is a worldwide problem. The scope of diseases, both oncogenic and nononcogenic, caused by HPV is broad. EGW is a manifestation of nononcogenic HPV subtypes 6 and 11. Therapeutic strategies to eradicate EGW have been developed and preventative vaccines are now widely available. Hopefully, the development of novel therapeutic molecules targeting EGW will supplement current tools in the treatment armamentarium against HPV and facilitate the eradication of this prevalent disease.

References

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  2. Wiley D, et al. Obstet Gynecol Surv 61(6 Suppl 1):S3-14 (2006 Jun).
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  4. Garland SM, et al. Cancer Epidemiol Biomarkers Prev 18(6):1777-84 (2009 Jun).
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  8. Maw RD, et al. Int J STD AIDS 9(10):571-8 (1998 Oct).
  9. 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.
  10. Hoy T, et al. Curr Med Res Opin 25(10):2343-51 (2009 Oct).
  11. Handsfield HH. Am J Med 102(5A):16-20 (1997 May 5).
  12. Winer RL, et al. J Infect Dis 191(5):731-8 (2005 Mar 1).
  13. Genital human papillomavirus (HPV) infections. Canadian guidelines on sexually transmitted infections. Public Health Agency of Canada (January 2008).
  14. Roy M, et al. J Obstet Gynaecol Can 29(8 Suppl 3):S37-41 (2007 Aug).
  15. Edwards L, et al. Arch Dermatol 134(1):25-30 (1998 Jan).
  16. Baker DA, et al. Infect Dis Obstet Gynecol 2011:806105 (2011). Available at: http://www.hindawi.com/journals/idog/2011/806105/cta/
  17. Ferris D, et al. Imiquimod 2.5% and 3.75% applied daily for up to 8 weeks to treat external genital warts. Poster (P-544) presented at The 26th International Papillomavirus Conference, Montreal, QC, July 3-8, 2010.
  18. Gunter J. Am J Obstet Gynecol 189(3 Suppl):S3-11 (2003 Sep).
  19. Scheinfeld N, et al. Dermatol Online J 12(3):5 (2006).
  20. Gooderham M. Skin Therapy Lett FP 5(2):1-4 (2009 Jun).
  21. Gardasil product monograph. Kirkland, QC: Merck Canada Inc.; August 26, 2011.
  22. Cervarix product monograph. Mississauga, ON: GlaxoSmithKline Inc.; July 12, 2010.
  23. Hsueh PR. J Microbiol Immunol Infect 42(2):101-6 (2009 Apr).

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