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The Forgotten HPV: External Genital Warts

Alejandra Varela1,2 and Daniel A. Carrasco, MD2
1University of Texas Health Science Center, San Antonio, TX, USA 2Dermatological Association of Texas, Houston, TX, USA

Background

Human Papilloma Virus (HPV) infection of the anogenital tract is extraordinarily prevalent with studies demonstrating that >50% of sexually active women have been infected with the 40-plus HPV types that affect this region of the body.1,2 Age matched males demonstrate similar infection rates, and data on first-time treatment seekers for genital warts show an increase in presentation of >500% in the past 3 decades.3-5 In 2005, the Centers for Disease Control estimated that 20 million people in the US had HPV.

Risk Factors

The single most established risk factor for genital HPV infection is an increased number of lifetime sexual partners. There is evidence that the number of partners a woman reports her current partner to have had is associated with her own risk.6-12 While some studies have suggested a correlation between HPV infection and the use of oral contraceptives or smoking, the literature does not support a consistent association between these. Currently, the peak point prevalence of genital HPV infection is in the 15-25 year-old age group with the number of lifetime partners determining the greatest risk.13,14

Pathogenesis

Infection with HPV occurs by direct inoculation of the virus into the epidermal layers of the skin through epithelial defects. Skin maceration is an important factor in transmission.15 Genital infections are predominantly obtained through sexual contact, which can then be transmitted vertically to newborns by passage through the infected birth canal.16-19 The rate of infectivity between sexual partners is estimated to be 60%.20

Condyloma Acuminatum

Condyloma acuminatum (anogenital warts) is the most common presentation of genital HPV infection. The vast majority of these lesions are clinically benign and due to infection with HPV 6 or 11. The warts can present as small, verrucous papules; discrete, sessile, smooth topped papules or nodules; and even as large exophytic masses. The color of the lesions can range from flesh colored to pink to reddish brown, and often they are multifocal. Most often genital warts are asymptomatic but may cause pruritus, bleeding, or mild burning.21

Diagnosis

Diagnosis is primarily clinical, but for hard-to-detect lesions, especially those on the cervix, a 5% acetic acid solution can be applied to the suspected region. Within minutes, condylomata should appear as whitish patches on the mucosa. If the practitioner finds the clinical diagnosis to be less than clear, a biopsy may provide the diagnosis.

Differential Diagnosis

  • Syphilitic condyloma lata
  • Molluscum contagiosum
  • Benign penile pearly papules
  • Hymenal remnants
  • Bowenoid papulosis
  • Seborrheic keratosis
  • Skin tags
  • Squamous cell carcinoma
  • Verrucous carcinoma (Giant condyloma of Buschke-Lowenstein)
  • Vulvar dysplasia
  • Linear epidermal nevus
  • Lichen nitidus
  • Angiokeratomas
  • Milium
  • Fordyce spots

Treatment

According to the Centers for Disease Control www.cdc.gov/std/treatment/2006/genital-warts.htm, treatment of genital warts should be guided by the preference of the patient, the available resources, and the healthcare provider’s experience. There is no definitive evidence to suggest that any of the available monotherapy treatments are superior to any other and no single treatment is ideal for all patients or all warts. However, combination therapies may be more successful at treating warts in particular when monotherapies have failed, because they debulk the tumor and take advantage of different mechanisms of action to treat the virus. The majority of genital warts respond within 3 months of therapy. The response to treatment and its side-effects should be evaluated throughout the course of therapy, and treatment should be changed if a patient has not improved substantially within that time frame.23 While genital warts are benign, they are often cosmetically unacceptable and embarrassing to patients. If left untreated, they commonly enlarge and multiply. Treatment options can be broken down into 5 categories:

  • Antiproliferative agents
  • Destruction/excision therapies
  • Immunomodulatory therapy
  • Combination therapy
  • Antiviral agents

It is essential to screen patients for other sexually transmitted diseases.

Anti-Proliferative Therapies

This class of agents includes podophyllin resin 10%-25%, which is provider-administered, and podophylox 0.5% solution or gel, which can be applied by the patient and is used as a first-line drug. It is free of the mutagenic substances that podophyllin resin contains.24

Destruction/Excision Therapies

The destructive therapies for condyloma include: local cryotherapy (safe during pregnancy), application of topical trichloroacetic acid (TCA), electrocautery, ablative laser treatment, or excision by scissor, curette, or scalpel.



Figure 1: Algorithm for treatment of suspect lesions

Immunomodulatory Therapy

Imiquimod is a relatively new addition to the pharmacologic arsenal. Applied topically, imidazoquinoline enhances the cytotoxic immune response. Wart recurrence is significantly lower with this drug, compared with many other commonly used therapies. It is applied directly to the affected skin three times per week, and it has the added benefit of treating subclinical lesions.

Combination Therapy

Because anogenital warts frequently persist despite monotherapy, namely excision/destruction, and combination therapy with immunomodulators may provide better results. Carrasco, et al. revealed that treatment with imiquimod followed by excision of residual lesions may provide long-term clearance of anogenital warts in those patients for whom monotherapy was insufficient.25

Antiviral Therapy

Cidofovir is an agent with antiviral activity that has been used in the treatment of genital warts refractory to other therapies. It is a nucleotide analogue with broad antiviral activity that has been used experimentally as a topical gel with fair success.26 Cidofovir is not commercially available, but can be compounded at a local specialty pharmacy.

Prophylaxis

In the forefront of medicine, the advent of a quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine, is now being administered as HPV prophylaxis. It is indicated for girls and women aged 9–26 years for the prevention of the following diseases caused by HPV types 6, 11, 16, and 18:

  • Genital warts
  • Cervical cancer
  • AIS (noninvasive cervical cancer)
  • CIN grades 1, 2 and 3 (cervical intraepithelial neoplasia)
  • VIN grade 2 and 3 (vulvar intraepithelial neoplasia)
  • VaIN grade 2 and 3 (vaginal intraepithelial neoplasia)

It should be administered IM as three separate 0.5ml doses. Studies with this agent are now ongoing in males.

Conclusion

HPV is a very common sexually transmitted disease that is associated with a number of benign, premalignant, and frankly malignant lesions of the anogenital tract. The majority of HPV infections are asymptomatic and are spontaneously cleared by a predominantly cell-mediated immune response. Condyloma acuminatum, generally due to HPV types 6 and 11, is the most common benign clinical manifestation of HPV infection, and a number of antiproliferative, destructive, antiviral, immunomodulatory, and combination therapies are available for this condition. The majority of genital warts respond within 3 months of therapy. The response to treatment and its side-effects should be evaluated throughout the course of therapy and treatment should be changed if a patient has not improved substantially within that time frame. A quadrivalent HPV recombinant vaccine is now available for HPV prophylaxis against types 6, 11, 16, 18 and is indicated in girls and women 9–26 years of age. Currently, studies with this agent are ongoing in males.

Editor's Commentary

The majority of clinicians will attempt to treat external genital warts (EGW) initially utilizing the various destructive techniques outlined by Dr. Carrasco. Healthcare provider-administered ablative methods are relatively simple, safe and expeditious. However, as noted repeatedly in the medical literature, both incomplete response and recurrence are common problems following the use of such modalities.1,2 While requiring prolonged and diligent application, the use of self-administered imiquimod is an effective and convenient treatment alternative. The efficacy is likely due to the establishment of adaptive immunological response and/or persistent immune memory against etiologic HPV.3 The FDA-approved imiquimod regimen for EGW calls for three times weekly application for 16 weeks. Recent clinical work from Australia suggests that far shorter courses (as little as 4 weeks) may be equally efficacious; this is particularly true in women who routinely demonstrate higher complete cure rates.4 Shorter courses of therapy are not only more convenient, but have been associated with considerably less treatment-related morbidity (e.g., erythema, erosion and pain).

Real-world use of imiquimod brings up the concern of safety in women of child-bearing potential who already may be, or may inadvertently become, pregnant during therapy. While documentation is limited, a recently published small case series is reassuring with regards to imiquimod safety during gestation.5

One unanticipated complication of imiquimod therapy has been the development of localized vitiligo-like depigmentation limited to the area of treated skin.6,7 This may be due to locally induced cytokines that are directly toxic to melanin producing cells or due to locally induced chemokines facilitating the ingress of melanocytotoxic immune effector cells. The Editor has observed this phenomenon, but also noted eventual spontaneous and complete remission in the affected patient.

The EGW therapeutic armamentarium will expand shortly due to FDA approval 15% Polyphenon® E Ointment. This is a standardized, polymolecular aqueous extract of green tea leaves, and it represents the first prescription botanical officially approved in the US. Application frequency and duration will closely resemble that of imiquimod 5% cream. Although the mechanism of action is uncertain, components of this formulation have been shown to inhibit epidermal cell proliferation, as an essential feature of HPV-induced lesions, including EGW.8

Future generations may be spared considerable EGW burden due to the development, approval, and release of HPV polyvalent vaccines. Not only will vaccination largely prevent incident EGW, but it will also protect against genital tract HPV-associated neoplasia.9

References

  1. Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol 32(Suppl 1):S16-24 (2005 Mar).
  2. zur Hausen H. Roots and perspectives of contemporary papillomavirus research. J Cancer Res Clin Oncol 122(1):3-13 (1996).
  3. Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites and sampling techniques for detection of human papillomavirus DNA in men. J Infect Dis 189(4):677-85 (2004 Feb 15).
  4. Simms I, Fairley CK. Epidemiology of genital warts in England and Wales: 1971 to 1994. Genitourin Med 73(5):365-7 (1997 Oct).
  5. Beutner KR, Becker TM, Stone KM. Epidemiology of human papillomavirus infections. Dermatol Clin 9(2):211-8 (1991 Apr).
  6. Wang SS, Schiffman M, Shields TS, et al. Seroprevalence of human papillomavirus-16, -18, -31, and -45 in a population-based cohort of 10000 women in Costa Rica. Br J Cancer 89(7):1248-54 (2003 Oct 6).
  7. Burk RD, Ho GY, Beardsley L, Lempa M, Peters M, Bierman R. Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women. J Infect Dis 174(4):679-89 (1996 Oct).
  8. Tarkowski TA, Koumans EH, Sawyer M, et al. Epidemiology of human papillomavirus infection and abnormal cytologic test results in an urban adolescent population. J Infect Dis 189(1):46-50 (2004 Jan 1).
  9. Hippelainen M, Syrjanen S, Hippelainen M, et al. Prevalence and risk factors of genital human papillomavirus (HPV) infections in healthy males: a study on Finnish conscripts. Sex Transm Dis 20(6):321-8 (1993 Nov-Dec).
  10. Wheeler CM, Parmenter CA, Hunt WC, et al. Determinants of genital human papillomavirus infection among cytologically normal women attending the University of New Mexico student health center. Sex Transm Dis 20(5):286-9 (1993 Sep-Oct).
  11. Franceschi S, Castellsague X, Dal Maso L, et al. Prevalence and determinants of human papillomavirus genital infection in men. Br J Cancer 86(5):705-11 (2002 Mar 4).
  12. Svare EI, Kjaer SK, Worm AM, Osterlind A, Meijer CJ, van den Brule AJ. Risk factors for genital HPV DNA in men resemble those found in women: a study of male attendees at a Danish STD clinic. Sex Transm Infect 78(3):215-8 (2002 Jun).
  13. Herrero R, Hildesheim A, Bratti C, et al. Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica. J Natl Cancer Inst 92(6):464-74 (2000 Mar 15).
  14. Cuschieri KS, Cubie HA, Whitley MW, et al. Multiple high risk HPV infections are common in cervical neoplasia and young women in a cervical screening population. J Clin Pathol 57(1):68-72 (2004 Jan).
  15. Kaye JN, Starkey WG, Kell B, et al. Human papillomavirus type-16 (HPV-16) in infants: use of DNA sequence analyses to establish the source of infection. J Gen Virol 77(Pt 6):1139-43 (1996 Jun).
  16. Doorbar J, Sterling JC. The biology of human papillomaviruses. In: Sterling JC, Tyring SK, editors. Human papillomaviruses: clinical and scientific advances. London: Arnold; 2001. p. 10-23.
  17. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 338(7):423-8 (1998 Feb 12).
  18. Moscicki AB, Shiboski S, Hills NK, et al. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet 364(9446):1678-83 (2004 Nov 6-12).
  19. Arany I, Tyring SK, Stanley MA, et al. Enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%. Antiviral Res 43(1):55-63 (1999 Aug).
  20. Palefsky JM. Cutaneous and genital HPV-associated lesions in HIV-infected patients. Clin Dermatol 15(3):439-47 (1997 May-Jun).
  21. Ahmed A, Madkan V, Tyring SK. Human papillomaviruses and genital disease. Dermatol Clin 24(2):157-65 (2006 Apr).
  22. Pecorelli S, Favalli G, Zigliani L, Odicino F. Cancer in women. Int J Gynaecol Obstet 82(3):369-79 (2003 Sep).
  23. Centers for Disease Control. STD Treatment Guidelines 2006. URL: http://www.cdc.gov/std/treatment/2006/genital-warts.htm. Last accessed 2006 Nov 21.
  24. Petersen CS, Weismann K. Quercetin and kaempherol: an argument against the use of podophyllin? Genitourin Med 71(2):92-3 (1995 Apr).
  25. 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).
  26. Snoeck R, Bossens M, Parent D, et al. Phase II double-blind, placebo-controlled study of the safety and efficacy of cidofovir topical gel for the treatment of patients with human papillomavirus infection. Clin Infect Dis 33(5):597-602 (2001 Sep 1).

Editorial References

  1. Beutner KR, Wiley DJ, Douglas JM, et al. Genital warts and their treatment. Clin Infect Dis 28(Suppl 1):S37-56 (1999 Jan).
  2. Brady S, Wilson JD. Closing the feedback loop: an audit of the use of imiquimod for the treatment of genital warts. J Eur Acad Dermatol Venereol 18(3):314-7 (2004 May).
  3. Smith KJ, Hamza S, Skelton H. The imidazoquinolines and their place in the therapy of cutaneous disease. Expert Opin Pharmacother 4(7):1105-19 (2003 Jul).
  4. Garland SM, Waddell R, Mindel A, Denham IM, McCloskey JC. 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).
  5. Einarson A, Costei A, Kalra S, Rouleau M, Koren G. The use of topical 5% imiquimod during pregnancy: a case series. Reprod Toxicol 21(1):1-2 (2006 Jan).
  6. Stefanaki C, Nicolaidou E, Hadjivassiliou M, Antoniou C, Katsambas A. Imiquimod-induced vitiligo in a patient with genital warts. J Eur Acad Dermatol Venereol 20(6):755-6 (2006 Jul).
  7. Brown T, Zirvi M, Cotsarelis G, Gelfand JM. Vitiligo-like hypopigmentation associated with imiquimod treatment of genital warts. J Am Acad Dermatol 52(4):715-6 (2005 Apr).
  8. Shimizu M, Deguchi A, Lim JT, Moriwaki H, Kopelovich L, Weinstein IB. Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin Cancer Res 11(7):2735-46 (2005 Apr 1).
  9. Siddiqui MA, Perry CM. Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine (Gardasil). Drugs 66(9):1263-71 (2006).

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