External Genital Warts

M. Bourcier, MD, FRCPC¹; D. R. Thomas, MD, FRCPC²
1. La Clinique de Dermatologie, Moncton, NB, Canada
2. Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Background

Human papillomavirus (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. In Canada, its prevalence varies depending on a number of risk factors, but appears to be highest in people between 15-25 years of age. [Varela A, et al. Skin Therapy Lett – US FP Ed 1(2): 1-3 (2006 Winter).] With a relatively new immunomodulator for treatment and the recent approval of a vaccine, the options for managing this condition have improved significantly.

Condyloma Acuminatum (anogenital warts) is a common form of HPV infection. The majority of these are due to infection with HPV 6 or 11, and are clinically benign. Genital warts are usually asymptomatic, but can cause pruritus, bleeding, or mild burning. The warts present as:

• small, wart-like papules
• discrete, sessile, smooth-topped papules or nodules
• large exophytic masses.

Lesion color can range from flesh colored to pink to reddish brown, and are often multifocal. Lesion distribution generally corresponds with the areas of highest friction during sexual activity.

Pathogenesis

The HPV virus is inoculated directly into the epidermal layers of the skin through epithelial defects, especially with maceration. Increased epidermal growth produced by the HPV infection leads to the formation of warts. Genital infections are primarily contracted through sexual contact. These infections can then be transmitted to newborns via passage through the infected birth canal. [Kaye JN, et al. J Gen Virol 77(Pt 6):1139-43 (1996 Jun).]

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Diagnosis of Genital Warts

• Primarily made by visual inspection.
• A biopsy may be useful if
• Diagnosis is uncertain.
• Lesions do not respond to standard therapy.
• The disease worsens during therapy.
• The patient is immunocompromised.
• The warts are pigmented, indurated, fixed, bleeding, or ulcerated.[Centers for Disease Control. Genital
Warts Treatment Guidelines 2006. URL: http://www.cdc.gov/std/treatment/2006/genital-warts.htm.]

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Management

For the majority of patients, treatment can induce wart-free periods. If left untreated, warts may resolve on their own, remain unchanged, or increase in size or number. Treatment can reduce, but does not eliminate, HPV infection. No definitive evidence suggests that any of the available treatments are superior to any other and no single treatment is ideal for all patients or all warts. Most patients require a course of therapy rather than a single treatment, and improvement will generally be seen within 3 months when administered by a health care professional. [Centers for Disease Control. Genital Warts Treatment Guidelines 2006. URL: http:// www.cdc.gov/std/treatment/2006/genital-warts.htm.]

Before beginning any treatment for genital warts, it is essential to screen patients for other sexually transmitted diseases. Most treatment modalities address the symptom of the disease (warts) vs. the cause of the disease itself. However, imiquimod goes further by inciting an immunologic response, thereby providing an attack on the obvious warts, as well as the virus that resides in normal looking skin around the warts, i.e., in both clinical and subclinical HPV.

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Four Treatment Modalities

• Antiproliferative agents
• Destruction/excision therapies
• Immunomodulatory therapy (imiquimod)
• Combination therapy.

Antiproliferative Therapies

• Podophyllin resin 10%-25%
• It is administered by a health professional.
• To minimize irritation, a petroleum-based product can be applied to adjacent tissue.
• Multiple applications may be needed.
• Should not be used in pregnant women.

• Podophylox 0.5% solution or gel
• Self-administered by patient.
• Does not contain the mutagenic substances that podophyllin resin has.
• Could be used in combination with destructive therapy.

Destruction/Excision Therapies

• Local cryotherapy is the most common destructive mode.
• It is safe during pregnancy.
• Application of topical trichloracetic acid
• Electrocautery
Ablative laser treatment
• Excision by scissor, curette, or scalpel.
• Administered by a health professional.
• All of these options have a risk of scarring.

Immunomodulatory Therapy

• Approved by Health Canada in 1999.
• Self-administered by patient, which improves patient compliance.
• Enhances the cytotoxic immune response, which is usually seen as an inflammatory response.
• Applied directly to the affected skin 3 times per nweek for up to 16 weeks. Initially the frequency of applications can be reduced if the patient is overly concerned by the degree of inflammation.
• Acts to reduce the viral load, thereby reducing recurrence rates to very low levels.
• A significant advantage is the ability to affect subclinical lesions.
• Is more effective in women than in men, possibly because warts are more commonly found on mucosal skin.

Combination Therapy

• Monotherapy can often be inadequate for treating anogenital warts.
• Combination therapy can provide a better result.

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.[Carrasco D, et al. J Am Acad Dermatol 47(4 Suppl):S212-6 (2002 Oct).] The patient and physician must decide when monotherapy has been given sufficient time. In many instances, combination therapy is used as initial treatment.

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Prevention

Prophylaxis

A quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine is now available and is indicated in girls and women aged 9-26 years for the prevention of the following diseases caused by HPV types 6, 11, 16, and 18, including genital warts, cervical cancer and other neoplasias of the cervix, vagina and vulva. It should be administered intramuscularly as three separate 0.5ml doses. Studies with this vaccine are now ongoing in males. There is no evidence for effectiveness in treating those who already have genital warts. Not only does the vaccination largely prevent incident external genital warts, but it also protects against genital tract HPVassociated neoplasia.

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Behaviour Modification

• Avoid sexual contact if infected.
• Barrier contraception may be of benefit.
• Regular cervical pap smears are recommended for all women, but especially important in those with exposure to genital warts.

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Patient Counseling

• Irritation and inflammation causing pain and discomfort are seen with all of the treatment modalities, whether self-administered or given by a health care professional.
• Imiquimod can cause redness and swelling.
• The most common issue reported by patients.
• Because this medication is designed to trigger the patient’s immune response, an inflammatory reaction can be expected.
• Inflammation is desirable and the patient needs to understand this to ensure that treatment is not interrupted.
• Resist efforts to suppress the redness using topical corticosteroids.
• Inflammatory response is variable.
• Some patients may need to apply the cream less often than is standard.
• It is reasonable to titrate the frequency of applications to best suit the patient.
• If the reaction is very brisk, the applications can be discontinued and restarted after the inflammation has decreased.
• Genital warts are caused by a viral infection, and the pathogens are found in the skin around the warts themselves so imiquimod should be applied on the surrounding skin, as well as on the warts.
• Apply medication at least 1cm around the obvious area of involvement.
• Only a thin layer needs to be applied to the genital region.
• The sachet can be used more than once. It is recommended that a pinprick be made in the packet and the cream squeezed out. It may be that only ½ a sachet is used if the area is not extensive.

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Conclusion

HPV infections can be asymptomatic and can spontaneously clear on their own. However if treatment is required, there are a number of antiproliferative, destructive, and immunomodulatory modalities available. Combination therapies have been shown to be advantageous in terms of enhanced efficacy. In general, time to response can be expected within 3 months of therapy. Patients should be evaluated throughout the course of therapy for treatment response and side-effects, and treatment should be changed if substantial improvement is not seen within that time frame. Cryotherapy combined with imiquimod is very commonly used, because it helps debulk or reduce the size of the warts, as well as enhance the patient's own immune response in the treated area. A quadrivalent HPV recombinant vaccine is now available for girls and women 9-26 years of age. While not affecting current infections, future generations may be spared considerable burden from external genital warts due to the development, approval, and release of HPV polyvalent vaccines.

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