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
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.
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
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. 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 (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 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.
- 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
- Fordyce spots
According to the Centers for Disease Control, 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.
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
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
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.
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
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.
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.
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.
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
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- 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).
- 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).
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- 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).
- 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).
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