Current Update on the Treatment of Genital Warts

Valerie R Yanofsky; Rita V Linkner; David Pompei; Gary Goldenberg

Disclosures

Expert Rev Dermatol. 2013;8(3):321-332. 

In This Article

Treatment

Numerous therapies are presently indicated for use in the treatment of EGW, which can target lesions through multiple modalities including topical, surgical or via immune modulation. Therapies often differ dramatically with respect to cost, side-effect profiles, dosing schedules, duration of treatment and overall effectiveness.

Despite a wide range of treatments capable of short-term eradication, clinical evidence shows that they remain largely ineffective in achieving long-term wart eradication, with average recurrence rates ranging from 30 to 70% within the first 6 months.[35] Similarly, it is unlikely that available EGW therapies play any significant role in halting or delaying malignant wart progression.

No single therapy has emerged as a gold standard of care in the treatment of EGW, and therapy selection is typically tailored to the specific goals and needs of the individual patient. Treatment options are described in order, based on the degree of evidence supporting their efficacy and the grading of recommendations put forth by the AHCPR in 1994.[36]

Podophyllotoxin 0.05% Solution or Gel & 0.15% Cream (Grade A)

Podophyllotoxin, an antimitotic chemical made from a purified extract of the podophyllum plant, binds cellular microtubules that arrest the cell cycle, resulting in cellular necrosis and death. Maximal efficacy is seen 3–5 days following administration, appearing as shallow erosions of sloughing wart tissue and healing skin.[37]

Podophyllotoxin is applied to warts twice daily for three consecutive days, but no more than 4 weeks. The solution-based product is recommended typically for penile lesion use, whereas cream or gel preparations are generally thought to be more comfortable for anal or vaginal lesions.[38] Podophyllotoxin has a well-characterized efficacy and safety profile, and has the advantage of self-administration. Randomized, placebo-controlled trials have demonstrated successful clearance rates that range between 45 and 77%, with recurrence rates as low as 38%.[39–41] A persistent presence of lesions following 4 weeks of treatment indicates therapy failure, and alternative options should be considered. Common adverse events include pain, inflammation, erosion, burning or itching at the application site. These events are typically associated with overexposure by the patient and can often be avoided with proper patient education.[42] Podophyllotoxin has not been thoroughly evaluated for teratogenecity and carries a category C classification, which is not recommended for use during pregnancy.[43]

Imiquimod Cream 5% & 3.75% (Grade A)

Imiquimod (imidazoquinolinamine) 5% cream, a potent immunomodulatory agent, became US FDA approved for the treatment of EGW in 1997. Since then, the cream has been used successfully for the treatment of a variety of benign and malignant skin conditions, including molluscum contagiosum, vulvar and vaginal intraepithelial neoplasms, actinic keratoses, superficial SCC and basal cell carcinomas.[44] Imiquimod, a patient-applied topical therapy, is thought to activate the immune system by binding to the endosome membrane TLR-7, commonly involved in pathogen recognition.[45] This results in the secretion of multiple cytokines such as IFN-α, IL-6 and TNF-α, which serve to activate the immune cells and help promote wart clearance.[46,47] Additionally, new research has shown that imiquimod may have direct antiproliferative effects independent of the immune system effect. This effect is thought to be mediated by increased levels of the OGF receptor.[48] Patients treated with imiquimod will demonstrate decreased HPV DNA viral loads and markers for keratinocyte proliferation, as mRNA expression shifts towards markers for tumor suppression.

Imiquimod 5% is applied at bedtime three-times per week for a maximum of 16 weeks, and must be left in place for 6–10 h following application. Clinical studies have revealed successful wart clearance in up to 56% of patients, with 72–84% showing some reduction in wart size.[49] Complete clearance rates were slightly higher in women when compared with men (77 vs 40%, respectively), with females also demonstrating a shorter median time to clearance (8 vs 12 weeks). Furthermore, successful treatment with imiquimod is associated with low recurrence rates ranging from 5 to 19%.[50]

While relatively safe, side effects of imiquimod treatment are fairly common and generally occur as a result of local inflammatory reactions. Adverse events include itching, erythema, burning, irritation, tenderness, pain and ulceration surrounding the affected area. Occasionally, patients may experience more widespread systemic side effects such as headaches, muscle aches, fatigue and general malaise. Moreover, while multiple clinical studies have validated the safety and efficacy of the current recommended dosing regimen, the lengthy duration and sporadic frequency of administration often results in poor patient compliance. Attempts to change the dosing frequency to a more simplified daily regimen resulted in poor patient tolerance secondary to severe local inflammatory side effects.[51]

In March 2010, the FDA approved a 3.75% formulation of topical imiquimod cream for EGW treatment.[102] This new treatment has several advantages, including application to large areas of skin, as well as having a more convenient dosing schedule with daily use required for approximately 6–8 weeks. Although two Phase III, double-blind, placebo-controlled studies have shown primary cure rates for the 3.75% formulation are not quite as high as its 5% counterpart, this treatment remains significantly more effective than placebo, achieving a 33% clearance rate in a protocol evaluation and a 28% clearance rate in an intention-to-treat study. Additionally, it was also found that recurrence rates were relatively low, with up to 85% of subjects maintaining complete clearance at a 12-week follow-up evaluation.[103] Imiquimod 3.75% is also thought to have the added benefit of a markedly less aggressive side-effect profile, with the main adverse effects comprising itching, burning or pain at the application site, and no reported systemic symptoms.[103]

Sinecatechins 15% Ointment (Grade A)

In 2006, Sinecatechins 15% officially received FDA approval for the treatment of EGW, making it the first botanical drug ever approved in the USA for prescription use.[52] The drug is made from the extract of green tea leaves, and the active ingredient is thought to be kunecatechins, which is a mixture of catechins and other tea components. Although the precise mechanism of action remains unknown, catechins are thought to possess antioxidant, antiviral and antitumor properties, which serve to modulate the inflammatory response. The catechins are believed to inhibit the transcription factors AP-1 and NF-κB, which are activated by the release of reactive oxygen species.[53] They have also been shown to downregulate the expression of COX-2, an inflammatory mediator linked to the prostaglandin E2 system, which may play a role in the stimulation of epithelial proliferation and subsequent dysplasia.[54]

Sinecatechins 15% are self-administered and applied topically to warts three-times daily for a maximum of 4 months. If no improvement is seen within the first few weeks of treatment, alternative therapies should be considered. Several randomized, double-blind, placebo-controlled trials have shown that sinecatechins are significantly more effective than placebo in treating EGW, achieving a complete clearance of warts in as many as 58% of subjects. Recurrence rates were also relatively low, with fewer than 10% of subjects affected at a 12-week follow-up.[54]

Sinecatechins are associated with a number of adverse events that may affect up to 20% of users. Most of these are mild and limited to local reactions at the application site, such as redness, burning, itching and pain. Although extremely rare, more severe systemic reactions such as lymphadenitis, vulvovaginitis, balanitis and ulceration have also been reported.[54]

Trichloroacetic Acid 80–90% Solution (Grade B)

Trichloroacetic acid (TCA) is a chemically destructive acid that burns, cauterizes and erodes the skin and mucosa, resulting in the physical destruction of warty tissue through protein coagulation. The destructive nature of the product frequently extends beyond the superficial wart to encompass the underlying viral infection. The acid is typically prepared in concentrations of 80–90% and, given the caustic nature of the solution, requires administration by a physician. Although there have been reports of successful wart clearance with as little as a single treatment, repeated application is always required. Treatment is applied once per week for an average course of 6–10 weeks.[55,56]

TCA is an inexpensive, cost-effective treatment most effective on small, moist patches of warts. Clearance rates ranging from 70 to 80% following several weeks of therapy have been observed; however, recurrence rates are still relatively high at approximately 36%.[55,56] One specific obstetric study that evaluated the use of 85% TCA in 50 female subjects with EGW found a complete clearance of warts in all subjects following 2–5 months of treatment. Treatment was effective for at least 6 months, with no cases of recurrence or new lesions reported. A 12-month follow-up visit, however, revealed that 18% of patients had recurrent lesions.[57]

Common side effects of acid treatments involve transient pain or burning during treatment administration, as well as destruction of the healthy tissue surrounding the wart. Dermal injury and scarring is rare, and can be minimized with petroleum jelly barriers and washing with soap and sodium bicarbonate immediately following overapplication.[58] Occasionally, tissue destruction can result in pain, ulceration and crust formation. High success rates combined with low morbidity and low danger of systemic absorption allow TCA to be used for the treatment of internal lesions. This is particularly relevant for internal lesions that occur during pregnancy, where it remains the treatment of choice.[57]

Cryotherapy (Grade B)

Cryotherapy is a process where abnormal warty tissue is removed by freezing using cooling agents such as nitrous oxide or liquid nitrogen. Temperatures must be cold enough to crystallize the cytosol of cells, causing permanent dermal and vascular damage. This damage activates immune system-initiated necrosis and clearance of destroyed cells.[58,59]

Cryotherapy is a fairly inexpensive and highly successful therapy, with a 79–88% clearance rate typically seen within the first three treatments.[12] This treatment is most effective when used for multiple small warts located externally on the penile shaft or vulva.[58,59] While treatment outcomes tend to be more favorable than many others, results may vary based upon the temperature used and the duration of contact to the affected area.[55] Cryotherapy, like all lesion-directed therapies, fails to treat any subclinical infection, which may be present in the surrounding skin. This may help explain the relatively high recurrence rates associated with the treatment, which are estimated to be anywhere between 25 and 40%.

Side effects of cryotherapy tend to be both common and severe, and are thought to occur as a result of local tissue destruction. This can lead to painful blistering, ulceration and infection, which may be irreversible, resulting in permanent scarring and a loss of tissue pigmentation. The long-term risks posed by local tissue damage often limit the ability of the physician to utilize treatment intensities, which would otherwise produce optimal results.[55] The focal nature of directly targeting lesions makes cryotherapy the treatment of choice for pregnant women with multiple, easily accessible warts.[59,60]

Electrosurgery (Grade B)

Electrosurgery is a procedure involving thermal coagulation or electrocautery to burn, desiccate and destroy warty lesions using high-frequency electrical currents; damaged or dead tissue is subsequently removed by curettage. Similar to cryotherapy, this technique is maximally effective in the treatment of smaller warts found externally on the shaft of the penis, the rectum or the vulva. Irreversible damage to surrounding tissues again limits the use of this therapy, and treatment of larger lesions has been associated with permanent scar formation.[61]

Electrosurgery is an extremely effective short-term technique, with randomized controlled trials demonstrating clearance rates as high as 94% at 6 weeks post-treatment. These rates tend to normalize after 3 months, however, with long-term effects that are comparable to cryotherapy.[61] Peri- and post-procedural pain are common with electrosurgery, and local or general anesthesia is usually required when carrying out the procedure. The elevated risk associated with general anesthesia makes electrosurgery a very involved and impractical treatment option. Moreover, electrosurgery is strictly contraindicated in patients with implantable cardiac devices due to the possibility of current interference and potentially fatal disruption of pacemaker rhythms.[62]

Surgical Scissor Excision (Grade B)

Surgical excision is one of the oldest documented therapies used for the treatment of EGW, and for many years was considered the gold standard of treatment. The procedure involves the physical removal of the lesion down to the normal skin or mucosa with the aid of scissors or a scalpel. The roots of the lesions may be cauterized, or alternatively healthy skin may be sutured together. Care should be taken to ensure that cauterization does not extend into the subcutaneous or submucosal fat, which may increase the risk of complications such as stricture formation. Excision of large lesions may require general anesthesia, which subjects patients to routine surgical risks such as infection and hemorrhage.

While now considered outdated, surgical excision remains a suitable and often preferred treatment for large lesions, which require immediate intervention, as well as those that are unresponsive to other forms of therapy. This includes precariously located lesions that may be causing obstruction, such as those involving the urethral meatus.[63] Excision is instantly effective, and is associated with up to a 72% clearance rate often evident over 1 year later. Samples should always be submitted for further histopathological examination in order to exclude the presence of premalignancy as well as malignancy such as SCC. This is particularly the case for large, suspicious-looking lesions, which may pose a greater risk of malignant progression.

Recent advents in surgical techniques allow for a considerably more sophisticated and less invasive means of wart removal. Although intended primarily for the treatment of cutaneous carcinomas, Mohs surgery is a microscopically controlled procedure, that allows for the precise removal of pathologic tissue while the surrounding healthy tissue is spared. The excised specimen is processed and analyzed immediately to ensure margins are clear of viral cell features. In the continued presence of infected cells, additional skin slices are removed until the entire lesion is definitively excised.[64] The obvious benefit of Mohs surgery is that it allows for the maximal preservation of healthy skin, resulting in minimal blood loss and scar formation. However, Mohs is significantly more expensive when compared with other surgical modalities, and is generally only considered in anatomically important areas where cosmetic appearance is of significant concern.

Carbon Dioxide Laser Therapy (Grade B)

Carbon dioxide (CO2) laser therapy is a procedure that utilizes a concentrated beam of infrared light to directly target warty lesions. The diseased tissue absorbs and converts the laser into heat energy, thereby vaporizing the affected regions. The special confinement of the laser beam allows for precise tissue ablation with little damage to the surrounding areas, resulting in rapid healing with minimal scar formation. Additionally, the intense light energy immediately cauterizes any unintentionally injured vessels, ensuring a virtually bloodless procedure.[65]

The efficacy of CO2 therapy for the treatment of EGW remains somewhat contentious due to clearance rates ranging between 23 and 52% and recurrence rates of 77%.[12] One potential benefit of this treatment is that the deep penetrating effect of the laser may allow for a more complete viral attack, rendering laser therapy as the treatment of choice for immunosuppressed individuals. Side effects such as a burning sensation, scarring and pain can be minimized by ensuring tissue destruction does not extend beyond 1 mm in depth.[66] The well-controlled, local effect of the laser allows for safe usage during pregnancy for lesions that are unresponsive to TCA or cryotherapy.

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