​​​Abstract and Introduction
Abstract
External genital warts (EGW) are currently the most common form of viral sexually transmitted disease found in the general population. EGW have been shown to occur as a direct result of infection with the human papillomavirus (HPV). Malignancy is typically associated with high-risk types of HPV; however, low-risk type association has been observed. Numerous therapies are presently indicated for use in the treatment of EGW, which can target lesions through multiple modalities including topically, surgically or via immune modulation. Therapies often differ dramatically with respect to cost, side-effect profiles, dosing schedules, duration of treatment and overall effectiveness. Routine HPV vaccination may play a powerful role in reducing the burden of disease by preventing viral infection and transmission. As HPV vaccination continues to gain widespread approval, it may prove instrumental in decreasing the incidence of HPV infection and eventually eradicating genital warts.


Introduction
External genital warts (EGW), also termed condylomata acuminata (CA), are at present the most prevalent form of viral sexually transmitted disease found within the general population.[1] It is estimated that approximately 3 to 6 million cases present each year in the USA alone, representing approximately 1% of the sexually active population.[2,3] EGW have been shown to occur as a direct result of infection with human papillomavirus (HPV).[4] Although EGW may present in both genders, there is thought to be a slight preponderance for females, with females accounting for 67% of the presenting population.[1] However, recent data from the UK has contraindicated this, with males being suggested to have a higher EGW prevalence than females.[101] In addition to genital warts, oncogenic HPV infection has been linked to the development of a variety of malignant and premalignant lesions of the anogenital and oropharyngeal regions. This helps to account for the tremendous economic burden imposed by HPV, which was estimated at US$4 billion in 2004 in the USA when considering both the direct costs of genital wart treatment as well as those associated with HPV-related invasive cervical cancer.[5]

There are currently over 160 distinct types of HPV that have been identified, with over 40 of these capable of infecting the anogenital tract.[1,6] These can be grossly subdivided into three separate categories based upon their phenotypic association with the development of intraepithelial cancers: low risk, intermediate risk and high risk. Low-risk types comprise those viral strains that rarely give rise to cervical cancers, such as HPV types 6 and 11. Infection by these genotypes, however, accounts for 90% of genital wart lesions. In contrast, HPV types 16 and 18 are strongly associated with cervical, vulvar, vaginal and anal dysplasia, and evidence of infection with these genotypes can be found in up to 70% of squamous cell carcinomas (SCC) of the cervix. They are therefore considered to be high-risk oncogenic types.[7] Intermediate-risk types, such as HPV types 29, 31, 33, 45, 51, 52, 56, 58 and 59, are often found in association with squamous neoplasms; however, some are thought to have a more indolent course of rare progression to cervical SCC.[7] Patients with CA may additionally be infected with multiple HPV strains, and the precise nature of the infection may be a critical prognostic indicator of cervical cancer. This does not play a major role, however, in the diagnosis or treatment of genital warts.[8]

Epidemiology
Both the incidence and the prevalence of HPV infection have steadily been increasing in the past 35 years. Current estimates suggest that as many as 20 million Americans may be infected, with approximately 5.5 million new infections being reported in the USA each year.[1,9] With the risk of contracting HPV decreasing sharply with age, nearly half of new infections are seen in young adults between the ages of 15 and 24 years.[10] In fact, it has been estimated that anywhere between 75 and 80% of sexually active adults will acquire a genital tract HPV infection before the age of 50 years.[11] This rising trend of HPV reported in the young population can be attributed to both a decreasing age of initial sexual contact, as well as an increased number of sexual partners.


HPV is highly contagious and transmitted primarily through sexual intercourse, although oral and anal sexual contact have also been implicated. In very rare circumstances, vertical transmission and autoinoculation can contribute to the spread of disease.[12] Following sexual contact with an HPV-infected individual, the risk of contracting the virus and further developing viral-related complications such as EGW is thought to be approximately 75%. This high transmission rate results in a 50% lifetime risk of acquiring EGW for individuals who are sexually active with no additional risk factors.[2] Rates may be higher still in individuals who consistently engage in unprotected sexual intercourse, use oral contraceptives alone as protection, have a history of sexually transmitted infections or are immunosuppressed.[13,14]

Dermatopathology
HPV-infected cells can often be identified under the microscope based on their unique histopathological features. Typically, the epidermis will demonstrate a marked acanthosis with varying degrees of papillomatosis, hyperkeratosis and parakeratosis. This is frequently associated with a complete effacement of the granular cell layer.[15] Rete ridges are often elongated and tend to point inward towards the center of the lesion, and the dermis often displays increased vascularization including thrombosed capillaries. The hallmark of HPV infection, however, remains as the development of koilocytes, which are morphologically atypical keratinocytes that are grossly enlarged and contain eccentric, pyknotic nuclei surrounded by a perinuclear halo.


Despite these characteristic features, lesions can occasionally be morphologically ambiguous, in which case electron microscopy and an immunohistochemical peroxidase–antiperoxidase stain can provide a definitive diagnosis,[16] enabling direct visualization of viral particles within host cells. Furthermore, this can be supplemented with the use of MIB-1, a monoclonal antibody that targets the cell cycle-associated Ki-67 antigen, and can help highlight the presence of rapidly proliferating HPV-infected cells.[17]

Clinical Presentation
Following initial exposure and infection, HPV requires an incubation period ranging from 3 weeks to 8 months prior to the appearance of clinical symptoms. On average, however, these present approximately 2–3 months after initial contact.[18] The virus can additionally lie dormant within epithelial cells for prolonged periods of time, resulting in subclinical infections that may remain undetected throughout an individual's lifetime. The degree of clinically silent HPV infection within the general population is thought to be as great as 40%, evidenced by the positive identification of viral samples through DNA analysis conducted on unaffected individuals with healthy appearing genital skin.[19]


Clinical manifestations of EGW may vary dramatically based upon the size, number and location of warts. Typically, EGW present on the moist tissues of the anogenital area, although they can sometimes develop in the mouth or throat following oral sexual contact with an infected person.[3] Lesions themselves may be highly variable in appearance, ranging from flat to dome-shaped, cauliflower-shaped or pedunculated.[13] The warty contour can also vary in color and appearance, and has alternatively been described as white, pink, purple, red or brown, and ranges from flat to ceribriform or verrucous.[20] EGW are frequently found in large warty clusters; however, they may also manifest individually as a solitary keratotic papule or plaque. Patients with small numbers of lesions are often asymptomatic. Initial presentation of EGW lesions usually begin as small, nondistinctive, 1–2-mm flesh-colored papules on the skin; this presentation can be retained for the duration of infection, or alternatively grow up to several inches in diameter.


EGW may be asymptomatic and, particularly when found in small numbers, are rarely described as painful. Large numbers of lesions, however, may be associated with severe discomfort, tenderness, burning and pruritus. Furthermore, large lesions may be subject to bleeding and irritation upon contact, which can result in pain during normal intercourse, defecation or childbirth. Initial infection is often believed to be transient in nature, and it is thought that within the first 4 months of infection approximately 30% of all warts regress spontaneously. An additional 20% are estimated to resolve within the next 2 years.[21] Despite this, long-term remission rates remain largely unknown. Even with the appropriate treatments, the majority of EGW are thought to recur within 3 months of infection.[22] Risk factors for long-term wart persistence include host immunosuppression, concurrent infection with HIV, an increased number of sexual partners, infection with high-risk HPV types and increased patient age.[22,23] Conversely, high rates of spontaneous regression have been linked to the presence of CD4+ lymphocytes in the dermis and epidermis, further supporting the critical role played by the immune system in determining the course of viral infection. Additionally, it is believed that persistent infection in the setting of other clinical risk factors, including pregnancy, may be associated with an increased risk of malignant progression.[24]


The vast majority of EGW infections can be accurately diagnosed on the basis of a careful clinical history and physical examination alone. Documenting findings and the extent of involvement is crucial during physical examination, which may be supplemented with vaginal speculum examination, high-resolution anoscopy, sigmoidoscopy, colposcopy or vaginal speculum examination when indicated.[25] In the case of mild or ambiguous infection, a 3–5% acetic acid solution (the acetowhite test) can be used to help visualize lesions by staining them white. Biopsy is almost never needed for diagnosis, yet it is often recommended for high-risk lesions with possible increased malignant potential. This includes lesions that are found in immunocompromised hosts, those that fail to respond to treatment, or those with atypical features such as ulceration, a rapidly changing appearance or fixation to an underlying structure.[13]

HPV Malignancy
Malignancy is typically associated with high-risk types of HPV, especially with types 6 and 11; however, low-risk type association has been observed. Verrucous carcinoma (VC), a low-grade, well-differentiated form of SCC, is believed to be associated with both high- and low-risk genotypes.[26] VC can be divided into three distinct clinicopathologic types based on anatomic area of involvement: oral florid papillomatosis (oral cavity), giant condyloma of Buschke and Löwenstein (anogenital area), and carcinoma cuniculatum (palmoplantar surface). These tumors rarely metastasize, typically spreading through local invasion.[27] While the authors are yet to establish a direct causal relationship between HPV and VC, persistent HPV infection and viral oncogene expression is known to promote the degradation of the p53 tumor suppression gene, which may result in a lower threshold for tumor formation.[28]


VC can vary in histopathologic appearance from benign lesions resembling pseudoepitheliomatous hyperplasia to VCs that are virtually indistinguishable from invasive SCC. Characteristic features of genital warts, such as vacuolation and prominent keratohyalin granules in the stratum granulosa, are not always detectable.[29,30] For more ambiguous lesions, VC and SCC may be differentiated based upon their immunoperoxidase staining pattern – more specifically, staining samples with p53 and Ki-67 will target the nuclei of basal proliferating cells, which are located predominantly in the lower third of the epidermis in VC. This can be contrasted with the staining pattern of SCC, which will be positive for these same markers throughout the full thickness of the epidermis.[31]
 

A further complication of HPV infections, as mentioned previously, is the increased risk for malignant progression, especially cervical dysplasia and a long-term risk of invasive cancer.[32] While most HPV infections will ultimately clear spontaneously, one-third of EGW harbor high-risk HPV[4] and 10–20% of exposed women will develop persistent oncogenic infections that are associated with a greater risk of progression to cervical intraepithelial neoplasm (CIN) grade II/III. These are thought to be precancerous lesions, which, if left untreated, may eventually give rise to invasive cervical cancer.[33] Penile cancer, which is less common, has shown a strong correlation to both high-risk HPV infection and a history of persistent EGW. This is evidenced by a case–control study involving over 100 men with penile cancer, which identified the risk of penile cancer to be 5.9-times higher in men with a history of EGW when compared with those without (95% CI: 2.1–17.6).[34]

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, sideeffect 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.

Therapies Not Generally Recommended


Several therapies that were commonly used in the past are now no longer recommended in the primary care setting based on both low efficacy and high risk of toxicity. These include podophyllin, 5-fluorouracil (5-FU) and interferon therapy.[67]

Podophyllin 25% Solution


Podophyllin was the first topical agent approved for genital warts. Despite podophyllin containing the same active ingredient as podophyllotoxin, efficacy is limited, with clearance ranging from 20 to 50% at 3-month follow-up, and an inability to induce a lasting remission.[68] When used as monotherapy, it is generally considered less effective than podophyllotoxin, cryotherapy or electrosurgery.[39,61] Furthermore, podophyllin is commonly associated with adverse skin reactions such as burning, redness, pain, itching, and swelling. This may be, in part, due to a lack of standardized drug preparation, which leads to significant variations between samples in the concentration of active ingredient. Application of the drug to the cervix or vaginal epithelium is contraindicated due to the high risk of chemical burns. Podophyllin has also been shown to enter the systemic circulation, and in rare circumstances has been linked to the development of enteritis, bone marrow suppression, abdominal pain and neurological compromise.[69]

5-FU 1% & 5% Cream or Solution


5-FU is a pyrimidine antimetabolite that interferes with DNA synthesis by blocking the methylation of deoxyruidylic acid, resulting in impaired mitosis and cell death. It is one of the oldest chemotherapeutic agents currently available, and has been effectively used in the treatment of cancer for over 40 years. More recently, 5-FU prepared as a cream or solution of 1–5% has been used experimentally for the treatment of EGW, and has been associated with highly variable response rates. Clearance rates are generally found to be comparable with those seen with imiquimod 5%; however, 5-FU is associated with higher rates of recurrence and a significantly more severe side-effect profile.[3,70] Although it is not officially approved by the FDA for the treatment of genital warts, topical 5-FU is still seen as a favorable option for urethral condylomata.[71–73]

Interferon Therapy


Interferons are cytokines released by cells of the immune system in response to the presence of invading pathogens. They are thought to both inhibit viral replication within a host cell and stimulate a more robust immune response. Interferon therapy can be administered both systemically via oral or intramuscular injection, as well as locally via direct intralesional injections. The dose and duration of treatment typically depends on the mode of administration, with anywhere between 1 and 3 million units being used daily or every other day, for a duration of 3 weeks.

To date, interferon therapy has been used predominantly for the treatment of cancers such as malignant melanoma. Recent evidence suggests, however, that it may be a useful therapy for EGW, either independently or as an adjuvant to surgical treatment.[74,75] A meta-analysis of 12 randomized clinical trials showed that, when compared with placebo, intralesional interferon injections resulted in significantly higher rates of complete wart clearance (p < 0.00001). In contrast, systemically used interferon therapy showed no such benefit (p > 0.05).[74,76]

Since interferon therapy is known to directly inhibit viral replication, as well as provide an immune-boosting effect, it is more likely to target all virally infected cells, including those that may be subclinical and difficult to detect. Ultimately, this may lead to lower recurrence rates and better long-term efficacy, especially when used in combination with other treatments. However, the benefit of interferon therapy as an adjunct to surgical treatment remains unclear, with several studies showing significant advantages relative to placebo, while others still showing no such effect.[75,77]

Side effects are more common with systemic injections, and include influenza-like symptoms such as headaches, nausea, vomiting, fatigue and myalgia. For their part, intralesional injections are typically quite painful, and often require the use of local anesthesia.[43]

Although interferon therapy seems like a promising treatment option, further comprehensive research is needed in order to more accurately evaluate its effectiveness.[74] Additionally, each interferon injection is extremely costly, and it therefore only considered as a last-resort therapy, reserved for severe cases, which are unresponsive to other forms of treatment.[74]

Preventative Treatments: The Role of the HPV Vaccine

Gardasil® (HPV4)

In 2006, the FDA approved the use of the first vaccine aimed at preventing infection with specifically targeted HPV types. Gardasil® (HPV4; Merck & Co., NJ, USA) is a recombinant, quadrivalent vaccine that protects against infection with HPV-6, -11, -16 and -18 by triggering the formation of host type-specific neutralizing antibodies directed against these specific types. Taken together, these generate immunity against those types responsible for 70% of cervical cancers, 80% of anal cancers, 60% of vaginal cancers, 40% of vulvar cancers and 90% of genital warts.[78] The vaccine has also been shown to prevent potentially precancerous dysplastic lesions of the cervix such as CIN grades I/II/III, as well as precursor lesions of the anus, vulva, vagina and penis.[79–81]


Gardasil injections are administered in three separate doses, at baseline, and 1 and 6 months. Vaccination is most effective in the HPV-naive population, and accordingly was initially recommended for young women between the ages of 9 and 25 years who had yet to be exposed. The vaccine is thought to be 99% effective in preventing genital wart formation in this population.[82] Current evidence suggests, however, that Gardasil may be of additional benefit to women up to the age of 45 years provided they have not yet contracted at least one of the HPV types targeted by the vaccine. This is likely due to the ability of Gardasil to reduce the incidence of recurrent or persistent HPV infection, which is associated with an increased risk of malignant progression.[83]


Evidence, which supports the efficacy of HPV4 includes multiple randomized, placebo-controlled, double-blinded Phase II and III clinical studies that evaluated over 20,000 adolescent and young women between the ages of 16 and 26 years. These studies found that, among the HPV-naive population, the efficacy of the quadrivalent vaccine in preventing CIN grade II and other severe HPV-related disease was 97–100%. This number dropped significantly to 44% when participants with prior HPV infection were included. The administration of HPV4, however, was able to significantly reduce the need for definitive therapies in the treatment of HPV-related genital lesions among all trial participants. This included a reduction in loop electrosurgical excision by 16.5% (95% CI: 2.9–28.2), as well as a drop in surgical lesion excision by 36.5% (95% CI: 3.6–44.2). This is due to the fact that individuals previously infected with one or more vaccine-related types were still protected from clinical disease caused by the remaining vaccine types. Gardasil therefore proved effective in providing sustained protection against both low- and high-grade lesions attributable to HPV types 6, 11, 16 and 18, as well as precipitating a substantial reduction in HPV-related morbidity and burden of disease.[84] Long-term follow-up studies have confirmed the ongoing protective effects of Gardasil up to 5 years postvaccination with no evidence of waning immunity.[85]

Side effects of HPV4 administration tend to be mild and include fainting, swelling at the injection site, headache, nausea and fever. These are thought to occur largely as a result of the method of administration rather than the vaccine content, since similar effects were seen with comparable frequency following the administration of placebo vaccines.[85] Although some controversy still persists with respect to Gardasil and possible adverse events, there is currently no evidence to support a causal link between vaccination and any serious complication including illness, hospitalization, permanent disability or death.[84]


The FDA recently expanded the therapeutic use of HPV4 to include boys and young men between the ages of 9 and 26 years.[86] The vaccine was shown to be equally as effective in males when compared with females in the prevention of EGW and the induction of a long-lasting immunogenic response. It was also found to be effective in reducing the incidence of precursor lesions to anal cancers, which, like CIN, are strongly associated with HPV infection.[84,87,88] Expanding the use of this vaccine to males has the additive benefit of reducing the incidence of infection in females by preventing viral transmission and directly targeting the viral pool. Decreasing the viral burden of HPV by potentially eliminating the host reservoir necessary for viral incubation is a critical step in the eventual eradication of the virus.[89] Furthermore, important population-based reports on the reduction of EGW in a real-life setting due to high coverage of HPV vaccination have now been reported in Australia, demonstrating not only a decrease in frequency of EGWs in females of vaccine-eligible age, but also protective effects in heterosexual men through herd immunity.[90] Four years after commencing this vaccination program, the disappearance of EGW in women and men under 21 years of age within this population has recently been reported.[91] In addition, similar results demonstrating a decline in the incidence of genital warts within target populations following HPV vaccination programs have been reported in both New Zealand and the USA.[92,93]

Cervarix (HPV2)


In the fall of 2009, the FDA approved the use of a second recombinant HPV vaccine (HPV2; GlaxoSmithKline, UK) in females between the ages of 10 and 25 years. Vaccinated women have been shown to benefit after treatment of EGW, demonstrating substantially less subsequent HPV-related disease.[94] Cervarix is similar to HPV4 in terms of dosing and administration schedules; however, it is a bivalent vaccine directed only against high-risk HPV types 16 and 18. These two oncogenic types are most commonly associated with cervical cancer, CIN grade I/II/III and adenocarcinoma in situ. Cervarix does not provide protection against the types commonly associated with genital warts. HPV2 was evaluated in two Phase II and III randomized, double-blind, placebo-controlled clinical trials that followed over 18,000 females for a mean duration of 35 months. Results of these trials revealed Cervarix to be 93% (95% CI: 79.9–98.3) effective in the prevention of HPVrelated CIN grade II or III and adenocarcinoma in situ in the HPV-naive population. Again, this number dropped significantly to less than 30% when all trial participants were included. Side effects following HPV2 administration occurred significantly more frequently compared with HPV4, and included injection site pain, redness and swelling. Additionally, general systemic symptoms such as fatigue, headache and myalgia were also more significantly reported.

To date, there has been only one randomized, observer-blinded head-to-head comparison of the efficacy, safety and immunogenicity of HPV4 and HPV2 in a single controlled population. The study included a well-defined population of over 1100 healthy females aged 18–45 years. Results of this study revealed that, for all ages, serum-neutralizing antibodies to HPV-16 and -18 were significantly higher following Cervarix administration than after treatment with Gardasil (p < 0.0001). This discrepancy in immune response may be explained by differences in the precise formulation of each vaccine. In particular, the use of unique adjuvant factors may serve to activate and enhance immune signals through highly specific adjuvant-dependent pathways. The clinical implication of this observed effect remains largely unknown, and a direct link between the level of serum antibody titers and the degree of immune protection is yet to be established.[83] Currently, the American Cancer Society and Advisory Committee on Immunization Practices continues to recommend routine vaccination for all females beginning at 9 years of age up to 26 years of age, for all males from 9 years of age up to 21 years of age, and for males who have sex with males up to 26 years of age with either HPV2 or HPV4.[5,95]

Conclusion

External genital warts occur as a result of underlying infection with HPV, and are considered among the most common sexually transmitted diseases affecting the general population. Between 3 and 6 million people will acquire symptomatic infections each year in the USA alone, representing approximately 1% of the sexually active population.[20] Although there are over 120 different HPV types, approximately 90% of wart lesions are caused by infection with HPV types 6 and 11. These are considered to be low-risk types due to their limited malignant potential, and only rarely progress to cancerous lesions. Conversely, warts associated with the high-risk HPV types 16 and 18 may be predisposed to oncogenic transformation.[7] Additionally, infection with these types has been linked to the development of a variety of different cancerous and precancerous lesions.


Current treatment options for genital warts mainly focus on removal of the superficial external lesion rather than targeting the underlying viral infection at the lesion source. Not surprisingly, these therapies have proven inadequate and ineffective in achieving long-term wart relief. Multiple different therapy modalities exist, ranging from topical treatments to surgical and immunomodulatory interventions, and these can differ dramatically with respect to cost, duration, dosing schedules and adverse effects. To date, no single therapy has emerged as significantly superior with respect to overall efficacy and wart clearance in both the short and long term. Selection of a given treatment is often patient dependent, and reflects both the needs and desires of the individual.


EGW and HPV infections remain a significant public health concern, with a remarkably high prevalence of disease and a lack of adequate therapy. These facts emphasize the importance of routine HPV vaccination with either HPV4 or HPV2, which may play a powerful role in reducing the burden of disease by preventing viral infection and transmission. Multiple large-scale randomized controlled trials evaluating the effectiveness of HPV vaccination have demonstrated it as both successful and safe in preventing genital wart infection in both sexes when administered prior to exposure. This supports the need for further research into the development of similar vaccines, which may target additional HPV types. As HPV vaccination continues to gain popularity and widespread approval for use in a broader population base, it may prove instrumental in decreasing the incidence of HPV infection and eventually eradicating genital warts.

Expert Commentary

EGW occur as a result of underlying infection with HPV, and are considered among the most common sexually transmitted diseases affecting the general population. Approximately 90% of wart lesions are caused by infection with low-risk HPV types 6 and 11 only rarely progress to cancerous lesions. Warts associated with the high-risk HPV types 16 and 18 may be predisposed to oncogenic transformation. Multiple different therapy modalities exist, ranging from topical treatments to surgical and immunomodulatory interventions, and these can differ quite dramatically with respect to cost, duration, dosing schedules and adverse effects. As of yet, no single therapy has emerged as significantly superior with respect to overall efficacy and wart clearance in both the short and long term. Selection of a given treatment is often patient dependent, and reflects both the needs and the desires of the individual. EGW and HPV infections remain a significant public health concern, with a remarkably high prevalence of disease and a lack of adequate therapy. This emphasizes the importance of routine HPV vaccination, which may play a powerful role in reducing the burden of disease by preventing viral infection and transmission.

Five-year View

Multiple large-scale randomized controlled trials evaluating the effectiveness of the HPV vaccination and newly developing EGW treatment modalities have changed the scope of what was once a very challenging disease for the dermatologist to properly manage. Now primary prevention and secondary eradication of EGW is clearly possible. Further research into the development of similar vaccines that can target additional HPV types is now required. Additionally, research is now being geared towards the combination of certain dermatologist and patient-administered treatment modalities as a means to not only increase overall effectiveness but also shorten the duration of treatment.

Sidebar

Key Issues


  • Estimates show that anywhere between 3 and 6 million cases of external genital warts present each year in the USA​ alone, representing approximately 1% of the sexually active population.
  • Low-risk types comprise viral strains (human papillomavirus [HPV] types 6 and 11) and rarely give rise to cervical​ cancers; however, these strains account for 90% of genital wart lesions.
  • In contrast, HPV types 16 and 18 are strongly associated with cervical dysplasia, and evidence of infection with these genotypes can be found in up to 70% of squamous cell carcinomas of the cervix.
  • Following initial exposure and infection, HPV requires an incubation period ranging from 3 weeks to 8 months prior to the appearance of clinical symptoms.
  • Malignancy is typically associated with high-risk types of HPV; however, low-risk HPV-type association has been observed.
  • Verrucous carcinoma, a low-grade, well-differentiated form of squamous cell carcinomas, is believed to be associated​ with both high- and low-risk genotypes. Verrucous carcinoma can be divided into three distinct clinicopathologic types​ based on its anatomic area of involvement: oral florid papillomatosis (oral cavity), giant condyloma of Buschke and Löwenstein (anogenital area) and carcinoma cuniculatum (palmoplantar surface). These tumors rarely metastasize​ and are typically spread by local invasion.
  • Numerous therapies are presently indicated for use in the treatment of external genital warts, which can target lesions through multiple modalities including topically, surgically or via immune modulation. Therapies often differ dramatically with respect to cost, side-effect profiles, dosing schedules, duration of treatment and overall​ effectiveness.
  • External genital warts and HPV infections remain a significant public health concern, with a remarkably high prevalence of disease and a lack of adequate therapy. This emphasizes the importance of routine HPV vaccination, which may play a powerful role in reducing the burden of disease by preventing viral infection and transmission.


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Triple Combination Therapy against HPV Anogenital Warts


An unbiased impartial summary of most all known therapies for anogenital warts - is published below:

Treatment of Genital Warts 

Published by Medscape.com, written by Valerie R Yanofsky; Rita V Linkner; David Pompei; Gary Goldenberg

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


​Whereas duel combination therapy has demonstrated promising results for most patients, triple combination therapy can be even more effective in the hands of an experienced physician. Numerous articles in medical Journals have touted the benefits of combination therapies: First, with topical medications – applied to the surface areas of the wart and skin. Second, in combination with CO2 laser vaporization of the warts. And third, with intralesional wart injections using interferon. 


A list of known HPV treatments, and how effective they are at clearing warty lesions, is charted below: