An evidence-based review of medical and surgical treatments of genital warts
1. St Lukes Roosevelt Hospital Center Department of Dermatology, New York NY. NSS32@Columbia.edu
Genital human papillomavirus (HPV) infection is the most common sexually transmitted disease. Each year 1 million new cases of genital warts are diagnosed, two thirds of which are in women. The estimated prevalence rate in the US population is 15 percent. HPV infects keratinocytes. Such infection can manifest clinically as warts. Treatment options for genital warts are numerous, well established, and effective. Topical treatments include podophyllin resin, imiquimod, trichloroacetic acid, and podophyllotoxin. Surgical or destructive therapies include carbon dioxide laser, surgical excision, loop excision, cryotherapy, and electrodessication. Interferon can be injected locally or administered systemically to treat genital warts. Evidence of efficacy in the treatment of genital warts is drawn from randomized blind-controlled trials, prospective studies, and retrospective cohort studies. Evidence of efficacy appears to be good, but more head-to-head studies and comparisons of combination therapies versus monotherapy need to be done. Treatment of choice depends on the number, size, and location of lesions. There is little certainty that any approach is more effective than another, however costs differ. It would seem that the first line destructive treatment is cryotherapy, but surgery and electrodesiccation are more effective. The first line topical treatments appear to be podophyllotoxin and imiquimod. Interferon is too expensive and trichloracetic acid is too inconsistent to be recommended as primary treatment. It is unclear if combinations of therapies are more effective than monotherapy. Side effect profile, cost, effectiveness and convenience (ability to attend physician's office or to undertake protracted home treatment) define the choice of therapy.
Human papilloma viruses (HPV) are non-enveloped, double-stranded DNA viruses. The HPV genome encodes 6 early-open reading frames (E1, E2, E4, E5, E6, E7) and 2 late-open reading frames (L1, L2). Differences in L1 define HPV subtypes. The E genes encode proteins regulating function, and the L genes encode for viral capsid proteins. Malignant tumors develop after long latency periods during which additional cellular modifications occur within the infected cell. The early region of these HPV types encodes two oncoproteins, E6 and E7, which associate with and neutralize the cellular tumor suppressors p53 and retinoblastoma (pRb), respectively [1, 2, 3, 4, 5, 6, 7]. The virus initially infects the basal cell layer, and its life cycle is linked to the progressive differentiation of epithelial cells.
More than 120 distinct HPV subtypes have been identified. Of the 120 subtypes of HPV, 30 infect genital epithelium [1, 2, 3, 4, 5, 6, 7]. These subtypes are divided into 3 categories based on their likelihood of inducing dyplasia and carcinoma (Table 1). HPV types 6 and 11 are considered to be low risk and are the most common cause of genital warts. HPV types 31, 33, 45, 51, 52, 56, 58, and 59 are referred to be intermediate risk because they are common causes of squamous intraepithelial neoplasia but less common causes of squamous cell carcinoma. HPV types 16 and 18 are strongly associated with cervical dysplasia and anogenital cancers. Patients who have visible genital warts can be infected simultaneously with multiple HPV types [2, 3]. Establishing the subtype of HPV helps to determine the likelihood of malignant degeneration but has no bearing on the diagnosis or treatment of genital warts.
Genetic mechanisms define the basis for HPV risk category. The E6 and E7 proteins of the low-risk types, HPV 6 and HPV 11, replicate as an episome and rarely incorporate their genetic material into the host DNA, although these proteins have been occasionally demonstrated in cancer cells [1, 2, 3, 4, 5, 6, 7]. Intermediate and high risk HPV DNA intercalates itself into human DNA. Their E6 and E7 genes can produce oncoproteins that alter cell growth regulation. E6 oncoprotein inactivates p53, the tumor suppressor gene. The oncoprotein produced by E7 inactivates pRB [1, 2, 3, 4, 5, 6, 7].
The immune system plays a central role in regression of genital HPV disease via both cellular and humoral immunity. Spontaneously regressing genital warts show significant epidermal and dermal influx of CD4+-activated memory lymphocytes compared to nonregressing lesions [6, 7]. Cellular immunity appears to be the prime means of repelling HPV infection. The association of serum antibodies to HPV proteins with HPV-related diseases is well documented, but what role these antibodies play is uncertain because their presence does not correlate with wart clearance. Evidence suggests that T cells in male and the female genital epithelium secrete protective antibodies against many HPV infections, the significance of this is unclear.
Genital warts are almost always spread by sexual contact but vertical transmission and autoinoculation do occur rarely. Approximately 70 percent of individuals who have sexual contact with an infected partner develop genital warts. The incubation period of HPV varies from 3 weeks to 8 months, with a mean of 2-3 months after initial contact. The rate of subclinical infection is as high as 40 percent when measured by polymerase chain reaction DNA analysis on genital skin . After the initial clinical manifestation, warts may increase in number and size, or may regress spontaneously (as many as 30 % over 4 months). The rate of long-term regression is unknown. Even with therapy, recurrence occurs within 3 months in 25-67 percent of cases. Recurrences are often at sites of previous genital warts, attributed to long-lived cells at the site of previous clearance that then reactivate. Infection with high-risk types of HPV and older age patients are risk factors for persistence .
The incidence of HPV infection has increased in the last 35 years, likely the result of earlier age of initial sexual contact and an increased number of sexual partners [1, 3]. The estimated prevalence rate of HPV genital infection in the US adult population is 10-20 percent . The prevalence of clinical manifestations of HPV genital infection is much lower that the rate of infection and is estimated to be 1 percent in the sexually active population [1, 3]. This observation holds true even after adjustment for lifetime number of sexual partners, which itself is a significant risk factor for HPV infection [1, 3]. Approximately 80 percent of individuals with genital warts are aged 17-33 years. Evidence suggests that at least 75 percent of sexually active adults have been infected with at least one genital HPV-type at some time.
Genital warts manifest as solitary or clustered, keratotic papules and plaques. They may be flat, or dome-shaped, cauliflower-shaped, or pedunculated (Fig. 1). Genital warts can occur on the penis, groin, cervix, urethral meatus, vagina, anus, pubis, and oral cavity. Their contour can be flat, ceribriform, or verrucous and their color white, skin colored, pink, purple, red, or brown (Fig. 1).
Neoplastic lesions (e.g., verrucous carcinoma), inflammatory lesions (e.g., lichen nitidus), and normal physical findings (e.g., pearly penile papules) can mimic genital warts. The performance of physical examination using bright light and magnification aids in the diagnosis of genital warts. Biopsy is recommended only when verrucous papules and plaques thought to be genital warts (1) are not responsive to therapy, (2) manifest with induration, (3) are fixed to underlying structures, (4) have ulceration, (5) grow suddenly or increase pigmentation, or (6) change in appearance. Acetic acid solutions (the acetowhite test) applied to warts to highlight them have a low positive predictive value for diagnosing genital warts. The quality of the data relating to the diagnosis of genital warts is included in the side bar.
Treatments reviewed and scope of treatment review
Treatments for genital warts can be classified as topical, surgical, destructive, or immunomodulatory. There are systemic treatments of warts that involve interferon (IFN), retinoids (isotretinoin), and cimetidine but they are not analyzed here. There is vaccine for the prevention of infection with high-risk HPV subtypes. This vaccine is not discussed in this review although it will impact the practice of all physicians who treat genital warts in the years to come.
Podophyllin resin is derived from the from the rhizome (underground root system) of the mayapple (Podophyllum peltatum), a plant that grows wild in eastern North America. Podophyllum hexandrum grows in India's mountains has even more of the active component.
Podophyllin was used as a medicine by native Americans. Doctors in New Orleans started using it for the treatment of genital warts in the 1930's. In 1942 the first description of this practice was published in the medical literature, the first topical treatment of genital warts. Podophyllin is reliable, inexpensive (at least when assessed by weight), easily obtainable, physician-applied treatment for genital warts. In the United States, podophyllin is sold to physicians as a 10-25 percent suspension in tincture of benzoin. The biochemical basis for the effectiveness of podophyllin has been defined. Podophyllin is an antimitotic agent that disrupts viral activity by inducing local tissue necrosis.
The disadvantages to the use of podophyllin include unstandardized preparation, side effects, lower effectiveness, failure to induce lasting remission, and teratogenicity. Podophyllin preparations vary greatly in their active component and contaminant concentrations. The shelf life and stability of podophyllin are unknown, and well-standardized preparations are not consistently available.
In rare instances the use of podophyllin is associated with side effects. It can be absorbed systemically; toxicity increases when it is applied to areas greater than 110 mm² or to skin surfaces that favor systemic absorption. Very rare side effects include bone-marrow suppression, liver dysfunction, neurological compromise, podophyllin hallucinations, psychosis, nausea, vomiting, diarrhea, abdominal pain, and genital burns. To minimize side effects, a thin layer of podophyllin should be applied to warts and allowed to air-dry completely. Over-application or failure to air dry can spread the podophyllin and increase the rate of local reaction, in particular on uninvolved skin.
Head-to-head studies conflict as to the relative effectiveness of podophyllin (see Table 2). A randomized comparison with once weekly podophyllin shows initial complete clearance of 93 percent versus 77 percent for surgical excision, and recurrence rates at 6 months of 22 percent versus 56 percent for excision . Other studies find that podophyllin resin is less effective than surgery. When compared individually with podofilox, cryotherapy, and electrosurgery, or when used with intralesional interferon as an adjunct therapy, podophyllin alone appears less effective. Recurrences are reported for 23-65 percent of clinical trial participants. The use of podophyllin is contraindicated in pregnancy.
Podophyllotoxin contains purified podophyllin in a standardized concentration in cream, gel, or solution preparations that can be self applied by the patient. Studies show that podophyllotoxin is more effective than podophyllin (see Table 3).
Lacey et al. report a randomized trial in 358 subjects comparing clinic-applied podophyllin with patient-applied podophyllotoxin solution and cream. Self-applied podophyllotoxin solution is three times more likely to be associated with short term cure than podophyllin, and podophyllotoxin cream is twice as likely . Both podophyllotoxin preparations are also more cost-effective than podophyllin. Podophyllotoxin solution is used for penile lesions; cream or gel formulations are easier to use for vagainal and anal lesions . Although data suggest that it is safer than podophyllin, podophyllotoxin is contraindicated during pregnancy.
Podophyllotoxin is applied twice daily for 3 consecutive days, then discontinued for 4 consecutive days. This one week cycle of treatment may be repeated until there is no visible wart tissue or for a maximum of four cycles. If there is incomplete response after four treatment cycles, discontinue treatment and consider alternative treatment. Safety and effectiveness of more than four treatment cycles has not been established. There is no evidence to suggest that more frequent application will increase efficacy, but additional applications do increase the rate of local adverse reactions and systemic absorption. Cost (by weight), number of actual treatment applications, and compliance aside, podophyllotoxin appears to be preferred over podophyllin.
Imiquimod is a patient-applied immunomodulatory topical treatment of genital warts. An imidazoquinolinamine, imiquimod induces macrophages to secrete cytokines IL-2, IFN-α 1 and 2, IFN-β, IFN-γ and TGF-α. IFN-α is probably the most important cytokine inducing genital wart clearance. A clinical response with imiquimod is accompanied by a decrease in the amount of HPV DNA and of messenger RNA for HPV proteins L1 and E7 . It is thought that imiquimod may stimulate a cell-mediated immune response against HPV. In vivo studies show enhanced cytolytic and lymphoproliferative responses with imiquimod use [19, 20, 21, 22, 23].
Imiquimod was studied in 1 percent and 5 percent creams, the latter is more efficacious and is the only available commercial preparation. In randomized placebo-controlled trials, 5 percent imiquimod cream shows clearance within 16 weeks of up to 50 percent of warts (see Table 4). Imiquimod is applied to genital warts at bedtime and washed off in the morning, 3 times per week (every other day) for 16 weeks. This duration of treatment is longer than that of any other genital wart treatment.
The side-effect profile of imiquimod is benign. Mild to severe erythema may occur with this treatment. Other side effects include localized erosions, an impetigo-like reaction, and itching or burning sensations. Less frequent side affects include irritation, induration, crust formation, and tenderness. Recurrences occur in up to 20 percent of patients. The safety of imiquimod during pregnancy is not established and thus its use is contraindicated in pregnancy. Animal studies do not show that imquimod to be teratogenic or fetotoxic, however, contraception is recommended for women of childbearing age using imiquimod.
Surgical and destructive treatments
There are several surgical and destructive treatments available for the treatment of genital warts, including cryotherapy, surgical excision, electrosurgery, and laser vaporization. All are very effective treatments of genital warts (see Table 5).
Surgical removal of genital warts can be performed either with scissors, a scalpel, or by electrocautery. It is appropriate for any genital wart, but especially for large lesions causing obstruction, i.e., involving the urethral meatus. Scissors or scalpel excision is best mode of treatment when a tissue specimen to be submitted for histopathological examination is needed to rule out malignancy. Larger lesions may require adequate anesthesia (local, regional, or general) and surgical instruments for hemostasis, bedcause large genital warts are highly vascular. Patients also may experience significant post-procedure pain, especially when there is a large treatment area.
Electrosurgery involves either thermal coagulation or electrocautery, to destroy HPV affected lesions. Local anesthesia is needed to perform electrosurgery. There are two forms of electrosurgery. In the direct-current form of electrosurgery, termed electrocautery, electricity flows only through the instrument producing heat that is applied to the lesion. In the alternating-current form of electrosurgery electricity flows from the instrument through the patient to a grounding plate. The alternating current systems produce cutting, coagulation, or a blend of both. Fine-wire loops can be used for excision [24, 25]. There are no recent studies of electrosurgical methods for genital wart treatment. Older studies show a 61-94 percent clearance within 3-6 weeks of treatment . Despite their effectiveness, electrosurgery should be considered second-line treatment . Two randomized trials show slightly greater efficacy for electrotherapy compared with cryotherapy; however, the differences in outcome is only short term and does not persist after 3 months of followup [28, 29].
The loop electrosurgical excision procedure (LEEP) has been compared with laser treatment for genital warts. Schoenfeld et al. studied 28 women and showed 86 percent of lesions treated with LEEP and 75 percent of lesions treated with a laser showed no HPV DNA within a 20-mm circumference of the treated lesion. In clinical studies, 14-22 percent of patients have recurrences. They were reexamined for recurrence after 3 months; there were 4 patients who harbored HPV-DNA genomes on the laser-treated side, adjacent to the original lesion, compared to 1 patient who developed recurrence on the LEEP side in a more distant, previously untreated, area .
Cryotherapy involves application of nitrous oxide or liquid nitrogen (-196°C) to genital warts, inducing dermal and vascular damage and edema, and leading to both epidermal and dermal cellular necrosis.
There are several methods of performing cryotherapy. Liquid nitrogen can be poured into a container with a applicator (cryoprobe) to form a cryostat unit. Liquid nitrogen is then sprayed onto wart until it turns white, indicating that it is frozen; the subsequent thaw produces cell lysis. Two freeze/thaw cycles are usually undertaken, but trials have not established the optimal number of applications. Discomfort is moderate enough so that anesthesia is not needed. Liquid nitrogen may be applied directly to warts with a cotton-tipped swab. Cryotherapy may be used for any anogenital wart that is accessible to treatment.
The advantage of cryotherapy include ease of application and rapid destructive effect. It may have special advantage in treating bulky lesions, grouped lesions, and lesions on hair-bearing areas. It does not have systemic side effects and only affects tissue to which it is directly applied. Following cryosurgery, treated areas require local care only and treated areas may be cleaned. Scar formation is rarely significant. Pigmentary alterations in the short term are not uncommon but usually (but not always) normalize. Genital warts on the prepuce, especially flat genital warts, have a greater predilection for scarring and fibrosis after treatment. Healing usually occurs in 1-2 weeks after cryotherapy, although sometimes complete healing may take more than eight weeks. Based on a study of 34 pregnant women treated with cryotherapy, three to four treatments of cryotherapy appear to be safe .
Crytotherapy is effective. Trials show genital wart clearance rates from 79-88 percent with recurrences in 25-39 percent despite multiple treatments (see Table 5). Most warts cleared with fewer than three treatments. Crytotherapy is relatively inexpensive. The equipment required for office cryosurgery using liquid nitrogen includes a Dewar flask with dispensing valve and a cryogun, all costing $1,000-3,000.
Handley  and Eron  each compare cryotherapy plus IFN injection versus cryotherapy plus placebo. Intralesional IFNα is injected directly into the base of each wart. The procedure is painful; local anesthesia is recommended to minimize discomfort. Data show no clear advantage of using subcutaneous interlesional interferon over cryotherapy alone [31, 32]. It appears that cryotherapy is superior to trichochloroacetic acid therapy [33, 34, 35]. (see Table 5: Trials involving cryotherapy, surgical and combination therapy of genital warts.)
Carbon dioxide laser therapy
The CO2 laser utilizes focused infrared light energy to vaporize affected tissues. It permits precise tissue ablation by spatial confinement of thermal damage and effective vaporization, which promotes rapid healing without scar formation in most cases. CO2 laser therapy is a useful treatment modality, especially for extensive warts (see Table 6). The principal advantages of CO2 laser therapy are precision (which results in sparing of normal tissue), probable elimination of the infective agent, and relatively good cosmetic result. Carbon dioxide laser can be used to treat extensive and thick warts quickly and without the drawing of blood. The carbon dioxide laser is able to effect such wart clearance in part because of deeper penetration than generally occurs with cryotherapy. The CO2 laser is best used at power settings of 2-10 Watts because it vaporizes tissue with a shallow depth of penetration at those settings.
However, laser treatment is more complex and costly than electrosurgery or cryotherapy. A CO2 laser costs $5,000-50,000 and requires maintenance and additional training to perform correctly. CO2 laser therapy is typically an office procedure. However, larger lesions and pediatric patients may require anesthesia and therefore can be done in the hospital under general anesthesia. HPV DNA may be released during laser vaporization of genital HPV infections; if appropriate evacuating equipment is used, contamination of the operator is unlikely [36, 37]. The surgeon and assisting personnel must wear laser masks and use a vacuum ventilation system . Risk factors for transmission of genital warts by vaporization inlude the HPV type, thinness of skin, and viral burden . A disadvantage of the lasers is that the risk of scarring, although small, is greater than of cryotherapy.
There are no new significant studies comparing the benefit of carbon dioxide laser therapy versus placebo. In former studies, the efficacy of laser treatment ranged from 23 to 52 percent with 3-18 months follow up. Recurrence rates ranged from 60 to 77 percent . Newer studies either are poorly designed or involve too small a sample size . Most studies require additional therapies [40, 41]. Carrozza et al. compared extensive genital warts in HIV-positive and HIV-negative patients. The clearance and recurrence rates were similar for both groups . (see Table 6: Trials involving laser treatment of genital warts)
Trichloracetic acid (TCA) can be used to treat genital warts. It is a caustic that erodes the skin and mucous membranes, but generally is not absorbed systemically. TCA is topically applied in a solution concentration of 60-90 percent. It is most effective when treating few small, moist lesions. TCA also can be used to treat vaginal and anal lesions . A small amount of TCA can be applied to a wart and allowed to dry until a white frosting develops. If excess TCA is applied to non-affected tissue, the area should be washed with liquid soap or sodium bicarbonate . The application of TCA is accompanied by a burning sensation that last for 2-5 minutes.
TCA treatment is delivered in a controlled manner to provide limited local destruction. Dermal injury or scarring is rare. Side effects are local and include pain, ulceration, and crust formation. Studies using TCA have report clearance rates of 70-81 percent after six applications and recurrence rates of 36 percent [33, 34]. TCA appears to be less effective than cryotherapy for treating warts. Common practice suggests that TCA has low systemic effects. TCA has been used in pregnancy, however it is not free of side effects in that setting. One study showed wart clearance in 97 percent of treated women, however the side effects included need for suprapubic catheterization in 7 of 32 women, premature labor in 2 women, and premature rupture of membranes in 3 woman . TCA did not appear linked to increased fetal morbidity or mortality or birth defects [44, 45].
Interferon is an effective treatment for warts (see Table 7: Trials involving intralesional and intramuscular interferon treatment of genital warts). It appears that combinations of interferon and other treatments are not more effective than such other treatments used alone. The high cost of interferon make it a treatment best reserved for genital warts recalcitrant to other treatments.
Interferon may not have a synergistic effect with other treatment modalities in the treatment of condyloma . Subcutaneous IFNα2a combined with cryotherapy was no more effective than cryotherapy alone in the treatment of primary anogential warts . Similarly, IFNα2a in combination with podophyllin was no more effective in the treatment of primary anogenital warts than podophyllin alone and is associated with more adverse events .
In some instances, however, combining interferon with other treatments increases the likelihood of effective treatment. In one study, the addition of subcutaneously administered interferon α-2b to laser treated patients with chronic therapy-resistant genital lesions significantly enhanced the chance of eliminating these warts, and it was fairly well tolerated . There are also data that suggest a gel containing interferon can help treat intravaginal warts . However, because of its high cost and inconsistent effect, interferon is best considered a treatment of last resort for the treatment of genital warts.
The most inexpensive medical therapy for HPV by weight is podophyllin. The expense of a product, however, does not dictate its cost effectiveness. In 1994 Mohanty studied the cost effectiveness of 25 percent podophyllin and 0.5 percent podophyllotoxin solution in the treatment of genital warts in genitourinary medicine clinic patients . He found that, although the average treatment cost for a course of podophyllotoxin was more than that for podophyllin (20.75 £ versus 14.95 £ respectively), the overall cure rate with podophyllotoxin was 66 percent as opposed to 34.6 percent with podophyllin. When the costing of secondary treatment options was considered, the cost per patient cured of warts with podophyllin resin was 27.15 £ compared with 25.73 £ for podophyllotoxin solution, which was not a significant difference.
Alam and Stiller assessed the costs of genital wart treatments and find that surgical excision is the most cost-effective treatment for simple and extensive warts and that podophyllotoxin is the most cost effective medical treatment for simple and extensive warts (see Table 8: Cost effectiveness of treatments of warts [55, 58]). The study date in this table might not fully account for the all the costs involved with setting up, training personnel, and maintaining a laser. It also seems to overestimate the cost of cryotherapy, which usually costs no more to apply to small areas than to large areas.
Mechanisms, dosing schedules and side effects of treatments for condyloma
In addition to effectiveness, mechanisms and dosing schedules inform a physician's decision on what therapy to select. For example, in an HIV positive patient whose interferon production is impaired, imiquimod is suboptimal therapy. Data regarding mechanisms of treatments are included in Table 9. (see Table 9: Mechanisms of treatment for condyloma [5, 56]). Also important in determining the treatment for a given patient is an understanding of the dosing schedule and need for office visit or home use with a topical treatment. Information regarding dosing schedule is included in Table 9. If patients cannot attend clinic regularly, dosing schedule closely influences treatment choice. (see Table 10: Typical treatment cycles for patients with genital warts )
It is important to understand the side effects of treatments of genital warts because side effects influence the choices that physician and patient make regarding choice of treatment. A summary of these side effects appears in Table 11. Because of its side effects podophyllin is likely not a preferred treatment. (see Table 11: Side effects of treatments of condyloma )
If warts must be treated in pregnancy, cryotherapy appears to be the best choice. The topical treatment that appears to have the best safety profile in treating warts that occur during pregnancy (warts that can adversely affect the fetus) is trichloracetic acid [44, 45].
Summary and conclusion
Genital infection by HPV is very common in sexually active adults. Most infections do not result in the manifestation of genital warts. The annual incidence of genital warts is 1-2 percent of the sexually active population (3-6 million people). Genital warts are not themselves cancerous, but warts caused by high risk types of HPV are predisposed to oncogenic transformation. All female patients with anogenital warts should be considered at risk for cervical, vaginal, and vulvar dysplasia, which can lead to cancer and death.
Selection of a treatment modality may depend on the number, size, and location of lesions. There is little certainty that one approach is more effective than another, although costs differ . Base on our review, it seems that the use of podophyllin should be limited to instances where side effects are discounted, and that compliance and medication cost are the dominant factors . Because of high cost and inconsistent effect, interferon is a treatment of last resort. Although imiquimod has few side effects and a low recurrence rate, it is expensive, requires protracted application, and is no more effective than the much less expensive podophyllotoxin. Cryotherapy is quick, easy, safe and relatively inexpensive. Thus cryotherapy is first line treatment for genital warts in pregnant women and in patients who tolerate the pain associated with application. Surgical excision and destruction are advantagous because of their immediate definitiveness and clearance of infected tissue (sometimes in only one visit) but can be expensive, painful, and frightening. They should only be used in appropriate patients. Determining the best treatment for genital warts takes into accoung efficacy, needs, preferences, financial resources and convenience to the patient.
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