|August 2011 · Vol. 23, No. 8
Current and emerging options for treating external genital warts
Anita L. Nelson, MD
Professor, Department of Obstetrics and Gynecology, Harbor UCLA Medical Center, Torrance, CA
Dr Nelson is a consultant to Graceway Pharmaceuticals, LLC.
The variety of therapies for external genital warts allows the clinician, working with the patient, to design a regimen that best suits not only her clinical problem but also her personal preferences and the resources offered by the medical practice.
From a public health perspective, it is the prevention of disease that has always had highest priority. So, as physicians deal with patients’ clinical problems, they can appreciate the importance of protecting them from infection with human papillomavirus (HPV) and all its sequelae.
For years, the mainstay of preventive advice regarding HPV has been: “Practice safer sex.” Stable mutual monogamy with an uninfected partner is, of course, the most salubrious option for sexually active people. But, given the ubiquitous prevalence of HPV and current sexual mores, until recently there has been only the correct and consistent use of the male condom as the means to significantly reduce the spread of HPV.
Regrettably, most people are notoriously poor condom users. In one study, 44% of women who relied on the male condom as their only method of contraception admitted that they had had at least one episode of unprotected intercourse in the previous 2 weeks.1
WHAT THE HPV VACCINE HAS MEANT FOR PUBLIC HEALTH
Introduction of bivalent and quadrivalent vaccines against HPV has created a much more effective way to prevent specific diseases associated with the viral types covered by those vaccines. The quadrivalent vaccine creates humoral immunity to HPV types 6 and 11, which cause 90% of external genital warts (EGW). FDA-approved for both men and women ages 9 to 26 years, this vaccine offers a means to prevent EGW in men and women.
The vaccine also protects women from cervical dysplasia and cancer in 2 ways:
It directly protects them from the so-called high-risk viral types 16 and 18 that cause 70% of cases of cervical cancer
It reduces the risk that an unvaccinated woman will be exposed to high-risk HPV by reducing the rate of infection among her sexual partners.
Although uptake of the vaccine has been variable,2 reports from Australia, where HPV vaccination is mandatory and generally funded for citizens, have documented a remarkable reduction in the numbers of cases of EGW among populations who were likely to have been vaccinated.3
OPTIONS FOR TREATING EGW
The Sexually Transmitted Diseases Treatment Guidelines, 2010 issued by the Centers for Disease Control and Prevention (CDC) emphasize the point that no single therapy is superior to any other for treating all EGW.4 The best way to ensure success is to have an array of options available to tailor therapy to an individual patient’s presentation and personal preferences. Often, one treatment can be used to provide partial clearance and a second one can be used to complete clearance of remaining lesions.
The primary objective for treating EGW is to eradicate the lesions to ameliorate symptoms. The patient may complain of burning or itching or suffer superinfection, but the presence of abnormal lesions alone provides sufficient rationale to initiate treatment.
The patient needs to understand 2 points before she and the clinician embark on therapy (especially if her lesions are few or small):
Watchful waiting may be appropriate, to see if the lesions spontaneously regress; even without therapy, lesions sometimes resolve spontaneously. It is also possible, however, that lesions will persist or even increase in size or number.
Treatment may remove warts, but it is not designed for, nor is it capable of, eliminating HPV infection. That message is particularly important today, as patients are learning more about HPV infection.
SPECIFIC CDC TREATMENT OPTIONS
Available treatments for EGW can be classified by:
their mechanism of action
categories of surgical or medical approach
the location (ie, the facility) at which therapy is provided.
The CDC organizes its discussion of treatments into those therapies that are patient-applied and those that are provider-applied. The TABLE summarizes treatments for EGW, each of which is discussed in detail below.
Selection of an initial treatment plan for any individual depends on several variables.
The warts. This refers to their morphology, number, and anatomic location. Warts on moist surfaces or intertriginous areas are most likely to respond to topical treatment. Those that are well pedunculated are easily removed with simple excision at the interface of the wart and unaffected skin. Multiple, thickly keratinized warts often require ablative therapy.
The patient. A patient’s preferences are often paramount and reflect her assessment of (1) her ability to successfully use the method (either by applying an agent at home or returning for additional visits), (2) the impact of potential side effects, (3) insurance coverage, and (4) cost, in time and money. The patient’s immunocompetence must also be considered.
The health care provider. What equipment is available? What expertise does she or he have in administering treatment?
Flexibility is also needed in treating a patient who has EGW. If initial therapy is ineffective or if the patient experiences significant side effects, the modality should be changed.
Treatments for External Genital Warts
Administered by a health care provider
Podofilox, 0.5% solution or gel
Imiquimod, 3.75% cream
Imiquimod, 5% cream
Sinecatechins, 15% ointment
Cryotherapy with liquid nitrogen or cryoprobe (repeat application every 1 or 2 wk)
Podophyllin resin 10%-25% in a compound tincture of benzoin
Trichloroacetic acid (TCA) or bichloroacetic acid (BCA) 80%-90%
Cryotherapy destroys the wart by freezing the water within the mitochondria. Cryotherapy with liquid nitrogen is recommended for vaginal warts, urethral meatus warts, and anal warts.
With this therapy-induced cytolysis, the wart may take days, or weeks, to liquefy and disappear. Careful application of liquid nitrogen or a proper selection of cryotips is important to avoid destroying tissue surrounding the wart.
Pain after application is common and can be reduced by applying a topical local anesthetic before freezing the wart. Injected anesthesia may be helpful for extensive or large lesions.
Treatments can be repeated every 1 or 2 weeks, as long as individual lesions continue to respond to therapy. Allow adequate time between treatments of each wart to prevent depressed or hypertrophic scars. For external lesions, treating only a portion of the lesions at one time may reduce the severity of side effects.
Cryotherapy can be combined with patient-applied treatments (with the caveats listed below, under that discussion). Longer-term pigment changes in treated areas may be noticeable.
Podophyllin resin 10% to 25% in tincture of benzoin can be applied to individual warts, but to reduce the risk of systemic absorption, with its attendant neurotoxicity, less than 0.5 mL of podophyllin should be used for any one treatment application and less than a total of 10 cm2 of warts should be treated at any session.
The solution should never be applied to disrupted skin or open lesions. The solution should be completely air-dried before the patient is allowed to dress, because residual liquid could be spread by clothing to adjacent skin. Repeat treatments can be scheduled each week as long as the lesion continues to respond.
Podophyllin resin preparations are not standardized—they vary in the concentration of active ingredients and contaminants. The shelf life and stability of podophyllin resin compounds are unknown. Consider using a fresh supply of the compound if a patient does not respond to treatment with an older bottle.
Trichloroacetic acid and bichloracetic acid (TCA/ BCA; 80%-90% solution). TCA and BCA are recommended for treating vaginal warts and anal warts. These agents destroy the wart by inducing chemical coagulation of proteins. Treatment is likewise nonspecific, inducing damage to all tissue it contacts. Careful technique must therefore be used in applying it to warts. These solutions have low viscosity, compared to water, and spread rapidly. Creating a moat around the wart with petroleum gel or lidocaine ointment can contain spread of the liquid.
Another technique that has been proposed is to pour only a limited amount of the solution into a container (ie, match fluid height to the height of the EGW). Dip the wooden end of the cotton-tipped applicator into the solution and apply only that amount of the TCA/BCA to the wart.
Ensure that all of the solution has completely dried before the patient dresses. Because a burning sensation is most prominent during drying, accelerating drying by using a hair dryer may be helpful—as long as the patient is comfortable with that approach.
Last, if some solution does spill onto other tissues, it can be neutralized with soap or sodium bicarbonate (baking powder). Excess material applied to a wart can be absorbed with talc, sodium bicarbonate, or liquid soap.
Surgical therapies. For pedunculated perianal warts that have a slender stalk, tangent excision with scissors or scalpel—separating the base of the wart from underlying upper dermis of the skin—is safe and effective. Hemostasis is generally easy to achieve with pressure, silver nitrate, chemical styptic (aluminum chloride solution) or Monsel’s (ferric subsulfate) paste.
Alternatively, a CO2 laser beam or electrocautery can be used to dissect the wart. Such surgical ablative therapies obviously require additional equipment and specialized training.
After local anesthetic is applied, warts can be destroyed by electrocautery, but attention must be paid to limit the depth of destruction to avoid scarring and future issues with chronic pain (vulvodynia) or hyperesthesia syndromes.
Surgical ablation with a CO2 laser is also highly effective but is generally reserved for extensive lesions and those that have been demonstrated to be resistant to other therapies. In such cases, the procedure is done with more extensive anesthesia in an operating room. Control of the smoke plume is important because of the potential to release particles of HPV.
Excisional biopsy can be performed in an operating room for extremely large lesions, particularly if they obstruct the vagina, urethra, or rectum. Take care around those structures to avoid scarring or fibrosis.
Podofilox is an antimitotic drug that destroys warts over time. It is available as a solution that is applied with a cotton swab or as a gel that is applied by finger. Applications are made twice daily for 3 consecutive days, followed by 4 days without treatment. The treatment cycle can be repeated for a total of as many as 4 cycles.
The same restrictions that applied to podophyllin therapy—ie, limiting the total volume of podofilox to 0.5 mL/d and limiting the total wart area to 10 cm2— apply here. The area should be washed off 6 to 8 hours after treatment. Mild or moderate pain or local ulceration might develop after application.
Sinecatechin ointment is a green-tea extract of catechins from leaves grown on specific farms in China to ensure product consistency. A 0.5-cm strand of ointment is applied 3 times a day with the finger to ensure that a thin layer covers each wart. Treatment is continued until the wart clears, but not for longer than 16 weeks.
The medication should not be washed off after use. All forms of sexual contact (oral, genital, anal) should be avoided while the ointment is on the skin. Use of a latex condom or diaphragm is discouraged because either may be damaged by the ointment.
The most common side effects are local skin reactions. Treatment with sinecatechin ointment is not recommended for immunocompromised persons (eg, HIV-infected or with clinical genital herpes) because the safety and efficacy of sinecatechin have not been established in those settings.
Imiquimod 5% cream is an immune modulator that stimulates local production of cytokines to destroy the HPV-infected cells within the wart. The drug is applied to warts only once daily at bedtime, every other day, for a total of 3 doses in a 7-day period. The regimen can be repeated until the lesion clears, but not for longer than 16 weeks.
Treated areas should be washed with soap and water 6 to 10 hours after application of the drug. Because imiquimod is mixed in a petroleum-based vehicle, latex condoms and a diaphragm should be avoided; couples should wait until the ointment is washed off or use a polyisoprene or polyurethane condom.
Local inflammatory reactions, such as erythema, are common, as these are manifestations of the mechanism of action; irritation, induration, ulcerations, erosions, and vesicles can also develop, however. Hypopigmentation has been reported after treatment.
A new therapy
Imiquimod 3.75% cream. The original imiquimod 5% cream amplified the natural (innate) cell-mediated immune system response to viral infection. The drug was able to successfully remove existing warts without increasing the risk that T cells recruited from surrounding tissue would leave those areas vulnerable and more prone to developing warts (the classic so-called ring of warts around the treated area).
The original treatment schedule with imiquimod 5% cream (3 nonconsecutive days a week) was selected because it was found that the more straightforward daily application schedule did not significantly reduce duration of therapy or enhance cure rates. It did, however, significantly increase side effects and complications, especially serious skin reactions.
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In an attempt to improve the therapeutic success of this compound, a series of formulations containing different concentrations of imiquimod was developed for daily use. The optimal concentration was found to be 3.75%, applied daily for as long as 8 weeks or until the lesion clears, whichever comes first. By simplifying application (daily administration) and by shortening the total treatment duration (8 weeks), without increasing significant side effects, it was hoped that, in the real world, patients would be more likely to adhere to the necessary length of the course of therapy.
The results of the clinical trials have been reported in detail elsewhere5; the important findings that may be of particular interest to clinicians are included here.
Overall, the 3.75% concentration was found to be well tolerated and effective, especially for women. Daily application was found to be easy to use.
Direct comparison between the 3.75% formulation and the existing 5% cream cannot be made because the difference in dosing (daily and 3 times a week) cannot be blinded. Comparison of the outcomes of the clinical trials for the 3.75% formulation cannot be made with outcomes of trials of the original 5% formulation, because the definition of “successful outcome” and the rules for patient recruitment have changed greatly over time.
The most important of these changes is the FDA expectation that all genital warts be counted when assessing treatment success. Even warts that developed at the very end of the 8 weeks of therapy and had been given little or no treatment must be counted. (For the original 5% preparation, only baseline warts in predefined areas were evaluated; new warts that developed during the 16-week study were not counted.)
This expectation, although stringent, reflects what matters to potential users: that they have no warts after treatment is completed. The subjects in the 5% trial had their EGW for (a median of ) 4.2 months; in trials of the 3.75% preparation, subjects had their warts for more than 4 times as long (median, 19.2 months).
Clinical trials of the imiquimod 3.75% cream have demonstrated that it is superior to placebo, even taking into account the more stringent study design expectations. In 78 centers, 981 immunocompetent men and nonpregnant, immunocompetent women were enrolled and randomized in a 2:2:1 ratio to receiving imiquimod 3.75% cream, imiquimod 2.5% cream, and placebo.5 Because results with the 2.5% cream were not statistically significant, the 3.75% formulation was selected for the next phase of the trial.
Subjects were instructed to use the 3.75% cream each night and wash it off in the morning. They were followed every 2 weeks for as long as 8 weeks of treatment. When all warts had cleared completely (ie, no visible external genital warts), subjects were enrolled in a 3-month follow-up observational period to investigate the rate of development of new or recurrent warts.
Recognizing that, once activated, a subject’s immune system might continue to attack HPV-infected cells even after the last dose of study drug, a study element was then added. Subjects whose warts did not all completely clear during the 8-week treatment period were observed off-therapy for an additional 8 weeks. Those whose residual warts all cleared during that 8-week extended observation period were then transitioned into the 12-week follow-up study of recurrence.
Overall, women who applied at least 75% of their protocol-directed doses of the drug had a 43.1% rate of complete clearance; 72.5% had at least a 50% reduction in the number of EGW by the end of the study. The numbers for the intent-to-treat populations were 36.6% for complete clearance and 62.5% for more than 50% clearance.5
The timeline for the intent-to-treat women (FIGURE) shows that compared to placebo users, (1) users of the imiquimod 3.75% cream started to clear at 2 weeks and (2) many continued to experience benefits in the weeks after they finished using their cream.5 This is important for clinicians to recognize, because they may want to delay using other therapies to eradicate remaining warts until the full benefit of the 8-week course of treatment is realized.
Ease of therapy was shown by the fact that 83.7% of users demonstrated correct and consistent use of the cream. The immune-modulating effect of the 3.75% cream was reflected in the relatively low rate (69.6%) of new wart development (ie, recurrence) during the 3 months of follow-up observation.
Only 1.5% of subjects discontinued the trial because of safety concerns. However, 17.5% reported experiencing a treatment-related adverse event at some time during the trial. Only 1.8% had a serious adverse event, and fewer than 0.3% experienced any systemic problems, such as fever, chills, myalgia, or nausea.
Local skin reactions were quite common. Overall, 75.9% had erythema that was noted by the investigator; 44.2% had edema. Only 16.3% had a severe local skin reaction (ie, spread outside the treatment area or requiring treatment with another medication). Most skin changes were well tolerated by subjects.
In short, the lower (3.75%) concentration formulation of imiquimod offers:
a shorter course of treatment (8 weeks instead of 16 weeks)
daily dosing (to facilitate ease of use)
a low rate of severe adverse events
a low rate of discontinuation because of side effects.
Other emerging treatments are on the horizon but have not yet been fully studied or evaluated and approved by the FDA.
Long-term management strategies, such as vaccination against HPV strains 6 and 11, have already demonstrated the potential to significantly reduce the prevalence of EGW. For women (and men) who already suffer from EGW, however, the variety of treatments available allows you, and them, to tailor treatment so that the selected regimen best suits not only the clinical problem (eg, the character and location of warts, immunocompetence, whether she smokes) but also the availability of resources (electrocautery, laser) and personal preference (is she willing to apply the prescribed treatment, or does she want her physician to?).
Each approach has its limitations, so patient and provider flexibility is likely to be an important contributor to success.
The availability of a new 3.75% imiquimod cream, which streamlines therapy and makes utilization easier to remember, offers a new option. The low intermediate-term recurrence rate seen with this new formulation will be an important consideration when selecting therapy.
Safer sex practices during treatment (eg, polyisoprene and polyurethane condoms) should always be encouraged. So should treatment of partners who have visible lesions.
As the new imiquimod 3.75% cream finds its way into the therapeutic armamentarium, and as other potential therapies are investigated, the frustration that both patients and providers experience when dealing with EGW may very well diminish.
1. Nelson AL. Recent use of condoms and emergency contraception by women who selected condoms as their contraceptive method. Am J Obstet Gynecol. 2006;194(6):1710–1715.
2. Cui Y, Baldwin SB, Wiley DJ, Fielding JE. Human papillomavirus vaccine among adult women: disparities in awareness and acceptance. Am J Prev Med. 2010;39(6):559–563.
3. Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis. 2011;11(1):39–44.
4. Workowski KA, Berman S. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1–110.
5. Data on File, Graceway Pharmaceuticals.
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