TREATMENT OF EXTERNAL GENITAL WARTS

For a summary of treatment by anatomic site and treatment options, see Tables 1 and 2 below.

Efficacy of Treatments

A Cochrane review assessed trials comparing the use of self-applied imiquimod with other patient-applied or provider-applied treatment modalities. The quality of trials was very low and the findings should therefore be interpreted with caution. Compared to other self-applied treatments it was not possible to determine if there was any difference between clearance and recurrence rates. Compared to other provider-applied treatments it was unclear whether there were differences in regression rates but there were less recurrences at 6 months with the use of imiquimod.(58)

Treatment of genital warts, particularly complex cases, is an art. Specialist consultation is recommended for cases which are difficult to treat.

Self-applied treatments (home therapy)

Imiquimod

Imiquimod is available as a 5% cream on prescription and is fully subsidised. These applications may lead to an increase in adverse skin reactions.(59)

Imiquimod 3.75% is not currently available in New Zealand.

Mechanism of action: An immune enhancer that stimulates production of interferon and other cytokines. It appears to have an advantage of reduced recurrence rate.(60)

Suitable for: Women, and some men with foreskin-associated warts. Particularly useful for ‘carpet warts’ (smooth, flat-topped and joined-up), where the female introitus and perianal area are involved.

Precautions: Not currently recommended in pregnancy. There are limited case reports of its use in pregnancy.

Application: Careful application of imiquimod cream is important.

Apply onto fingertip and rubbed onto clean, dry, wart area until cream vanishes, once daily, three times per week, prior to normal sleeping hours and after sexual activity (imiquimod weakens condoms and vaginal diaphragms). Wash off next morning (including from skin folds) or after 6–10 hours. The standard duration of treatment is 16 weeks, although the majority who clear their warts will do so by 8 weeks. There is no data on use of imiquimod beyond 16 weeks and non-responders by 12–16 weeks should be switched to an alternative treatment.

The manufacturer recommends that a sachet be used for single use to cover an area of up to 20cm².

Side effects: Imiquimod frequently causes localised erythema, swelling and/or (rarely) superficial ulceration of the treated area which is due to the direct therapeutic action of the agent, i.e. switching on the immune response, rather than to hypersensitivity. These local skin reactions can be managed by having a break from treatment for a few days. Skin reactions result in discontinuation of the treatment in less than 2% of patients. Hypopigmentation may occur. Imiquimod can also cause flu-like symptoms in a small percentage of patients.

Imiquimod should be used with caution (it is not a contraindication) in patients with autoimmune conditions, or those on systemic immunosuppressive drugs, although systemic absorption from topical treatment is likely to be negligible.

Podophyllotoxin

Podophyllotoxin is dispensed as a 0.5% solution (Condyline^TM ). The 0.15% cream is not available in New Zealand. These contain purified podophyllin in a more standardised form. Podophyllotoxin has been extensively studied in randomised and placebocontrolled trials. It is licensed for 4- to 5-week courses and supervision by medical staff is recommended when the lesion area is greater than 4cm² .

Mechanism of action: The active moiety is an antimitotic and causes localised tissue necrosis. Localised epidermal pallor, caused by intracellular oedema, can usually be seen within 48 hours of application.

Suitable for: Men with external warts that can be visualised. May be less effective for keratinised warts.(59)

Not for use in women because of difficulty in application.

Contraindications: A history of hypersensitivity (incidence approximately 1%). They are not used in pregnancy or lactation, or in children. Should not be used on warts which cannot be visualised, on internal warts, and they are not recommended for extensive wart areas (>10cm² ).

Application: Patients must be able to visualise, identify and reach their warts, and if necessary should be shown what is wart and what is normal skin, using a mirror. Podophyllotoxin solution should be applied carefully to the warts using one of the applicators enclosed with the product, taking care that the solution does not come into contact with healthy skin and allowing drying after application to avoid inadvertent spreading of the solution. Applying Vaseline or zinc ointment on healthy skin around the wart(s) can be protective. The solution should be applied twice daily for 3 consecutive days followed by 4 days rest each week until the warts have resolved, or for a maximum of 5 consecutive weeks.

Side effects: Mild erythema with slight pain and/or superficial ulceration of the treated area can be expected. More severe skin ulceration, erosions, erythema, irritation, scarring, phimosis, pain, burning and soreness can occur. These effects are usually only mild to moderate in severity and resolve when the warts necrose.(59)

Physician-applied treatments

Cryotherapy

Mechanism of action: Destroys the wart tissue by freeze/thawing, resulting in sloughing and wart destruction.

Suitable for: External and internal warts. Dry and moist warts. Can be used in pregnancy.

Application: Adequate training and expertise in this technique is required. Effective cryotherapy may be achieved by a cryoprobe or application of liquid nitrogen by spray or by loosely wound cotton on a wooden applicator (not with tightly wound, typical cotton swabs). The full thickness of the wart should be frozen until there is whitening of the surrounding skin area for 2mm. (Note: It is difficult to visualise the lesion using a cotton bud method of application and a spray method is preferred.) Treatment is repeated weekly until the warts have resolved. Some sexual health clinics have facilities for more focused freezing using fine probes with nitrous oxide or carbon dioxide cryoguns. Patients can be referred for treatment.

Side effects: Pain and necrosis following application of cryotherapy are fairly universal, and blistering may occur. The treatment of large warts or areas at one time can create wound care problems. Adverse effects include irritation, local oedema, necrosis, ulceration and pain, especially when the treated area thaws. Both hypo- and hyperpigmentation can occur, but this is usually temporary. Although the use of injected local or topical anaesthesia (e.g. tetracaine hydrochloride gel 4% cream) is rarely necessary, it may facilitate cryotherapy by reducing pain when a large number or area of warts is present.

Curettage and scissor or scalpel excision

Mechanism of action: Directly remove genital warts.

Suitable for: Exophytic warts.

Contraindications: Known bleeding abnormality. Can be used in pregnancy.

Technique: Direct removal with extension of the wound only into the upper dermis. Haemostasis can be secured with an electrosurgical unit or a chemical styptic (e.g. silver nitrate sticks); suturing is rarely required or indicated when removal is done properly.

Side effects: Localised pain, for which mild analgesics may be required, and bleeding. If operating-room surgery is required there are the additional hazards of a general anaesthetic.

Electrocautery or diathermy (hyfrecation)

Mechanism of action: Coagulates proteins of treated tissues.

Suitable for: Anogenital and oral warts.

Contraindications: None. Can be used in pregnancy.

Technique: Both electrocautery and laser therapy require masks and a smoke evacuator to prevent inhalation of aerosol HPV and oropharyngeal transmission. Advanced training and expertise is required to minimise scarring. Once anaesthesia is attained, physical destruction of warts can commence. Usually, no additional haemostasis is required.

Side effects: Local pain and possible infection. Scarring is more common than after cryotherapy.

Laser therapy

Mechanism of action: Vaporisation of warts.

Suitable for: Vulval, vaginal, cervical and perianal warts. Not considered first-line treatment because of expense. Can be considered if there are obstructive or large lesions.(61)

Contraindications: None. Can be used in pregnancy.

Technique: Advanced training and expertise required. Specialist only.

Side effects: Local pain. Scarring and hypo- or hyperpigmentation can be minimised by controlling depth and avoiding treatment beyond the dermal papillae.

Trichloroacetic acid (TCA)

Mechanism of action: TCA is a caustic agent that destroys warts by chemical coagulation of proteins. Treatment solution concentrations have not been standardised and saturated concentrations of 85–95% have been used.

Suitable for: Small warts on moist surfaces.

Application: Specialist clinic settings only. Training is necessary before applying this treatment. TCA solutions should be applied sparingly and allowed to dry before the patient sits or stands. If there is intense pain, the acid can be neutralised with soap and sodium bicarbonate. TCA solution has a low viscosity (comparable to that of water), and if over-applied can spread rapidly and ‘run’, damaging a significant area of normal tissue.

Contraindications: Nil, but most suitable for small moist warts. Can be used in pregnancy.

The following treatments are not recommended because of side effects, toxicity and difficulty in application:

• Podophyllin resin
• 5% flurouracil cream
• Systemic interferon

Selecting treatment(s) for individual patients (see Table 3 below)

Many patients require a course of therapy rather than a single treatment. Studies have not systematically evaluated the factors that influence the selection of therapy, although a survey found that patients expressed a desire for topically applied therapies that may be used at home. As no one treatment is ideal for all patients or all warts, consideration should be given to a change of treatment modality or onward referral if there is no significant response within 4–6 weeks. Most treatment modalities are eventually effective in eliminating small numbers of warts. Patients with limited disease (i.e. one to five warts) may benefit most from cryotherapy or simple office surgery. Ablative therapy (cryotherapy) should be considered in those with large or extensive areas of warts to at least debulk their warts.

For self-applied therapeutic modalities, treatment beyond the manufacturer’s recommendations is not advisable and concurrent use of multiple therapeutic modalities on a single wart is not recommended as routine treatment. It should be borne in mind that a continuing lack of response to therapy might indicate other pathology and referral for assessment should be considered in such cases.

Continually evaluate the response to treatment to avoid over-treatment and a therapeutic course worse than the disease itself. Persistent hypo- and hyperpigmentation is a possible complication of ablative therapeutic modalities. Depressed or hypertrophic scars rarely occur. Ablative treatment, especially to the introitus, can result in disabling chronic pain syndrome or hyperaesthesia at the treatment site.

Surgical removal of warts, by diathermy, laser ablation or excision under local or general anaesthesia, may render the patient wartfree, usually in a single visit. However, the disadvantages are that significant training, a moderate amount of equipment, and a longer patient visit are required. Although surgery is obviously of most benefit when warts are present in large numbers or over large surface areas, it can be used for average cases. While the cost of a single surgical visit may be greater, surgery can accomplish in one visit what other ablative modalities often require multiple visits to accomplish, which may result in greater cost effectiveness for some patients. However, recurrence rates may be the same as other therapeutic modalities and the morbidity of treatment may be greater with increased risk of pain, infection and scarring.

Combination treatment

Although treatments are commonly combined, few studies have been published to show that clearance rates or recurrence rates are improved. Possible combinations include:

• Cryotherapy and podophyllotoxin versus cryotherapy alone.
• Cryotherapy applied once followed by topical agent such as podophyllotoxin.
• A combination of laser and imiquimod has been shown to be safe and well tolerated.(62)

Symptomatic therapy

• For ongoing management by the GP or health professional, the patient should be advised to return weekly for treatment until all the warts have gone. Patients may be referred to a specialist or sexual health clinic when there is a poor response to treatment, or warts continue to recur after 3 months.
• Saltwater baths are a useful thing the patient can do to help soothe and heal the genital area during treatment. Two handfuls of plain salt per bath or two tablespoons in a large bowl, preferably twice daily, and dry with hairdryer.
• Lignocaine gel 2% (Xylocaine^TM ) is a useful local anaesthetic to put on raw areas 2 minutes prior to micturition and defaecation.
• A concomitant thrush infection is common. Local imidazole preparations often help, and/or oral fluconazole.
• For large areas made raw by wart ablations, 1% silver sulphadiazine cream is useful.