Levels of evidence (I-IV) and grades of recommendation (A-C) are defined at the end of the "Major Recommendations" field.

Diagnosis

• Naked eye examination in most cases
• If in doubt, or if the lesion is atypical or pigmented, suggesting possible intraepithelial neoplasia, biopsy under local anaesthetic for histology should be performed prior to any therapeutic intervention. This may be aided by the use of a colposcope.

Assessment of Lesions

• Examine the external ano-genital and surrounding skin under good illumination.
• Females, vaginal speculum examination
• Both sexes, proctoscopy may be indicated if history of anal receptive sex, or following clearance of perianal warts. Meatoscopy and proctoscopy should be performed if there is a history of distortion of urine flow or bleeding from the urethra or anus, respectively. Occasionally urethroscopy is indicated for more proximal warts.
• Classify warts as to morphology.
• Recording of lesions on genital maps at each visit is useful, providing a visual record of approximate number, distribution, and response to treatment.
• Extragenital sites (e.g., oral cavity) examined if clinically indicated.

Management

General Advice

• Patients should be given a detailed explanation of their condition with particular emphasis on the long term implications for the health of themselves and their partners. This should be reinforced by giving them clear and accurate written information.
• Although data are conflicting, condoms have been shown to protect against the acquisition of human papillomavirus (HPV) infection and genital warts and may also have a therapeutic effect when both partners are infected, possibly by preventing continued re-exposure to the virus. Considering current data, condom usage may prove beneficial and their use advisable, particularly in new relationships. (IIb, B)
• Latex condoms may be weakened if in contact with imiquimod.
• For some patients the psychological impact of warts is the worst aspect of the disease. Where psychological distress is apparent, referral for counselling may be appropriate.
• There are data suggesting that smokers may respond less well to treatment than non-smokers.

Further Investigations

Many patients will have other concurrent sexually transmitted infections (STIs). Therefore, an appropriate screen for STI is recommended.

Subclinical Lesions

Subclinical lesions of the external ano-genital skin are those not seen by the naked eye, but detectable by soaking the skin with 5% acetic acid and examining with magnification (e.g., a colposcope). These lesions are usually asymptomatic, but may cause irritation and inflammation of the skin—for example, atypical balanoposthitis or vulvitis.

Problems associated with the identification of such lesions:

• Many aceto-white lesions are not caused by HPV.
• Histological changes are not specific for HPV infection.
• HPV detection is not routinely available.

Treatment of these has not been shown to:

• Affect the course of disease in patients or their partners.

For the above reasons and the fact that identification may cause unnecessary distress, it is not recommended that these lesions be sought unless there is a clinical indication (IIb, B).

Treatment

Treatment choice depends on the morphology, number, and distribution of warts and patient preference. Treatment decisions should be made after discussing the appropriate options with the patient, taking into account their preference and convenience.

• The evidence base to direct first and second line treatments is not strong.
• All treatments have significant failure and relapse rates.
• Treatment may involve discomfort and local skin reactions. Written information on management of treatment side effects is recommended.
• Soft non-keratinised warts respond well to podophyllin, podophyllotoxin, and trichloroacetic acid.
• Keratinised lesions are better treated with physical ablative methods such as cryotherapy, excision, or electrocautery.
• Imiquimod may be suitable for both keratinised and non-keratinised warts.
• People with a small number of low volume warts, irrespective of type, are best treated with ablative therapy from the outset.
• Podophyllotoxin, for 4 week cycles, and imiquimod for up to 16 weeks are suitable for home treatment by patients. If chosen, the patient should be given a demonstration on lesion finding and treatment application.
• Local anaesthetic creams plus or minus injection with an injectable local anaesthetic (e.g., 2% lignocaine) could be used before ablative therapy to minimize discomfort. Adrenaline-containing anaesthetic should be avoided for lesions on the penis and around the clitoris.
• No treatment is an option at any site and may apply particularly to warts in the vagina and anal canal.
• Practitioners should consider developing a treatment algorithm or protocol. This has been shown to significantly improve clinical outcome.

Treatments Available

Clearance and recurrence rates for individual treatments are shown in table 1 of the original guideline document.

Chemical Applications

Podophyllin

Podophyllin is a non-standardised cytotoxic compound. It has been associated with severe local reactions. Serious systemic adverse events have occurred when used outside guidelines. Podophyllin is licensed for prescription use only. Best practice described in the British National Formulary recommends supervised application in genitourinary medicine clinics or general practice by trained nurses after screening for other STIs. Animal experiments indicate teratogenic and oncogenic properties but evidence of these in humans is lacking.

• 15-25% solution can be carefully applied to lesions, in clinic, once or twice weekly. Wash off 4 hours later (Ib, A).

Caution:

• Podophyllin has caused serious systemic side effects if applied in excess. Increased systemic absorption is likely if used internally. Limit application to 10 cm² or 0.5 mL for external warts, and less than 2 cm² for vaginal warts (IV, C).
• The potential oncogenic and teratogenic effects as noted indicate it should be avoided on the cervix and in the anal canal, and in pregnancy (IV, C).

In view of the adverse problems associated with podophyllin and its inferior efficacy to podophyllotoxin (IIa, B)—greater than 20% clearance in each of the quoted studies in favour of podophyllotoxin—its use in the routine management of ano-genital warts is no longer recommended. This is in keeping with European opinion.

Combination Therapy

Applications of podophyllin in conjunction with cryotherapy is used in the United Kingdom although there are no studies to validate this approach.

Podophyllotoxin

Podophyllotoxin (Warticon and Condyline), a purified extract of podophyllin in the form of a 0.5% solution or 0.15% cream, is suitable for home treatment (Ib, A). It is licensed for 4 and 5 week courses respectively and supervision by medical staff is recommended when the lesion area treated is greater than 4 cm². Podophyllotoxin has a license for the treatment of genital warts but not extragenital lesions such as anal warts.

• Treatment cycles consist of twice daily application for 3 days, followed by 4 days' rest for 4-5 cycles.
• The cream may be easier for many patients to apply, especially at the anus.
• Discontinue treatment if significant side effects (e.g., soreness, ulceration).
• Unprotected sexual contact should be avoided soon after application because of a possible irritant effect on the partner.

Caution: Avoid in pregnancy.

Trichloroacetic Acid

Trichloroacetic acid (TCA) 80-90% solution is suitable for weekly application in a specialist clinic setting only. It acts as a caustic agent resulting in cellular necrosis (Ib, A).

• An intense burning sensation may be experienced for 5-10 minutes after application.
• Ulceration penetrating into the dermis may occur, and it is therefore not recommended for large volume warts.
• TCA can be used at most anatomical sites.

Caution: TCA is extremely corrosive to the skin. Careful application and protection of the surrounding skin with petroleum jelly is recommended. A neutralizing agent, for example sodium bicarbonate, should always be available in case of excess application or spills.

5-Fluorouracil

5-Fluorouracil is a DNA anti-metabolite, available in a 5% cream. Its use is limited by severe local side effects, which may result in long term problems—for example, neovascularisation and vulval burning. It may be teratogenic and therefore should not be used in pregnancy.

As satisfactory alternatives exist, this treatment is no longer recommended for the routine management of ano-genital warts. (IV, C)

Interferons

Various regimens have been described using interferons alpha, beta, and gamma as creams and as intra-lesional or systemic injection (Ib, A).

• Its use is limited by expense, systemic side effects, and a variable response rate.
• Cyclical low dose injection used as an adjunct to laser therapy has resulted in a lower relapse rate.
• Interferons are not recommended for routine management of ano-genital warts and should only be used on expert advice (IV, C).

Imiquimod

Imiquimod is an immune response modifier.

• Available as a 5% cream, it induces a cytokine response when applied to skin infected with HPV.
• Suitable for use on all external ano-genital warts, but is not recommended for use in pregnancy or internally (Ib, A).
• Use in uncircumcised men has been shown to be safe.
• Cream is applied to lesions three times weekly and washed off 6-10 hours later for up to 16 weeks.
• Response to treatment may be delayed for some weeks.
• Clinical trials of imiquimod versus placebo have shown response rates comparable with other chemical agents (Ib, A). An apparently low relapse rate has not been compared in clinical trials against other currently available therapies.
• Recent studies suggest fewer recurrences in patients using Imiquimod pre or post surgical excision of lesions.
• Unprotected sexual contact should be avoided soon after application because of a possible irritant effect on the partner.
• Latex condoms may be weakened if in contact with imiquimod.

Caution: Not approved for use in pregnancy or internally.

Physical Ablation

Excision (Ib, A)

• Removal of warts under local anaesthetic injection is particularly useful for pedunculated warts and small numbers of keratinised ones at anatomically accessible sites. The use of an anaesthetic cream (e.g., EMLA®) prior to injection is recommended.
• Haemostasis can be established using electrosurgery, silver nitrate, or application of a haemostatic solution.
• Treatment can be repeated as required. This is a good method of treatment for small numbers of warts and may be underused.

Cryotherapy (Ib, A)

The following are available:

• UK national guidelines on sexually transmitted infections and closely related conditions. Introduction. Sex Transm Infect 1999 Aug;75(Suppl 1):S2-3.
• Revised UK national guidelines on sexually transmitted infections and closely related conditions 2002. Sex Transm Infect 2002;78:81-2

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