Condyloma acuminata

Management Strategy

AGWs are contagious, associated with slow spontaneous clearance, significant impact on the quality of life and healthcare costs, and, potentially, progression to in situ squamous cell carcinoma (erythroplasia of Queyrat in penile mucosa) or to transformation into squamous cell carcinomas and other invasive cancers (cervical, vaginal, vulvar cancer, etc.). It is essential to identify effective treatment strategies and appraise evidence from controlled studies.

In the absence of an ‘anti-HPV’ drug per se, current treatments focus on stimulation of the host’s immune response to enhance virus recognition. Treatments are categorized as either patient-administered (i.e., podophyllotoxin, imiquimod, sinecatechins, and 5-fluorouracil cream ) or provider-administered (bi- or trichloroacetic acid [TCA] application, podophyllin resin, CO ₂ laser, cryotherapy, surgery, electrosurgery, intramuscular prophylactic or intralesional therapeutic HPV vaccine). In the latter, reduction or clearance was achieved by a cross-protection (HPV L1 capsids) or a non-specific upregulation (aluminum-containing adjuvant’s immunity) in prophylactic vaccines and by a cytotoxic response against papilloma-transformed cells in therapeutic vaccines.

Podophyllotoxin treatment consists of twice daily application for 3 days, followed by 4 days’ rest, for 4–5 cycles. Supervision is recommended if total area is >4 cm ² . Repeat cycles may be used if lesions are responding. Imiquimod 5% activates dendritic cells (adaptive T-cell response). It is applied overnight and washed off 6–10 hours later, 3 times a week, for 16 weeks. Longer courses have been used without clear evidence. Other concentrations (3.75%) have been approved by the US Food and Drug Administration (FDA) in 2010 and showed similar cure rates, similar patient compliance, and fewer side effects compared with 5%. Sinecatechin 15% extract of green tea ( Camellia sinensis ) contains epigallocatechin gallate, exhibiting antiviral, anti-tumor, and immunostimulatory properties. It is applied 3 times a day for 16 weeks. Other green tea-based ointments are available. 5-Fluorouracil cream is not recommended for routine management.

Provider-administered therapies are either topical or surgical. Topical modalities include podophyllin resin, bi- or TCA, intralesional bleomycin, and ingenol mebutate. TCA 80–90% is not recommended for large volumes and requires a weekly application in a specialist clinic setting only. Podophyllin resin is applied for 1–6 hours and is less effective on dry areas (penile shaft, scrotum, and labia majora). Intralesional interferon- α and bleomycin are also effective therapies. Surgical treatments include cryotherapy, surgical removal by tangential shave (cold knife or scissors), curettage with or without electrosurgery, and lasers (CO ₂ and pulsed dye laser [PDL]). Cryotherapy causes thermolysis and necrosis of keratinocytes hosting HPV. Liquid nitrogen usually requires one or two freeze–thaw cycles per session for two or three sessions. Recurrence rates are up to 40%. As this is the most used therapeutic intervention, a meta-analysis to compare the efficacy and safety of cryotherapy concluded, with low-level quality of evidence, that no evidence supports cryotherapy superiority or inferiority when compared with TCA, imiquimod, or podophyllin (see later). Surgery and CO ₂ lasers are useful for treating extensive giant (i.e., Buschke–Löwenstein tumor) intraurethral and recalcitrant warts. Excision and electrosurgery require local anesthetic and are useful for large volume warts and difficult anatomic sites. Several case reports mentioned imiquimod as a successful treatment of Buschke–Löwenstein. All electrosurgical and laser techniques may generate a plume of smoke, which contains HPV DNA, potentially infectious to the respiratory tract in the operating personnel. Therefore, masks should be worn during these procedures.

Estimates of clearance and recurrence rates with various therapies are difficult due to differences in method of analysis, patient population, and duration of follow-up. No available therapy can be guaranteed to clear AGWs without any recurrence. Combination therapy using an immunomodulator after physical ablative therapy reduces recurrence rates with risky adverse events.

The development of the three FDA-approved multivalent HPV vaccines have shown high efficacy for HPV prevention. Cervarix and Gardasil were the first vaccines for cervical cancer prevention. Cervarix targets types 16 and 18 (responsible for 70% of all cervical cancer), while Gardasil also adds activity against types 6 and 11 (cause 90% of AGWs). In addition to these four types, the 9vHPV vaccine contains type 31, 33, 45, 52, and 58 antigens. Vaccines are safe with minor adverse effects. They also protect against precancerous lesions caused (types 16 and 18) in a naive population. They are available for both males and females, preferably before they become sexually active, and are being successfully implemented in many developed countries with different inclusion criteria.

During pregnancy, podophyllotoxin and 5-fluorouracil should be avoided (teratogenic). Imiquimod is not approved for use (no data). Treatment is not always warranted but aims at preventing vertical transmission. Caesarean section is not indicated as it has not been shown to prevent the neonatal exposure to the virus. Caesarean section is only indicated in case of gross cervical warts. For the newborn, the only serious (rare) complication is recurrent respiratory papillomatosis. Cryotherapy, excision, and ablative methods are safe in pregnancy.

Treatments in children and adolescents follow the same principles as in adults. Anuscopy and/or speculum examination are used to evaluate the anal canal, vagina, or cervix. Biopsy is indicated for atypical-looking and recalcitrant lesions or in immunocompromised patients. Sexual abuse should be suspected but is not systematic.

Immunocompromised people (organ transplant recipients or living with HIV) experience lower response and increased relapse rates. Treatment recommendations are not modified but longer courses may be required.