Condyloma Acuminata

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Condyloma Acuminata

Brian Berman and Sadegh Amini

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

External anogenital warts develop on the skin and mucosal surfaces of the genitalia and perianal areas. They are caused by the human papillomavirus (HPV), sexually transmitted in approximately 65% of cases, with at least 40 of the more than 100 types identified capable of infecting the genital tract. Condyloma acuminata (CA), the classic form of anogenital warts, and the more difficult to detect flat condylomata, are frequently associated with ‘benign’ HPV types 6 and 11 (up to 95%), but may also be caused by oncogenic HPV types such as 16, 18, 31, 33, and 35.

Management strategy

Most cases are asymptomatic; however, they can be disfiguring, lead to physical discomfort, induce psychological suffering, guilt, anger, and severely impact the patient’s quality of life. Untreated genital warts may increase in size or number, remain unchanged, or resolve spontaneously.

The treatment of external genital warts depends on patient preference, resource availability, and provider experience.

Current treatments focus on stimulation of the host’s immune response to enhance virus recognition. Treatments are categorized as either patient-applied (i.e., podofilox, imiquimod, and sinecatechin) or provider-administered. Podofilox (podophyllotoxin) is applied twice daily for 3 days, then no treatment for 4 days for four to six cycles, if necessary.

Imiquimod 5% or 3.75% cream stimulates the host’s immune response. Imiquimod 5% is applied overnight and washed off 6 to 10 hours after application, three times a week, until clearance of the warts or a maximum of 16 weeks. Imiquimod 3.75% is applied nightly for up to 8 weeks.

Sinecatechin 15% ointment extract of green tea from Camellia sinensis contains epigallocatechin gallate, exhibiting antiviral, antitumor and immunostimulatory properties. It is applied three times a day until clearance of the warts or a maximum of 16 weeks.

Provider-administered therapies are either topically applied or surgical. Topical modalities include podophyllin resin, podofilox (podophyllotoxin), bichloroacetic acid (BCA) and trichloroacetic acid (TCA). Surgical treatments include cryotherapy, surgical removal either by tangential shave using a cold knife or tangential scissor excisions, curettage with or without electrosurgery and lasers (CO2 and pulsed dye laser, PDL). Intralesional interferon-α is also an effective therapy. Podophyllin-applied resin is applied for 1 to 6 hours and is less effective on dry areas such as the penile shaft, scrotum, and labia majora.

The safety of podofilox, imiquimod, and sinecatechin (all category C) during pregnancy has not been established. Both TCA and BCA 80–90% solutions are applied weekly as needed.

Cryotherapy causes thermolysis and necrosis of keratinocytes hosting HPV. Liquid nitrogen either with cryospray or cryoprobe usually requires one to two freeze–thaw cycles per session for two to three sessions. However, HPV DNA is detectable up to 1 cm from the wart periphery, and recurrence rates are up to 40%, limiting the practicality of this modality.

Surgery and CO2 lasers are useful for treating extensive, giant (i.e., Buschke–Lowenstein tumor), intraurethral, and recalcitrant warts.

Recombinant HPV quadrivalent (6–11–16–18) vaccine is safe and efficacious in decreasing the incidence of persistent anogenital warts and cervical cancer by 90%, and is approved for females and males aged 9 to 26 years.

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. Over the years many treatment modalities have emerged, but no single treatment has proved superior to others. No available therapy can be guaranteed to clear genital warts without any recurrence. Combination therapy using an immunomodulator after a physical ablative therapy reduces recurrence rates; however, the possibility of additive adverse events should be considered.

Specific investigations

First-line therapies

imageImiquimod (5%, 3.75%) A
imagePodofilox (podophyllotoxin) A
imageSinecatechin extract of green tea A
imageCryotherapy A
imagePodophyllin B

Human papillomavirus (HPV) viral load and HPV type in the clinical outcome of HIV-positive patients treated with imiquimod for anogenital warts and anal intraepithelial neoplasia.

Sanclemente G, Herrera S, Tyring SK, Rady PL, Zuleta JJ, Correa LA, et al. J Eur Acad Dermatol Venereol 2007; 21: 1054–60.

Imiquimod 5% was evaluated in 37 HIV-positive males with anogenital warts or anal intraepithelial neoplasia (AIN). Imiquimod was applied three times per week for at least 8 hours overnight for 16 weeks. At week 20, 46% of patients cleared 100% whereas 14 patients had >50% clearance. Recurrences occurred in 29% of patients who cleared 100%. Clearance was independent of patient’s CD4 count, wart location, HIV viral load or HPV viral load. Imiquimod is effective for AIN in HIV-positive patients.

A multicentre, randomised, double-blind, placebo controlled study of cryotherapy versus cryotherapy and podophyllotoxin cream as treatment for external anogenital warts.

Gilson RJ, Ross J, Maw R, Rowen D, Sonnex C, Lacey CJ. Sex Transm Infect 2009; 85: 514–19.

Patients (n = 140) received cryotherapy plus podophyllotoxin or cryotherapy alone. Podophyllotoxin cream or placebo was applied twice daily for 3 days per week for up to 4 weeks, with weekly cryotherapy continued to week 12 if required. Complete clearance rates with the combination versus cryotherapy alone were 60.0% and 45.7%, respectively (no statistical difference). At week 24 both groups had similar clearance rates, with new and recurrent lesions in 16.7% and 18.8% of patients, respectively. Both regimens were equally tolerated.

Treatment of external genital warts: a randomized clinical trial comparing podophyllin, cryotherapy, and electrodesiccation.

Stone KM, Becker TM, Hadgu A. Kraus SJ Genitourin Med 1990; 66: 16–19.

All treatments were provided weekly, until all warts had cleared or until a total of six treatments had been administered. Patients were instructed to wash off the podophyllin 2 hours after the first treatment; this interval was lengthened by 2 hours to a maximum of 12 hours with each successive treatment. After evaluating 450 patients, complete clearance was observed in 41% of podophyllin-treated, 79% of cryotherapy-treated, and 94% of electrodesiccation-treated patients. The 3-month clearance rates were 17%, 55%, and 71%, respectively. Cryotherapy with cryoprobe is only used for patients who do not have extensive disease.

Cryotherapy is safe to use during pregnancy. Podophyllin, however, has been demonstrated to have severe systemic toxicity and should not be used in pregnant women.

Second-line therapies

imageSurgical excision (with cold knife or scissors) B
imageLasers (CO2 and PDL) B
imageLoop electrosurgical excisional procedure B
imageElectrodesiccation (see also above) B
imageTrichloroacetic acid (see also above) B

Third-line therapies

imageIntralesional interferon-α A
imageInterferon-β gel A
imageOral isotretinoin B
imageIntralesional fluorouracil/epinephrine gel A
imageCidofovir B
imageALA–photodynamic therapy B

Topical cidofovir (HPMPC) is an effective adjuvant to surgical treatment of anogenital condylomata acuminata.

Coremans G, Margaritis V, Snoeck R, Wyndaele J, De Clercq E, Geboes K. Dis Colon Rectum 2003; 46: 1103–8.

Patients were treated with repetitive electrocoagulations (n = 27) (control) or cidofovir (n = 20) 1% cream applied to warts daily for 5 hours for 5 consecutive days per week. The applications were repeated at intervals of 1 week for up to 18 weeks or until complete clearance. The remaining lesions post cidofovir received additional coagulations. Complete and partial responses with cidofovir were 32% and 60%, respectively. Fewer patients had remaining lesions after cidofovir requiring fewer coagulations. Recurrence rates were 3.7% and 55%, respectively. Local reactions were reported in 33% and 100%, respectively. Interestingly, smoking was a factor decreasing efficacy of cidofovir.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Condyloma Acuminata

Brian Berman and Sadegh Amini

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

External anogenital warts develop on the skin and mucosal surfaces of the genitalia and perianal areas. They are caused by the human papillomavirus (HPV), sexually transmitted in approximately 65% of cases, with at least 40 of the more than 100 types identified capable of infecting the genital tract. Condyloma acuminata (CA), the classic form of anogenital warts, and the more difficult to detect flat condylomata, are frequently associated with ‘benign’ HPV types 6 and 11 (up to 95%), but may also be caused by oncogenic HPV types such as 16, 18, 31, 33, and 35.

Management strategy

Most cases are asymptomatic; however, they can be disfiguring, lead to physical discomfort, induce psychological suffering, guilt, anger, and severely impact the patient’s quality of life. Untreated genital warts may increase in size or number, remain unchanged, or resolve spontaneously.

The treatment of external genital warts depends on patient preference, resource availability, and provider experience.

Current treatments focus on stimulation of the host’s immune response to enhance virus recognition. Treatments are categorized as either patient-applied (i.e., podofilox, imiquimod, and sinecatechin) or provider-administered. Podofilox (podophyllotoxin) is applied twice daily for 3 days, then no treatment for 4 days for four to six cycles, if necessary.

Imiquimod 5% or 3.75% cream stimulates the host’s immune response. Imiquimod 5% is applied overnight and washed off 6 to 10 hours after application, three times a week, until clearance of the warts or a maximum of 16 weeks. Imiquimod 3.75% is applied nightly for up to 8 weeks.

Sinecatechin 15% ointment extract of green tea from Camellia sinensis contains epigallocatechin gallate, exhibiting antiviral, antitumor and immunostimulatory properties. It is applied three times a day until clearance of the warts or a maximum of 16 weeks.

Provider-administered therapies are either topically applied or surgical. Topical modalities include podophyllin resin, podofilox (podophyllotoxin), bichloroacetic acid (BCA) and trichloroacetic acid (TCA). Surgical treatments include cryotherapy, surgical removal either by tangential shave using a cold knife or tangential scissor excisions, curettage with or without electrosurgery and lasers (CO2 and pulsed dye laser, PDL). Intralesional interferon-α is also an effective therapy. Podophyllin-applied resin is applied for 1 to 6 hours and is less effective on dry areas such as the penile shaft, scrotum, and labia majora.

The safety of podofilox, imiquimod, and sinecatechin (all category C) during pregnancy has not been established. Both TCA and BCA 80–90% solutions are applied weekly as needed.

Cryotherapy causes thermolysis and necrosis of keratinocytes hosting HPV. Liquid nitrogen either with cryospray or cryoprobe usually requires one to two freeze–thaw cycles per session for two to three sessions. However, HPV DNA is detectable up to 1 cm from the wart periphery, and recurrence rates are up to 40%, limiting the practicality of this modality.

Surgery and CO2 lasers are useful for treating extensive, giant (i.e., Buschke–Lowenstein tumor), intraurethral, and recalcitrant warts.

Recombinant HPV quadrivalent (6–11–16–18) vaccine is safe and efficacious in decreasing the incidence of persistent anogenital warts and cervical cancer by 90%, and is approved for females and males aged 9 to 26 years.

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. Over the years many treatment modalities have emerged, but no single treatment has proved superior to others. No available therapy can be guaranteed to clear genital warts without any recurrence. Combination therapy using an immunomodulator after a physical ablative therapy reduces recurrence rates; however, the possibility of additive adverse events should be considered.

Specific investigations

First-line therapies

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imageImiquimod (5%, 3.75%) A
imagePodofilox (podophyllotoxin) A
imageSinecatechin extract of green tea A
imageCryotherapy A