Published on 19/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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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
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.
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.
Papanicolaou (Pap) smear
HPV typing (not standard of care)
Biopsy
Acetic acid 3%-5% (not recommended)
Kulasingam SL, Hughes JP, Kiviat NB, Mao C, Weiss NS, Kuypers JM, et al. JAMA 2002; 288: 1749–57.
HPV DNA testing has higher sensitivity but lower specificity than thin-layer Pap screening. In some settings (i.e., long or haphazard screening intervals), HPV DNA screening may be an alternative to cytology-based screening in women of reproductive age.
Thornsberry L, English JC. J Pediatr Adolesc Gynecol 2012; 25: 150–4.
The diagnosis of anogenital warts is generally clinical. HPV DNA typing and 3–5% acetic acid testing to reveal subclinical lesions are not recommended. Anoscopy, and/or speculum examination are useful for evaluation of the anal canal, vagina, or cervix. A biopsy is not indicated for typical condylomas; however, it must be performed for atypical-looking and recalcitrant lesions or in immunocompromised patients.
Beutner KR, Tyring SK, Trofatter KF Jr, Douglas JM Jr, Spruance S, Owens ML, et al. Antimicrob Agents Chemother 1998; 42: 789–94.
A multicenter, double-blind, vehicle-controlled, trial (n = 279) evaluated daily application of imiquimod for 16 weeks. At week 16, 52% of 5% imiquimod-treated patients, 14% of 1% imiquimod, and 4% of vehicle-treated patients cleared the warts (p < 0.0001). Recurrence rate after a complete response was 19% with 5% imiquimod..
Baker DA, Ferris DG, Martens MG, Fife KH, Tyring SK, Edwards L, et al. Infect Dis Obstet Gynecol 2011; 806105 [E-pub].
Multicenter, double-blind trials evaluated imiquimod applied once daily for 8 weeks versus placebo (n = 534). Imiquimod 3.75% was superior, achieving complete clearance (p < 0.001), and reducing the number of warts (p < 0.001), versus placebo. At post-treatment week 28, 65.3% of patients with complete clearance remained lesion-free.
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.
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.
Tyring S, Edwards L, Cherry LK, Ramsdell WM, Kotner S, Greenberg MD, et al. Arch Dermatol 1998; 134: 33–8.
In a double-blind, multicenter, vehicle-controlled trial, 326 patients received podofilox 0.5% gel twice daily for 3 consecutive days followed by a 4-day treatment-free period (one treatment cycle). Treatment was repeated by the patient until all study warts had cleared, for a minimum of two and a maximum of eight treatment cycles. At week 8, 88.4% of warts in the vehicle-treated group and 35.9% in the podofilox-treated group remained (p = 0.001).
Podofilox gel was safe and significantly more effective than vehicle in the treatment of anogenital warts.
Tzellos TG, Sardeli C, Lallas A, Papazisis G, Chourdakis M, Kouvelas D. J Eur Acad Dermatol Venereol 2011; 25: 345–53.
Three double-blind studies (n = 1247) evaluated sinecatechin ointment, obtaining complete clearance ranging from 52.6% to 64.6%. Recurrence ranged from 5.9% to 10.6%. These results are consistent with previous studies.
Sinecatechin ointment is applied three times a day for up to 16 weeks.
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.
Jensen SL. Lancet 1985; 2: 1146–8.
Patients (n = 60) randomly received podophyllin applied for 6 hours weekly for 6 weeks or surgery. Complete clearance was 76.6% and 93.3%, respectively. At 3 months, the cumulative recurrence rates were 43% and 18%, respectively.
D’Ambrogio A, Yerly S, Sahli R, Bouzourene H, Demartines N, Cotton M, et al. Sex Transm Dis 2009; 36: 536–40.
Patients (n = 140) with anal canal condylomas had surgery followed by cauterization. Recurrence rate was 25% after day 120 of follow-up. HPV type 11 was statistically associated with higher recurrence rates.
Aynaud O, Buffet M, Roman P, Plantier F, Dupin N. Eur J Dermatol 2008; 18: 153–8.
Patients (n = 106) were treated with CO2 laser for condylomatous or neoplastic anogenital lesions. At 6 months, 83% of patients were in remission after an average of 1.4 laser treatments. Excision of HPV-induced anogenital lesions using CO2 laser remained an efficient treatment for long-standing lesions.
Badawi A, Shokeir HA, Salem AM, Soliman M, Fawzy S, Samy N, Salah M. J Cosmet Laser Ther 2006; 8: 92–5.
Patients (n = 174) with 550 uncomplicated anogenital warts underwent flashlamp-pumped pulsed-dye laser. Complete resolution was achieved in 96% of lesions, with a recurrence rate of 5%.
Ferenczy A, Behelak Y, Haber G, Wright TC Jr, Richart RM. J Gynecol Surg 1995; 148: 9–12.
In 208 patients, the efficacy and adverse effects of loop electrosurgical excision procedure (LEEP) were similar to those associated with laser ablation. LEEP adverse events included bleeding and scarring.
Scarring of the penis can result in dysfunction, therefore most physicians prefer CO2 laser ablation or cryotherapy for penile warts.
Abdullah AN, Walzman M, Wade A. Sex Transm Dis 1993; 20: 344–5.
In this trial (n = 86), complete clearance was 86% with cryotherapy versus 70% with 95% TCA after up to six treatments. Application site reactions developed in 30% of the TCA-treated patients.
Friedman-Kien AE, Eron LJ, Conant M, Growdon W, Badiak H, Bradstreet PW, et al. JAMA 1988; 259: 533–8.
In this double-blind, placebo-controlled trial, complete clearance was 62% (with intralesional interferon-α injections twice weekly for up to 8 weeks) versus 21% (placebo).
The results of combining interferon treatment with cryosurgery, podophyllin, or laser ablation have been promising.
Tsambaos D, Georgiou S, Monastirli A, Sakkis T, Sagriotis A, Goerz G. J Urol 1997; 158: 1810–12.
Oral isotretinoin 1 mg/kg daily during a 3-month period achieved complete response in 39.6% of 56 male patients with history of refractory condyloma acuminata. Oral isotretinoin may be considered an effective, and fairly well-tolerated, alternative treatment for immature and small condyloma 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.
Orlando G, Fasolo MM, Beretta R, Merli S, Cargnel A. AIDS 2002; 16: 447–50.
In a trial, 74 HIV positive patients received electrocautery or cidofovir 1% gel applied for 5 days per week for up to 6 weeks, or electrocautery plus cidofovir for 5 days per week for 2 weeks within 1 month of cautery. Complete response was achieved in 93.1%, 76.2%, and 100% of patients, respectively (p = 0.033). After 6 months the recurrence rate was 73.68%, 35.24%, and 27.27%, respectively (p = 0.018).
Liang J, Lu XN, Tang H, Zhang Z, Fan J, Xu JH. Photodermatol Photoimmunol Photomed 2009; 25: 293–7.
In a trial 91 patients received ALA–PDT or CO2 laser. Complete response was 95.93% and 100%, respectively (p > 0.05). At week 12 of follow-up, 9.38% and 17.39%, respectively, had recurrent lesions (p < 0.05). Adverse reactions were 8.82% and 100%, respectively (p < 0.05). ALA–PDT was as effective as CO2 laser in the treatment of anogenital condylomas with fewer adverse reactions.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Imiquimod (5%, 3.75%)
Podofilox (podophyllotoxin)
Sinecatechin extract of green tea
Cryotherapy
Podophyllin
Surgical excision (with cold knife or scissors)
Lasers (CO2 and PDL)
Loop electrosurgical excisional procedure
Electrodesiccation (see also above)
Trichloroacetic acid (see also above)
Intralesional interferon-α
Interferon-β gel
Oral isotretinoin
Intralesional fluorouracil/epinephrine gel
Cidofovir
ALA–photodynamic therapy
