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Clinical Updates

Chanal Johan

Genital Warts

Johan Chanal

Tuesday, May 07, 2013

Overview

External genital warts (EGW) or condylomata, related to the infection of the squamous epithelium in the genital and anal area by the human papillomavirus (HPV), are the most frequent sexually transmitted disease (STD) worldwide, alongside genital herpes simplex. Its prevalence reaches 1-2% of the population in industrialized countries,1 and the cumulative life-long risk for a sexually active person is nearly 10%.

There are more than a hundred known genotypes of HPV. Some are associated with a higher risk of epithelial dysplasia, evolving into intraepithelial neoplasia (vulvar intraepithelial neoplasia, penile intraepithelial neoplasia and anal intraepithelial neoplasia) and invasive carcinoma (16 and 18 preferentially), and others are at lower risk of transformation. HPV 6 and 11 (low-risk group) are the most frequent genotypes associated with EGW but genotypes 16, 18, 31, 33, 35, 39, 41, 45, 56 and 59 can also be found.2

Clinically, EGW are well shaped lesions, papillomatous or verrucous, fleshy or brown, sometimes exophytic (cauliflower-like), pediculated or flat, and located around the genitals areas (corona glandis, vulva, vagina and cervix, anus, urethral meatus). Rarely, the lesions can become large and invasive (Buschke-Lowenstein tumor) with a mortality of nearly 20% at 5 years and a risk of carcinoma transformation of over 50%. The rate of recurrence is high (50%) despite radical surgery.3

Histologically, genital warts are papillomatous tumors with koilocytes (squamous epithelial cells with nuclear enlargement and hyperchromasia). Epidermis may also present acanthosis, parakeratosis on the tips of the papillae, and a coarse, granular layer.

The lesions are highly infectious, with a risk of transmission after contact of 60-86%.4 The delay of appearance of EGW after transmission varies from 3 to 18 months.5

Risk Factors

The major risk factor is the number of sexual partners during life. Immunosuppressed patients (HIV, organ transplants etc.) are also at higher risk of EGW.

Smoking is associated with EGW; however, it is difficult to fully ascertain whether this is a genuine risk factor or whether there are confounding variables implicated.6

Protective Factors

There is controversy within the literature regarding the protective role of male circumcision in HPV infection. Nevertheless, two recent meta-analysis including 217 and 23 studies8, respectively, have shown an odds ratio of 0.56 associated with circumcision.

Condoms remain the best protective method against EGW infection but their efficacy in practice is also controversial. Infection may still occur through intimate contact around the unprotected pubic area or major vulva in women.

Risk of Neoplasia

Patients with EGW are at high risk of developing intraepithelial neoplasia. In one study, genotyping and detection of HPV in 423 patients (209 men and 214 women) who presented with EGW, showed that 33% had a history of high-risk HPV association (predominantly HPV 16).9 In this study, women were more likely to be infected with high-risk HPV (40%) than men (25%).

Treatment

Treatments of EGW are classically divided into two groups: patient-applied therapy or provider-applied therapy (Table 1).

Table 1. Treatments

Patient applied-therapy

 

Dose

Clearance rate

Recurrence at 3 months

Side effects

Imiquimod cream 5%

3 times a week up to 16 weeks

40-70%

19%

Erythema, burning sensation, pruritus, erosion, ulceration, hyper or hypo-pigmentation,

Podophyllotoxin 0.5% solution or 0.15 cream

5 days a week up to 5 weeks

37-88%

38%

Erythema, burning sensation, pruritus, erosion, ulceration

Polyphenon E 15% Ointment

3 times per day up to 16 weeks

65%

9%

Erythema, pruritus, burning sensation, erosion and ulceration

Provider applied-therapy

 

Dose

Clearance rate

Recurrence at 3 months

Side effects

Cryotherapy

Every two weeks

37-88%

21-39%

Pain, bulla, erosion, hypo or hyper-pigmentation, bleeding, erosion, ulceration

Electrocauteriz-ation/ laser vaporization

One session

100%

20%

Pain, bulla, ulceration, hypo or hyper-pigmentation, provider exposure to HPV, bleeding, scars 

Trichloracetic acid 15-25%

One application per week

81%

36%

Burning sensation, pain, bleeding, chemical burns of normal skin, erosion, caustic dermatitis

 Advantages and disadvantages

 

Advantages

Disadvantages

Imiquimod cream 5% 

Low rate of recurrence

cost, variation of efficacy among patients, tolerance

Podophyllotoxin 0.5%
solution or 0.15 cream

Availability, duration of treatment

Tolerance, rate of recurrence

Polyphenon E 15% ointment

Low rate of recurrence, psychological effect (green tea leaves extracts)

Price, not approved in all industrialized countries

Cryotherapy

Low cost, availability, high rate of clearance, 

Modalities of application, side effects, rate of recurrence

Electrocauterization/

laser vaporization

Clearance rate

Side effects, provider exposure to HPV, cost, local anesthesia or general anesthesia required for extensive treatment, rate of recurrence, devices needed

Trichloracetic acid 15-25%

Availability, low cost

No strong evidence in literature, side effects




Patient-applied Therapies

  1. Imiquimod cream is a toll-like receptor 7 (TLR-7) agonist inducing local production of IFN-γ, TNF-α and interleukins of the Th1 pathway (IL-1, 6, 12). The approved dosing is three times a week for up to 16 weeks. The 5% cream is applied before bedtime and must be rinsed off in the morning. Clearance rates are between 40-70% with recurrence at three months up to 19%10 and 23%11 at 6 months. Imiquimod could be more effective in women than in men with total clearance ranging up to 72% for women and 33% for men 11,12 and could be more effective in uncircumcised men than in circumcised men.13 Local erythema with burning sensation and pruritus are the most frequent adverse events. Patients should be encouraged to use moisturizing or repair cream in the morning, and on days imiquimod cream is not applied. Another formulation of the cream with 3.75% of imiquimod has been approved in the US and in Canada. Imiquimod 3.75% cream is applied daily for up to 8 weeks.
  2. Podophyllotoxin (a non-alkaloid toxin lignin extracted from Mayapples) inhibits tubulin polymerization stopping the cell cycles leading to apoptosis. It is available as a cream, a gel or a solution in varying concentrations under 1%. The product is applied 5 days a week for up to 5 weeks. Local erythema with burning sensation, ulcerations or erosions and pruritus are the most frequent adverse events. Clearance rates are between 37% and 88%, with a recurrence rate up to 38%.14
  3. Polyphenon E 15% ointment contain sinecatechins which are extracts from green tea leaves.  The drug is approved in the US, Germany, Switzerland, Spain and Austria. Clearance rates are up to 65% with a rate of recurrence of 9%.15 Polyphenon E 15% ointment is applied 3 times per day up to 16 weeks.

Provider-applied Therapies

  1. Cryotherapy is probably the most used therapy in practitioners' offices. It consists of the application of liquid nitrogen. Clearance rates are between 37-88% but it depends of the number of applications during the session, the frequency of the application and technique (cotton tipped applicator vs. Cry-Ac® spray device). Recurrence rates range from 21-39% at 3 months.16
  2. Laser vaporization and electrocauterization need local or general anesthesia. It can cause bleeding, scars and is very often painful following the procedure. DNA of HPV can be found in the vapors during the procedure and could infect the practitioner. Smoke evacuator systems, gloves and masks are therefore required. Clearance rates are up to 100%; however, recurrence rates are around 20% at 3 months.
  3. Trichloroacetic acid is also often used in dermatologists' offices but the literature is weak with regards to clearance rates and recurrence. It can induce burns, scars and caustic dermatitis.

Provider-applied treatments have low level of evidence. Modalities such as cryotherapy and trichloracetic acid application (frequency, duration of application, number of freeze-thaw cycles for cryotherapy) have level 4 of evidence.

Cryotherapy has shown superior clearance rates to trichloracetic acid or electrocauterization in randomized control trials.17,18

Exceptional Therapies

Other therapies used for controlling EGW include intralesional cidofovir or intralesional or systemic interferon-α, but are limited in both cases by secondary effects. Topical cidofovir could also be an interesting option.19

Vaccination

Tetravalent vaccination against HPV 6, 11, 16 and 18 should be protective against EGW.20

Conclusion

Although EGW are common and typically benign infections, the risk of co-infection with high-risk HPV may lead to HPV-related neoplasia, particularly in women (cervical screening). Patients presenting with EGW must also be tested for other STDs (including HIV, syphilis, hepatitis B and C, and Chlamydia trachomatis  infection). Treatment of EGW has a high rate of recurrence, regardless of therapy, resulting in a seemingly never-ending condition for patients. Preventative steps, in the form of tetravalent vaccination, must be undertaken in women and men in order to reduce the prevalence of EGW.

Johan

 

Johan2

 

Johan3 

References

  1. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 1997;102(5A):3-8.
  2. Anic GM, Lee J-H, Stockwell H, et al. Incidence and human papillomavirus (HPV) type distribution of genital warts in a multinational cohort of men: the HPV in men study. J Infect Dis 2011;204(12):1886-92.
  3. Chu QD, Vezeridis MP, Libbey NP, Wanebo HJ. Giant condyloma acuminatum (Buschke-Lowenstein tumor) of the anorectal and perianal regions. Analysis of 42 cases. Dis Colon Rectum 1994;37(9):950-7.
  4. Burchell AN, Winer RL, de Sanjosé S, Franco EL. Chapter 6: Epidemiology and transmission dynamics of genital HPV infection. Vaccine 2006;24 Suppl 3:S3/52-61.
  5. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis 2005;191(5):731-8.
  6. Feldman JG, Chirgwin K, Dehovitz JA, Minkoff H. The association of smoking and risk of condyloma acuminatum in women. Obstet Gynecol 1997;89(3):346-50.
  7. Albero G, Castellsagué X, Giuliano AR, Bosch FX. Male circumcision and genital human papillomavirus: a systematic review and meta-analysis. Sex Transm Dis 2012;39(2):104-13.
  8. Larke N, Thomas SL, Dos Santos Silva I, Weiss HA. Male circumcision and human papillomavirus infection in men: a systematic review and meta-analysis. J Infect Dis 2011;204(9):1375-90.
  9. Aubin F, Prétet J-L, Jacquard A-C, et al. Human papillomavirus genotype distribution in external acuminata condylomata: a Large French National Study (EDiTH IV). Clin Infect Dis 2008;47(5):610-5.
  10. Beutner KR, Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM Jr. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol 1998;38(2 Pt 1):230-9.
  11. Garland SM, Sellors JW, Wikstrom A, et al. Imiquimod 5% cream is a safe and effective self-applied treatment for anogenital warts--results of an open-label, multicentre Phase IIIB trial. Int J STD AIDS 2001;12(11):722-9.
  12. Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus. Arch Dermatol 1998;134(1):25-30.
  13. Gotovtseva EP, Kapadia AS, Smolensky MH, Lairson DR. Optimal frequency of imiquimod (aldara) 5% cream for the treatment of external genital warts in immunocompetent adults: a meta-analysis. Sex Transm Dis 2008;35(4):346-51.
  14. Scheinfeld N, Lehman DS. An evidence-based review of medical and surgical treatments of genital warts. Dermatol Online J 2006;12(3):5.
  15. Tzellos TG, Sardeli C, Lallas A, Papazisis G, Chourdakis M, Kouvelas D. Efficacy, safety and tolerability of green tea catechins in the treatment of external anogenital warts: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2011;25(3):345-53.
  16. Gormley RH, Kovarik CL. Human papillomavirus-related genital disease in the immunocompromised host: Part II. J Am Acad Dermatol 2012;66(6):883.e1-17; quiz 899-900.
  17. Stone KM, Becker TM, Hadgu A, Kraus SJ. Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodesiccation. Genitourin Med 1990;66(1):16-9.
  18. Godley MJ, Bradbeer CS, Gellan M, Thin RN. Cryotherapy compared with trichloroacetic acid in treating genital warts. Genitourin Med 1987;63(6):390-2.
  19. Snoeck R, Bossens M, Parent D, et al. Phase II double-blind, placebo-controlled study of the safety and efficacy of cidofovir topical gel for the treatment of patients with human papillomavirus infection. Clin Infect Dis 2001;33(5):597-602.
  20. Castellsagué X, Muñoz N, Pitisuttithum P, et al. End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24-45 years of age. Br J Cancer 2011;105(1):28-37. 
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