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A Review of Therapeutic Options for Genital Warts

M. Gooderham, MSc, MD, FRCPC
Peterborough, ON, Canada

Introduction

Condylomata acuminata (genital or venereal warts) pose a significant health concern, especially amongst young adults. Considered to be one of the most common forms of sexually transmitted infections (STIs), external genital warts (EGWs) are caused by infection with the human papillomavirus (HPV), the same virus that causes the majority of cervical cancers. Relatively recent therapeutic advances include a topical immunomodulatory agent and a prophylactic vaccine, which have significantly broadened the options for management. Herein, a review of conventional and newer therapies will be discussed.

Background

HPV Facts

Over 100 HPV types have been described, 40 of which infect the anogenital tract; the most common of these are HPV types 6, 11, 16, and 18.1 HPV 6 and 11 are low risk for causing cancer, but they cause 90% of genital warts. HPV 16 and 18 are considered to be high risk types and contribute to 70% of cervical cancers.

HPV Pathogenesis

The principal route of genital infection is through sexual contact. The virus is believed to enter through micro-abrasions in the epithelium. Transmission to newborns by way of passage through the infected birth canal can also occur.2 The infection rate between sexual partners is approximately 60%.3 The incubation period for EGWs can range from weeks to years before clinical lesions are detectable. Consequently, unless sexual contact has been limited to a single partner, it is not advisable for patients to attempt to identify the source.

Risk Factors

It is estimated that 550,000 Canadians are affected by HPV annually.4 The rate of infection appears to accelerate following the onset of sexual activity and decrease with increasing age. Prevalence is highest amongst individuals under 25 years of age. The risk level is based on a combination of factors including age, lifestyle, immunocompetency, and other variables, such as:

  • becoming sexually active at an early age;
  • previous infection with another form of STI;
  • lifetime number of sexual partners;
  • engaging in unprotected sex;
  • sexual promiscuity of partners;
  • immune status.

Male circumcision may reduce the incidence of HPV infection according to a recent study by Tobian, et al.5 Also, because HPV can be present anywhere along the anogenital tract, the use of condoms may only provide partial protection.

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Diagnostic Features

Prior to making a confirmed diagnosis, it is necessary for clinicians to obtain a medical and sexual history from patients, if not already known. Examination of the pelvic region, entire genital tract, and the thighs, as well as mouth and throat, may reveal nodules indicative of, but not limited to, infection with HPV. Screening for other STIs may also be considered, especially in high-risk individuals.

  • In most cases, direct visual inspection can identify the growths on the genital mucosa.
  • Anogenital warts are generally asymptomatic, but can cause pruritus, bleeding, mild burning, and present as:
    • lesions that appear primarily on surface areas of the vulva, penis, and perianal skin.
    • small, discrete, sessile, flat or raised papules or nodules.
    • large exophytic masses.
    • a singular papule or multiple verrucous clusters.
    • lesions that range in colour from whitish, pink, flesh-coloured to reddish brown.
    • a multifocal distribution that generally correlates with regions sustaining the greatest degree of friction during sexual activity.
  • The lesion prevalence in women may be attributable to larger surface areas of mucosal skin.
  • For hard-to-see warts, a 3%-5% acetic acid solution (i.e., white vinegar) can be applied to the suspect lesion (Figure 1). After a few minutes, the condylomata should appear as whitened patches on the mucosa. Positive changes are not diagnostic for HPV, as these results can also be produced by lichen planus, yeast infections, and other skin disorders.
  • A biopsy may be considered if:6
    • diagnostic uncertainty exists.
    • lesions are unresponsive to convention treatments.
    • lesions worsen during therapy.
    • the patient is immunodeficient.
    • the warts are pigmented, indurated, fixed, bleeding, or ulcerated.
  • The lesion prevalence in women may be attributable to larger surface areas of mucosal skin.
  • A Pap test can help to establish the presence of a cervical lesion.7

Figure 1: Algorithm for treatment of suspect lesions8

Treatment

The primary treatment objectives are to eliminate visible warts and limit the psychological distress caused by EGWs. In about 10%-30% of patients, EGWs are usually self-limited in immunocompetent individuals and typically resolve within 12-24 months if left untreated; however, lesions may also remain unchanged, or proliferate in size and number.6,7

  • The spectrum of available treatments includes self-applied and provider-administered therapies.
  • The most widely used treatment modalities can be broadly categorized as antiproliferative, destruction/excision,immunodulatory, and combination therapies (Table 1).
  • The majority of therapeutic options provide symptomatic relief rather than treat the disease itself. The one exceptionis a topical immune response modifier (i.e., imiquimod), which exerts a field effect that can target both clinical andsubclinical manifestations of HPV.
  • Therapeutic decisions should be guided by wart type, location, number, sex, patient preferences, physician experience,and unique circumstances (e.g., young age, immunosuppression, pregnancy).
    • For vaginal mucosal warts, treatment options include cryotherapy and topical TCA 80%-90% (physician-applied).
  • Given the wide range of patient and treatment variables, there is a lack of conclusive evidence confirming the superiorityof any one modality, or combination thereof, over another.
  • The majority of patients require a course of therapy rather than a single treatment.6
  • It is important to iterate to patients that available treatments can induce wart-free periods, but none provide completeclearance of HPV infections.
Method Treatment Comments
Antiproliferative
Therapies
Podophyllum resin
10%-25%
  • Physician-administered
  • Removal of warts by destruction of infected tissue
  • Potential for systemic toxicity
Podophyllotoxin 0.5%
solution or gel
  • Can be applied by the patient
  • Low cost, low toxicity
  • Contains no mutagenic substances, unlike those found in podophyllum resin
Immunomodulatory
Therapy
Imiquimod 5% cream
  • Self-administration may improve patient compliance
  • Enhances the cytotoxic immune reaction, which is usually seen as an inflammatory response
  • Applied directly to the affected skin 3 times/week for up to 16 weeks - frequency of applications can be reduced if there is concern over the degree of inflammation
  • Low rate of recurrence due to reduction of the viral load
  • Effective for treating multiple warts covering larger areas, as well as subclinical lesions
  • Side-effects are mild to moderate and include local erythema and erosion at the site of application
  • Has a higher drug cost than podophyllotoxin
Destruction/Excision
Therapies


All options have the potential to cause scarring
Topical trichloracetic
acid 85% (TCA)
  • Causes cellular destruction by chemical cautery
  • Most effective when treating small, moist lesions
  • Damage to surrounding tissue can be minimized by protection with petroleum jelly
  • If TCA is applied to nonaffected tissue, instruct patients to wash the area with liquid soap or baking soda
  • Can cause pain and ulceration
Local cryotherapy
  • Most common destructive mode
  • Involves freezing with liquid nitrogen
  • Offers ease of use with no systemic effects
  • Can cause pain and ulceration
  • Safe for use during pregnancy
Electrodesiccation
  • Warts are burned off with a low-voltage electrical current
Excision by scissors,
curette, or scalpel
  • Provides definitive clearance of abnormal tissue
  • Particularly suitable for larger exophytic warts
  • Local anesthesia is required
Ablative laser
  • Use of CO2 laser therapy is usually reserved for extensive and/or treatment resistant warts
  • May require a long time for recovery and is expensive
Combination Therapy

Combination therapy
can provide a better
result over monotherapy
Excision/destruction +
imiquimod
  • Cryotherapy combined with imiquimod appears to be very commonly
  • used
  • Initial therapy with imiquimod may reduce wart size and improve
  • surgical outcomes
  • Initial treatment with imiquimod followed by excision of residual
  • lesions may provide long-term clearance of EGWs, especially if prior
  • monotherapy was insufficient9
Excision/destruction +
cidofovir
  • Due to cidofovirís broad antiviral activity, it has been used successfully
  • as a topical gel for refractory patients8
Table 1: Treatment options for genital warts7,10

The therapeutic horizon may include a topical formulation whose active constituent is a defined mixture of catechins extracted from green tea with demonstrated efficacy and safety for EGWs.11 This herbal prescription drug gained US FDA approval in 2006 for the treatment of external genital and perianal warts caused by certain strains of HPV.

A Prophylactic Approach

In 2006, Health Canada approved a quadrivalent HPV vaccine that acts against HPV types 6, 11, 16 and 18.
  • It is indicated for use in females 9-26 years of age and is given as a 0.5ml injection intramuscularly in 3 doses at 0, 2, and 6 months.
  • The quadrivalent vaccine is 97% effective in preventing vaginal and vulval intraepithelial neoplasia, and is 99% effective in preventing genital warts caused by HPV types 6 and 11.1
  • There is no evidence suggesting that therapeutic benefits may be derived from the immunization vaccine if patients are already infected with vaccine HPV types.
  • Recent studies suggest that the quadrivalent vaccine may also provide cross-protection against HPV strains that are not contained in the vaccine, but are closely related. However, durability of immunity and the significance of these findings remain to be established.12,13
  • Studies investigating this vaccine in males are underway.

Conclusion

  • For the initial treatment of genital warts, many patients prefer self-applied therapies.
  • Because monotherapy is often insufficient, combination therapy may be more advantageous.
  • Throughout the course of treatment, patients must be monitored for response rate and side-effects.
  • An inadequate response to treatment necessitates a transition to other therapies or modification of the existing approach.
  • According to the Canadian Consensus Guidelines on HPV,7 due to its favourable efficacy, safety, and tolerability profiles, as well as lowest recurrence rate, imiquimod represents an effective strategy for the management of genital warts, and should be considered prior to initiating more invasive strategies, such as destructive/excision or laser therapies.

The increasing incidence of HPV infections is of mounting concern and the most prevalent clinical manifestation of this communicable disease is genital warts. Upon confirmation of diagnosis, patient-specific treatment that is accompanied by education on limiting the risk of transmission and HPV-associated diseases, as well as recommendations for regular screening, are warranted. Although disease morbidity can be mild, the emotional distress of having genital warts can result in severe psychological impacts; hence, successful management is essential.

References

  1. Dobson S, et al. Canada Communicable Disease Report 33(ACS-2):1-31 (2007 Feb 15).
  2. Kaye JN, et al. J Gen Virol 77 (Pt 6):1139-43 (1996 Jun).
  3. Palefsky JM. 15(3):439-47 (1997 May-Jun).
  4. Money DM, et al. J Obstet Gynaecol Can 29(8 Suppl 3):S3-6 (2007 Aug).
  5. Aaron AR, et al. N Engl J Med 360(13):1298-309 (2009 Mar 26).
  6. Centers for Disease Control and Prevention. Genital warts treatment guidelines 2006. Available at: http://www.cdc.gov/std/treatment/2006/genital-warts.htm. Accessed March 17, 2009.
  7. Roy M, et al. J Obstet Gynaecol Can 29(8 Suppl 3):S37-41 (2007 Aug).
  8. Varela A, et al. Skin Therapy Lett-FP US Ed 1(2): 1-3 (2006).
  9. Carrasco D, et al. J Am Acad Dermatol 47(4 Suppl):S212-6 (2002 Oct).
  10. Bourcier M, et al. Skin Therapy Lett-FP Ed 3(2): 1-3 (2007 Jun).
  11. Stockfleth E, et al. Br J Dermatol 158(6):1329-38 (2008 Jun).
  12. Brown DR, et al. J Infect Dis 199(7):926-35 (2009 Apr 1).
  13. Wheeler CM, et al. J Infect Dis 199(7):936-44 (2009 Apr 1).

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