Campaigns to encourage vaccination against human papillomavirus (HPV) infection have chiefly targeted adolescent girls and young women. Another population now warrants attention. At the end of 2011, the Centers for Disease Control's Advisory Committee on Immunization Practices (ACIP) recommended routine use of the quadrivalent HPV vaccine for adolescents boys at age 11 or 12, as well as vaccination for young men ages 13 to 21 who have not been vaccinated or did not complete the three-dose series.1
The quadrivalent HPV vaccine has been proven efficacious in preventing infection in populations at high risk for HPV, as well as in reducing the negative sequelae of infection. Immunocompromised populations, including HIV-positive men and women, organ transplant recipients and patients with chronic conditions, have an increased risk for HPV-associated malignancies and therefore are important targets for vaaccination.2
Of the 120 known HPV genotypes, types 16 and 18 are of greatest concern because they are linked to nearly all cervical neoplasias, as well as to 30% of oropharyngeal malignancies and to 80% of all anal malignancies.3 HPV types 6 and 11 pose minimal cancer risk but are implicated in 90% of genital warts.4 Approximately 20 million people in the United States are infected with HPV, and 6.2 million infections occur annually.4
Incidence and Prevalence
HPV is the most common sexually transmitted infection. In 2000, 74% of reported cases occurred in people ages 15 to 24.4 Infection rates are probably much higher than this because there is no mandate to report HPV infection.5
Fewer than 25% of HPV-related cancers occur in men, but certain populations of men experience higher rates of HPV-related malignancies.1 Men infected with human immunodeficiency virus are at increased risk for HPV-associated cancers.1 Men who have sex with men have higher rates of anal malignancy, and 90% of anal cancers are attributed to the oncogenic types of HPV.3 A study by Goldstone et al estimates that 30.5% of HIV seronegative men who have sex with men are infected with HPV.6
The pathophysiology of HPV infection is complicated, and research to identify the contributors to persistent viral infection is ongoing. HPV infects the epithelial cells within the basement membrane of the genitalia, oropharynx and anogenital areas through microabrasions. Viral replication takes place within the epithelial cells, rendering the virus undetectable by the host immune system.7,8
HPV may result in latent, subclinical or clinical infection. Multiple factors contribute to its manifestation.7 Because the virus is contained within the basement membrane, a latency period ensues before outward manifestation of infection.9
HPV types 6 and 11 are responsible for the majority of all genital warts but are nononcogenic types.4 Amplification of the HPV 6 or 11 genome occurs with normal epithelium growth and regeneration because the infected cells become more differentiated as they move from the basal layer of the epithelium.8 The resulting epithelium contains highly atypical keratinocytes.8 Through normal epithelial regeneration, viral particles are sloughed off and capable of infecting adjacent tissues and structures of the original host or a sexual partner.8,9
Malignant transformation occurs with persistent HPV exposure; this process may take more than 10 years.10 HPV types 16 and 18 are identified in a majority of anogenital and oral malignancies. The E6 and E7 proteins found on the HPV virion are believed to be responsible for the proliferation and disruption of normal cell cycles. E6 contributes to apoptosis via direction of the p53 tumor suppression proteins, while E7 competes for the retinoblastoma protein.10 The aberrant cell cycle with alteration of the normal mechanism for apoptosis initiates the start of the malignant cell cycle.7
A study to identify health-seeking behaviors among men found that most would seek initial treatment for sexually transmitted infections from their primary care providers.11 Inquiry about sexual behaviors that asks about multiple partners, multiple same-sex partners, lack of barrier contraceptive use, and high-risk sexual behaviors should be initiated whenever a patient presents with possible exposure to a sexually transmitted infection.4 Men who participate in unprotected anal intercourse are six times more likely to be infected with HPV within the anal canal.12
Genital warts within the perineal region caused by the human papillomavirus. courtesy CDC
A patient presenting with HPV growths of the penis 12 hours following podophyllin application. courtesy CDC
HPV is typically asymptomatic. Genital warts may or may not occur with infection, and the degree of symptoms varies with the size and location of the lesions.4 HPV lesions may appear singly or in multiples, and they may be papular or nodular proliferating masses.9 HPV lesions may appear flat, papular or pedunculated, surfacing on any part of the penis, scrotum, urethral meatus or perianal area.4 High-risk types may be indistinguishable from nononcogenic types, but a lesion that is dome-shaped or flat and hyperpigmented may indicate malignancy.5,10 Urethral and intranal lesions are common among men who practice receptive anal intercourse.4
The diagnosis of genital warts caused by HPV 6 and 11 is based on inspection.4 Flat genital lesions associated with HPV types 16 and 18 are easily missed and may be indistinguishable from nonmalignant forms. The Centers for Disease Control and Prevention recommends biopsy of lesions only in cases where diagnosis is uncertain, lesions do not respond to standard treatment, lesions are atypical in appearance, the patient is immunocompromised, or lesions appear pigmented, fixed, indurated or bleed easily.4
The application of acetic acid 3% to 5% turns genital warts white, but for diagnostic purposes, the application of acetic acid demonstrates a low specificity and is not routinely recommended.4 Immediate referral is indicated in all cases of suspicious lesions. The CDC does not recommend HPV DNA testing because testing is expensive and does not alter the course of treatment.4 Further, most forms of HPV infection resolve spontaneously and require no treatment. No federal agency has issued a recommendation for routine HPV screening in men, but some providers advocate for anal pap smears for men considered at high risk for anogenital malignancy.54
HPV vaccination is highly effective at preventing anal lesions in young men.3,13,14 The Advisory Committee on Immunization Practices recommends that young adolescent boys and their parents should be counseled about the risks of acquiring HPV and the use of the quadrivalent HPV vaccine in the prevention of associated cancers and genital warts.4 Ideally, vaccination should occur prior to sexual debut.1,3
Young men require education about safe sexual practices in order to minimize high-risk sexual behaviors. Patients (and for preadolescents, parents) must be thoroughly educated about the spread of HPV.5 Because HPV resides on the surface of epithelial cells on the skin and mucous membranes,13 participation in sexual intercourse is not a prerequisite for infection.4,13
Available evidence suggests that no treatment for HPV is superior to any other. Therefore, treatment must be guided principally by patient preference, the size of the involved area, and provider experience.4 Condylomata acuminate are the most commonly occurring lesions, and they are associated with substantial morbidity and a high rate of treatment failure.14 If no response to a particular treatment has occurred within 3 months, the CDC recommends a change in treatment approaches.4 Genital lesions are usually treated for cosmetic reasons, pain and pruritus.
Provider-administered therapies include cryotherapy with liquid nitrogen.4 Blistering and pain are common during application. Only areas less than 10 cm2 should be treated with cryotherapy, and only providers who have received proper training should administer cryotherapy.4 A major limitation to the administration of cryotherapy is the destruction of treated tissues that require further analysis.17
Current guidelines recommend the use of topical treatments for intertriginous areas and moist surfaces.4 Topical agents are generally considered safe for self-application provided that the lesions are readily visualized by the patent.4 Podofilox 0.5%, iquimod 5% and sinecatechins 15% are topical treatments commonly used for the treatment of genital warts. All topical treatments can cause burning or pain at the application site, as well as local irritation.4
Pedophyllin resin 10% to 25% can be applied to each lesion and allowed to air dry.4 The treatment is repeated weekly for approximately 6 weeks or until warts disappear.4 Podofilox is fairly inexpensive and easily applied to areas that do not exceed 10 cm2.4 A treatment-free period of 4 days during four cycles is prescribed.4 Podofilox is applied with the fingers or a cotton swab twice daily. Mild pain and irritation are common following treatment.4
Imiquimod 5% cream is an immunomodulator that enhances the production of interferon.15 Optimally, imiquimod is applied daily at bedtime, three times per week for approximately 16 weeks.4,15 Six to 10 hours after application, the area should be washed with soap and water. Local inflammation is a common side effect and results in increased redness, induration and vesicle formation.4 Vitiligo-like hypopigmentation is a common occurrence with the use of imiquimod.17 Other potential concerns to address include findings that imiquimod may weaken condoms and increase the risk of viral transmission to sexual partners.4
In HPV cases involving the genital region, referral to a specialist such as a urologist is recommended. For lesions involving the rectal mucosa, a referral to a proctologist is warranted. All patients who are immunosuppressed are at an increased risk for squamous cell carcinoma and require biopsy for diagnosis.4 The increased risk for anal cancer in HIV-positive men who have sex with men may benefit from cytologic screening for intraepithelial neoplasia. However, the reliability of such screening methods is the subject of debate.4
1. Advisory Committee on Immunization Practices. Recommendations on the use of quadrivalent human papillomavirus vaccine in males. MMWR. 2011;60(50):1705-1708.
2. Palefsky JM, et al. Chapter 16. HPV vaccines in immunocompromised women and men. Vaccine. 2006;(24 Suppl 3):S140-S146.
3. Kim JJ, Goldie SJ. Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States. BMJ. 2009;339:b3884.
4. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2010. MMWR. 2010;59(RR-12):1-110.
5. Hoy T, et al. Assessing incidence and economic burden of genital warts with data from a US commercially insured population. Curr Med Res Opin. 2009;25(10):2343-2351.
6. Goldstone S, et al. Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men. J Infect Dis. 2011;203(1):66-74.
7. Lehoux M, et al. Molecular mechanisms of human papillomavirus-induced carcinogenesis. Public Health Genomics. 2009;12(5-6):268-280.
8. Holt, C. Human papillomavirus: Should males be immunized too? Presented at Pharmacotherapy Conference sponsored by the University of Texas at Austin College of Pharmacy. Jan. 15, 2010. http://www.utexas.edu/pharmacy/divisions/pharmaco/rounds/01-15-10.pdf
9. Shanley J. Papillomavirus. eMedicine. 2010. http://emedicine.medscape.com/article/224516-overview
10. World Health Organization. Initiative for Vaccine Research. Viral Cancers. http://www.who.int/vaccine_research/diseases/viral_cancers/en/index1.html
11. D'Souza G, et al. Anal cancer screening and intentions in men who have sex with men. J Gen Intern Med. 2008;23(9):1452-1457.
12. Nyitray AG, et al. Age-specific prevalence of and risk factors for anal human papilloma virus (HPV) among men who have sex with women and men who have sex with men: the HPV in men (HIM) study. J Infect Dis. 2011;203(1):49-57.
13. Palefsky J. Human papillomavirus-related disease in men: not just a women's issue. J Adolesc Health. 2010;46(4 Suppl):S12-S19.
14. Giulino AR, et al. Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men. J Infect Dis. 2008;198(6):827-835.
15. Gotovtseva EP, et al. 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):346-351.
16. Mashiah J, Brenner S. Possible mechanisms in the induction of vitiligo-like hypopigmentation by topical imiquimod. Clin Exp Dermatol. 2008;33(1):74-76.
17. Gaisa MM, et al. Diagnosis and treatment of anal intraepithelial neoplasia and condylomata. Semin Colon Rectal Surg. 2011;22(1):21-29.
Casey Hense is a family nurse practitioner who is an adjunct instructor in the School of Nursing at the University of North Florida in Jacksonville.