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Human papillomavirus (HPV) infects cutaneous and mucosal squamous epithelium. More than 100 distinct types of HPV exist (868Munoz N, Castellsagué X, de González AB, et al. Chapter 1: HPV in the etiology of human cancer. Vaccine 2006;24(S3):S1-S10.). They can be categorized on the basis of the site at which they occur (genital, cutaneous) and as highor low-risk on the basis of their potential to induce malignant proliferation. Of the approximately 40 genital (i.e., muscosal) HPV types, 12 types are identified as established high risk (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59), and six, as probable high risk (HPV 26, 53, 66, 68, 73, 82) (868Munoz N, Castellsagué X, de González AB, et al. Chapter 1: HPV in the etiology of human cancer. Vaccine 2006;24(S3):S1-S10.). Genital HPV types can infect the genitals, conjunctiva, mouth, throat, and respiratory tract. Nongenital (i.e., cutaneous) HPV types that cause skin warts (such as HPV 2) are distinct from those causing genital infections. Children with compromised cellular immunity might have intense and widespread appearance of both cutaneous and mucosal warts.

HPV-associated cutaneous warts are transmitted by close person-to-person contact that is facilitated by minor trauma to the skin. HPV-associated anogenital warts are transmitted by sexual contact but also might be acquired at delivery. There is some evidence that transmission may occur from nongenital sites. Genital warts (condyloma accuminatum) in young children might be a sign of sexual abuse (869Gutman LT, St Claire K, Herman-Giddens ME, et al. Evaluation of sexually abused and nonabused young girls for intravaginal human papillomavirus infection. Am J Dis Child 1992;146:694-9., 870Beutner KR, Reitano MV, Richwald GA, et al. External genital warts: report of the American Medical Association Consensus Conference. AMA Expert Panel on External Genital Warts. Clin Infect Dis 1998;27:796-806.).

Mother-to-child transmission of HPV is not surprising because pregnant women have high rates of HPV infection(871Rintala M, Grénman SE, J?rvenkyl? ME, et al. High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study. Clin Infect Dis 2005;41:1728-33., 872Smith EM, Ritchie JM, Yankowitz J, et al. Human papillomavirus prevalence and types in newborns and parents: concordance and modes of transmission. Sex Transm Dis 2004;31:57-62.). HPV DNA has been identified in 5%-42% of pregnant women without HIV infection (873Hernandez-Giron C, Smith JS, Lorincz A, et al. High-risk human papillomavirus detection and related risk factors among pregnant and nonpregnant women in Mexico. Sex Transm Dis 2005;32:613-8., 874Chan PK, Chang AR, Tam WH, et al. Prevalence and genotype distribution of cervical human papillomavirus infection: comparison between pregnant women and non-pregnant controls. J Med Virol 2002;67:583-8., 875Fife KH, Katz BP, Brizendine EJ, et al. Cervical human papillomavirus deoxyribonucleic acid persists throughout pregnancy and decreases in the postpartum period. Am J Obstet Gynecol 1999;180:1110-4.). Although a few studies have demonstrated an increased prevalence of detectable HPV DNA during pregnancy, this finding has not been consistent across studies (874Chan PK, Chang AR, Tam WH, et al. Prevalence and genotype distribution of cervical human papillomavirus infection: comparison between pregnant women and non-pregnant controls. J Med Virol 2002;67:583-8., 875Fife KH, Katz BP, Brizendine EJ, et al. Cervical human papillomavirus deoxyribonucleic acid persists throughout pregnancy and decreases in the postpartum period. Am J Obstet Gynecol 1999;180:1110-4.). Among nonpregnant women, HPV DNA is detected more frequently among HIV-infected than HIV-uninfected women, with reported prevalence rates of 12%-77% (876Hagensee ME, Cameron JE, Leigh JE, et al. Human papillomavirus infection and disease in HIV-infected individuals. Am J Med Sci 2004;328:57-63., 877Moscicki AB, Ellenberg JH, Vermund SH, et al. Prevalence of and risks for cervical human papillomavirus infection and squamous intraepithelial lesions in adolescent girls: impact of infection with human immunodeficiency virus. Arch Pediatr Adolesc Med 2000;154:127-34.). Few data have been reported about HPV prevalence in HIV-infected pregnant women, with one study reporting a prevalence of 35% (878Bollen LJ, Chuachoowong R, Kilmarx PH, et al. Human papillomavirus (HPV) detection among human immunodeficiency virus-infected pregnant Thai women: implications for future HPV immunization. Sex Transm Dis 2006;33:259-64.).

HPV DNA has been detected in cord blood and amniotic fluid, indicating the potential for in utero infection (879Armbruster-Moraes E, Ioshimoto LM, Leo E, et al. Presence of human papillomavirus DNA in amniotic fluids of pregnant women with cervical lesions. Gynecol Oncol 1994;54:152-8., 880Tseng CJ, Lin CY, Wang RL, et al. Possible transplacental transmission of human papillomaviruses. Am J Obstet Gynecol 1992;166(1 Pt 1): 35-40.). Duration of membrane rupture has been associated with mother-to-child HPV transmission, and reports of HPV transmission to infants born by cesarean delivery suggest that HPV can cross the placental barrier (881Tseng CJ, Liang CC, Soong YK, et al. Perinatal transmission of human papillomavirus in infants: relationship between infection rate and mode of delivery. Obstet Gynecol 1998;91:92-6., 882Tenti P, Zappatore R, Migliora P, et al. Perinatal transmission of human papillomavirus from gravidas with latent infections. Obstet Gynecol 1999;93:475-9.). Most transmission studies report on the detection of HPV DNA because clinical disease (i.e., warts) is rare in infants. Reported rates of HPV DNA detection in nasopharyngeal aspirates, buccal brush swabs, or genital swabs from infants born to HPV-infected mothers have varied from 2% to 80% (871Rintala M, Grénman SE, J?rvenkyl? ME, et al. High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study. Clin Infect Dis 2005;41:1728-33., 872Smith EM, Ritchie JM, Yankowitz J, et al. Human papillomavirus prevalence and types in newborns and parents: concordance and modes of transmission. Sex Transm Dis 2004;31:57-62., 881Tseng CJ, Liang CC, Soong YK, et al. Perinatal transmission of human papillomavirus in infants: relationship between infection rate and mode of delivery. Obstet Gynecol 1998;91:92-6.). Neonatal clinical abnormalities at birth are rare. Genital condylomata can occur within weeks to months after birth but are rare. Respiratory papillomatosis, a rare condition in which respiratory papillomas develop and typically recur (i.e., juvenile onset recurrent respiratory papillomatosis), usually manifests within 2-5 years after birth. Respiratory papillomatosis in children is thought to be secondary to HPV transmitted from mother to child through aspiration of infectious maternal genital secretions during delivery; however, other methods of transmission are possible (871Rintala M, Grénman SE, J?rvenkyl? ME, et al. High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study. Clin Infect Dis 2005;41:1728-33.). A recent parent-child study found that the cumulative detection rate for high-risk HPV from the child's genital samples was 53% over 3 years; 1.5% persisted with the same HPV type at the end of study. During the same period, HPV was detected more commonly from oral samples, with a cumulative rate of 63% with 10% persistence (871Rintala M, Grénman SE, J?rvenkyl? ME, et al. High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study. Clin Infect Dis 2005;41:1728-33.). Persistence in infant oral samples was associated with persistent oral HPV detection in the mothers. Persistent genital infections were associated with the mother's history of genital warts. The prevalence of HPV DNA in the oropharynx in 1235 children in Iowa was assessed in one study; a bimodal age distribution was found, with highest HPV prevalence in the youngest and oldest groups: 2.5% at age <1 year, 0.8% at 1-4 years, 1.2% at 5-11 years, 1.5% at 12-15 years, and 3.3% at 16-20 years (883Smith EM, Swarnavel S, Ritchie JM, et al. Prevalence of human papillomavirus in the oral cavity/oropharynx in a large population of children and adolescents. Pediatr Infect Dis J 2007;26:836-40.). These data support the high rate of HPV clearance in children, even if the infant is exposed to HPV during infancy.

Although perinatal transmission is possible, genital HPV is most commonly sexually transmitted. Young age at first intercourse and a higher number of recent sex partners are strong risk factors for HPV (884Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA 2001;285:2995-3002., 885Burchell AN, Winer RL, de Sanjosé S, et al. Epidemiology and transmission dynamics of genital HPV infection. Vaccine 2006;24:S52-61., 886Winer RL, Lee SK, Hughes JP, et al. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157:218-26., 887Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 2006;354:2645-54., 888Munoz N, Méndez F, Posso H, et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results. J Infect Dis 2004;190:2077-87.). Prevalence of HPV is common in sexually active adolescent girls, with prevalences of 12%-64% compared with 2%-7% in women aged >35 years (885Burchell AN, Winer RL, de Sanjosé S, et al. Epidemiology and transmission dynamics of genital HPV infection. Vaccine 2006;24:S52-61., 889Brown DR, Shew ML, Qadadri B, et al. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis 2005;191:182-92., 890Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr 1998;132:277-84., 891Tarkowski TA, Koumans EH, Sawyer M, et al. Epidemiology of human papillomavirus infection and abnormal cytologic test results in an urban adolescent population. J Infect Dis 2004;189:46-50.). Cervical HPV is acquired shortly after onset of sexual activity, with 50% cumulative exposure within 3 years (884Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA 2001;285:2995-3002., 886Winer RL, Lee SK, Hughes JP, et al. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157:218-26.), even among young women with one sex partner (892Winer RL, Feng Q, Hughes JP, et al. Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis 2008;197:279-82.).

Although the incidence of anogenital HPV infection in sexually active youth is high, longitudinal studies have demonstrated that 80%-90% of infections among youth without HIV infection might be transient and spontaneously regress (890Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr 1998;132:277-84., 893Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423-8.). Repeated infections with new types are common (889Brown DR, Shew ML, Qadadri B, et al. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis 2005;191:182-92.), but whether repeat detection of same HPV type infections result from new exposures or from reactivation of latent infection is not known (894Strickler HD, Burk RD, Fazzari M, et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst 2005;97:577-86.). Even though the prevalence of HPV consistently has been higher among HIV-infected men and women, acquisition rates of HPV appear similar among HIV-infected and HIV-uninfected persons (895Moscicki AB, Ellenberg JH, Farhat S, et al. Persistence of human papillomavirus infection in HIV-infected and HIV-uninfected adolescent girls: risk factors and differences, by phylogenetic type. J Infect Dis 2004;190:37-45.). The higher prevalence results from the increased rate of HPV persistence in HIV-infected persons. In one study of adolescents with HIV, only 50% cleared their HPV infections (895Moscicki AB, Ellenberg JH, Farhat S, et al. Persistence of human papillomavirus infection in HIV-infected and HIV-uninfected adolescent girls: risk factors and differences, by phylogenetic type. J Infect Dis 2004;190:37-45.). Other possible risk factors for persistence have included multiple types or high-risk types of HPV (e.g., 16 and 18), older age, smoking cigarettes, and duration of HPV detection for >12 months (896Moscicki AB, Schiffman M, Kjaer S, et al. Updating the natural history of HPV and anogenital cancer. Vaccine 2006;24(Suppl 3):S42-51.). Detection of anal HPV also is higher among HIV-infected youth (897Moscicki AB, Durako SJ, Houser J, et al. Human papillomavirus infection and abnormal cytology of the anus in HIV-infected and uninfected adolescents. AIDS 2003;17:311-20. 124 MMWR September 4, 2009). Receptive anal sex is a risk for anal HPV among HIV-infected and HIV-uninfected men; the association between anal HPV infection and anal sex is not as clear for women (897Moscicki AB, Durako SJ, Houser J, et al. Human papillomavirus infection and abnormal cytology of the anus in HIV-infected and uninfected adolescents. AIDS 2003;17:311-20. 124 MMWR September 4, 2009, 898Palefsky J. HPV infection and HPV-associated neoplasia in immunocompromised women. Int J Gynaecol Obstet 2006;94(Suppl 1): S56-64.). In one study of HIV-infected women, anal HPV infection was more prevalent than cervical infection (899Palefsky J, Holly EA, Ralston ML, et al. Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis 2001;183:383-91.).

Persistent infection with high-risk HPV is associated with increased risk for cervical intraepithelial neoplasia (CIN) and cervical and vulvovaginal carcinoma in women and for anal intraepithelial neoplasia and anal carcinoma in both women and men. Rates of all these HPV-associated cancers are higher among HIV-infected persons (900Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000;92:1500-10.) and believed to result predominantly from the increased risk for persistent infection in this group. Interestingly, the risk for these HPVassociated cancers is highest among young persons with HIV (900Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000;92:1500-10.). Adolescent girls differ biologically from adult women (e.g., cervical squamous metaplasia) that might increase their susceptibility to either persistent infection or disease (877Moscicki AB, Ellenberg JH, Vermund SH, et al. Prevalence of and risks for cervical human papillomavirus infection and squamous intraepithelial lesions in adolescent girls: impact of infection with human immunodeficiency virus. Arch Pediatr Adolesc Med 2000;154:127-34., 901Moscicki A, Burt VG, Kanowitz S, et al. The significance of squamous metaplasia in the development of low grade squamous intraepithelial lesions in young women. Cancer 1999;85:1139-44.). The risk for HPV-associated cervical abnormalities increases among HIV-infected youth. In one study, 33% of HPV-infected youth with HIV progressed to high-grade squamous intraepithelial lesions (HSIL) within 3 years of observation (902Moscicki AB, Ellenberg JH, Crowley-Nowick P, et al. Risk of high-grade squamous intraepithelial lesion in HIV-infected adolescents. J Infect Dis 2004;190:1413-21.). CD4 immunosuppression correlated with HPV persistence but not with HSIL. Even though HAART has dramatically altered HIVs natural history, its impact on HPV and HPV-associated neoplasia is less clear. Other risks associated with cervical cancers include lack of cervical cancer screening, prolonged hormonal contraceptive use, parity, smoking, and immunocompromising conditions (other than HIV) (888Munoz N, Méndez F, Posso H, et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results. J Infect Dis 2004;190:2077-87.).

Genital HPV types cause hyperplastic, papillomatous, and verrucous squamous epithelial lesions on skin and mucus membranes, including anal, genital, oral, nasal, conjunctival, GI, bladder, and respiratory tract mucosa. Wart lesions can appear as papules, flat, smooth, or pedunculated lesions. Sometimes they can be soft, pink, or white cauliflower-like sessile growths on moist mucosal surfaces (condyloma accuminatum), or keratotic lesions on squamous epithelium of the skin with a thick, horny layer. Because HPV requires access to basal epithelial cells through disruption of the squamous epithelium, common sites for skin warts are the hand, elbows, knees, and feet.

Most cutaneous and anogenital warts can be diagnosed by physical examination. Diagnosis of laryngeal papillomas requires laryngoscopy, and children with suspected respiratory tract papillomas need to be evaluated by a pediatric otolaryngologist.

Whether all cervical HPV infections result in microscopic abnormalities described as squamous intra-epithelial lesions (SIL) remains debatable. Most HPV DNA detected from cervical samples is associated with normal cervical cytology. These infections either have microscopic lesions not detected by the insensitive cytologic test or are truly latent. The Pap test (conventional or liquid-based) is a screening test for HPV-associated disease, including cervical cancer. However, histology remains the gold standard for confirming HPV-associated cervical and anal precancerous lesions and invasive cancers.

Biopsies for histologic diagnosis usually are directed by colposcopy or high-resolution anoscopy. No screening tests are available for vaginal and vulvar disease; however, these lesions often are diagnosed in women referred to colposcopy for abnormal cytology or because of abnormalities noted on macroscopic examination. Histology also should be confirmed for vulvar and vaginal squamous intraepithelial lesions and cancer.

HPV DNA can be detected using several platforms (903Arbyn M, Sasieni P, Meijer CJ, et al. Clinical applications of HPV testing: a summary of meta-analyses. Vaccine 2006;24(Suppl 3): S78-89.). The only FDA-approved test is HybridCapture, which detects any of 13 high-risk HPV types and is not type specific. Detection and typing of HPV is not recommended for diagnosing or managing anogenital or cutaneous warts or papillomas (870Beutner KR, Reitano MV, Richwald GA, et al. External genital warts: report of the American Medical Association Consensus Conference. AMA Expert Panel on External Genital Warts. Clin Infect Dis 1998;27:796-806.). HPV testing is not recommended in any circumstance for adolescent girls (aged ≤20 years) (904Wright TC, Jr, Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007;197:340-5.), regardless of whether they are HIV-infected or HIV-uninfected, because of the high rates of HPV infection. These recommendations may change once specific HPV testing has been studied in clinical trials.

Monitoring is required during and after treatment of genital warts because each treatment has associated toxicity and recurrences are common after treatment. Patients can be monitored by physical examination for evidence of recurrence. The major toxicity of podophyllotoxin and topical podophyllin resin is local skin irritation. Also, if podophyllin is applied to a large treatment area, systemic absorption can cause nausea, vomiting, and CNS effects. The major toxicity of imiquimod is inflammation at the application site. The major toxicity of cryotherapy is local pain. The major side effects of surgical treatment for genital warts are local pain, bleeding, and secondary infection. The major adverse events associated with acid cauterization are local pain and irritation or ulceration of adjacent normal skin. Intralesional interferon can be associated with systemic toxicities of interferon, including fever, fatigue, myalgia, malaise, depression, and other influenza-like symptoms. Infrared coagulation may lead to bleeding and abscess formation. Scarring can occur with any of the above treatment modalities. Topical cidofovir may result in systemic absorption and be associated with renal toxicity (914Bienvenu B, Martinez F, Devergie A, et al. Topical use of cidofovir induced acute renal failure. Transplantation 2002;73:661-2.). Secondary infections are not uncommon if ulcerations occur. Patients should be monitored regularly after each treatment.

Because risk for recurrence of CIN and cervical cancer after conventional therapy increases among HIV-seropositive persons, patients should be carefully followed after treatment with frequent cytologic screening and colposcopic examination according to published guidelines (AII) (920Wright TC, Koulos J, Schnoll F, et al. Cervical intraepithelial neoplasia in women infected with the human immunodeficiency virus: outcome after loop electrosurgical excision. Gynecol Oncol 1994;55:253-8., 921Fruchter RG, Maiman M, Sedlis A, et al. Multiple recurrences of cervical intraepithelial neoplasia in women with the human immunodeficiency virus. Obstet Gynecol 1996;87:338-44.). Treatment of CIN with ablative and excisional modalities can be associated with several adverse events such as pain and discomfort, intraoperative hemorrhage, postoperative hemorrhage, infection and cervical stenosis.

The major toxicity of topical agents for treatment of external genital warts is local pain or irritation of adjacent normal skin. HIV-infected patients with immunosuppression might have a lower response rate to all of these modalities. Secondary infections are not uncommon if ulcerations occur. Patients should be monitored regularly after each treatment.

Because of the frequent recurrence of squamous intraepithelial lesions after treatment, close surveillance with colposcopy and cytology are recommended.

An “immune reconstitution”-like syndrome related to HPVassociated oral warts among HIV-infected adults has been observed in which the occurrence of oral warts was associated with decreased HIV RNA levels with HAART (915King MD, Reznik DA, O' Daniels CM, et al. Human papillomavirusassociated oral warts among human immunodeficiency virusseropositive patients in the era of highly active antiretroviral therapy: an emerging infection. Clin Infect Dis 2002;34:641-8.). Immune reconstitution in response to viral load reduction might result in a return of marked inflammatory responses against latent oral HPV infection.

Treatment failure is defined as the persistence or recurrence of lesions after appropriate therapy. For persistent or recurrent genital warts, retreatment with any of the modalities previously described should be considered, preferably with an alternative modality to the one that previously failed (AIII). Genital warts often require more than one course of treatment. Recalcitrant warts should be managed by experienced clinicians and referred for excisional therapy. Recurrence of CIN may require additional treatments (i.e., LEEP and laser).

No recommendations exist for preventing recurrence of external genital warts. Patients should be monitored with cytologic screening according to published guidelines and, when indicated, colposcopic examination for recurrent lesions (AI) (922Goldie SJ, Kuntz KM, Weinstein MC, et al. The clinical effectiveness of screening for anal squamous intraepithelial lesionsi homosexual and bisexual HIV-positive men. JAMA 1999;281:1822-9., 923Kurman RJ, Henson DE, Herbst AL, et al. Interim guidelines for management of abnormal cervical cytology. The 1992 National Cancer Institute Workshop. JAMA 1994;271:1866-9.). In one study, use of low-dose intravaginal flurouracil reduced recurrence of CIN after LEEP, but lack of additional studies do not warrant routine use (924Maiman M, Watts DH, Andersen J, et al. Vaginal 5-fluorouracil for high-grade cervical dysplasia in human immunodeficiency virus infection: a randomized trial. Obstet Gynecol 1999;94:954-61.). Efudex should not be used in pregnant women.

Not applicable.