Adolescent Health Care: A Practical Guide

Chapter 66

Human Papillomavirus Infection and Anogenital Warts

Jessica A. Kahn

Human Papillomavirus

Human papillomavirus (HPV) infection is the most prevalent sexually transmitted infection (STD) in the United States. Most HPV infections are asymptomatic. However, HPV infection may cause anogenital warts, oral warts, recurrent respiratory papillomatosis (RRP), abnormal Pap tests, cervical intraepithelial neoplasia (CIN), and cervical cancer. Other anogenital and oropharyngeal malignancies also are strongly associated with HPV infection. This chapter focuses on the epidemiology of HPV infection and the diagnosis, treatment, and prevention of anogenital warts. Cervical cancer screening and management of abnormal Pap tests are reviewed in Chapter 54.

Human Papillomavirus Genotypes and Clinical Sequelae

Human papillomaviruses are small, nonenveloped, double-stranded DNA viruses of the Papillomaviridae family. More than 130 HPV types have been sequenced and typed, and they are classified as cutaneous or as mucosal (de Villiers et al., 2004). Cutaneous types (e.g., types 1, 2, and 4) cause common skin warts and plantar warts. Mucosal types cause diseases of the anogenital and aerodigestive tracts. Approximately 40 mucosal types have been identified. HPV classification is based on genetic similarities in the viral capsid peptide L1—different types share <90% homology. Genital HPV types are classified as low risk (e.g., 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81) and high risk (e.g., 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82), depending on their clinical sequelae. Low-risk types (primarily types 6 and 11) cause anogenital warts and are also associated with mild vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), CIN, penile intraepithelial neoplasia (PIN), and anal intraepithelial neoplasia (AIN). Vertical transmission of low-risk types from mother to child during delivery rarely may cause RRP in young children. High-risk types (primarily types 16 and 18) may cause mild, moderate, or severe VIN, VAIN, CIN, PIN, and AIN as well as cervical cancer. Persistent infection with high-risk types is a key risk factor for development of CIN and cervical cancer.

The HPV genome is divided into two functional regions. One region encodes for early proteins (E1, E2, E4, E5, E6, and E7). These control viral replication, transcription, and cellular transformation. The E6 and E7 proteins in high-risk HPV types interact with the tumor suppressor gene products p53 and retinoblastoma protein, resulting in cell proliferation and contributing to carcinogenesis. Another region of the genome encodes for the nucleocapsid proteins L1 and L2. When HPV infection occurs, the low-risk types tend to remain extrachromosomal (episomal); in contrast, viral DNA sequences integrate into the host genomes in human cervical carcinomas.

Epidemiology

Prevalence

At least 75% of sexually active adult men and women in the United States have been exposed to genital HPV types at some point in their lives. Approximately 20% of adults are currently infected and approximately 5.5 million new infections occur each year. The prevalence of HPV infection peaks during adolescence and young adulthood, and declines with age. Studies have shown that over a 2- to 3-year period, approximately 30% to 40% of college-aged women will acquire HPV infection. In a nationally-representative sample of U.S. women, 20% of 14- to 17-year-olds, 38% of 18- to 21-year-olds, and 42% of 22- to 25-year-olds were HPV-positive. The majority of women with HPV had at least one high-risk type (Kahn et al., 2007). As methods for detection of HPV DNA in men improve, it has become clear that prevalence rates in men are similar to those in women. HPV DNA has been detected from the penile shaft, glans, foreskin, scrotum, and urine in men—sampling additional sites increases detection of HPV DNA.

Prevalence rates of symptomatic anogenital warts vary depending on the population studied. The prevalence rate among U.S. adults is estimated to be 1% to 5%, but prevalence rates up to 40% have been reported in patients presenting to STD clinics. HPV has also been found by polymerase chain reaction (PCR) techniques in 13% to 30% of women who have sex with women (WSW). The prevalence of RRP is approximately 4 cases per 100,000 in children; approximately 7 of 1,000 children born to mothers with genital warts will develop RRP.

Transmission

In adolescents, HPV transmission occurs primarily through sexual contact, including genital–genital, oral–genital, and digital–genital contact. Both heterosexual and homosexual transmission occurs. HPV infections as

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well as high- and low-grade squamous intraepithelial lesions have been detected on Pap tests in WSW who have reported no sexual encounters with men (Marrazzo JM et al., 2001). Adolescents acquire HPV infection rapidly after sexual initiation, often within a few months.

Infants, young children, and preadolescents may acquire HPV infection in several ways—transplacentally through amniotic fluid during gestation, through direct exposure to cervical and genital lesions during birth, through heteroinoculation or autoinoculation after birth, as a result of sexual abuse, and perhaps through fomites. Infection in infants and children presents most commonly as anogenital warts or RRP. Although sexual abuse is less likely than other modes of transmission in children with HPV-associated anogenital warts or RRP, especially in those younger than 4 years, sexual abuse should be carefully considered in all children with these conditions. The likelihood of sexual abuse as the cause for HPV infection increases with age.

Risk Factors

The behavioral and biological risk factors for HPV acquisition are as follows:

1. Multiple sexual partners: The number of male sexual partners is strongly linked to HPV infection in women, as is male partners' number of sexual partners.
2. Early age at sexual initiation: The association between early age of first sexual intercourse and HPV infection appears to be mediated primarily by sexual behaviors; that is, those who initiate sexual intercourse at an early age tend to practice sexual behaviors that put them at risk for HPV infection.
3. Nonuse of condoms: In the past, evidence was inconsistent as to whether condom use reduces the risk of HPV acquisition. However, studies have indicated that condom use reduces the risk of genital warts, moderate and severe cervical dysplasia, and invasive cervical cancer. Recent studies have provided more convincing evidence that consistent condom use substantially reduces incident genital HPV infection (Winer et al., 2006).
4. Cigarette smoking: Smoking is linked to HPV acquisition and appears to be a cofactor in cervical carcinogenesis.
5. Immunosuppression: Human immunodeficiency virus (HIV) infection and organ transplantation are important risk factors for HPV acquisition, persistence of infection, progression to cervical cancer and other anogenital cancers, and lack of response to treatment for anogenital warts.
6. Cervical ectopy: Cervical ectopy occurs during puberty when the columnar epithelium that lines the endocervix extends out onto the ectocervix. The process of squamous metaplasia then causes columnar epithelium to differentiate into squamous epithelium. Columnar and metaplastic cells may be particularly vulnerable to infection with STDs such as HPV because their thin epithelium may facilitate HPV infection. In addition, metaplasia is a process of rapid cell proliferation and differentiation, which provides a good environment for HPV replication and protein expression.
7. Oral contraceptive use: It is unclear what impact oral contraceptive pills have on HPV acquisition, as some studies show a protective effect in adolescents (Moscicki et al., 2001;Boardman et al., 2005). However, some studies suggest that oral contraceptive pills may be a cofactor in cervical carcinogenesis.
8. History of genital warts and other STDs, including genital herpes.

Pathophysiology and Natural History of Human Papillomavirus Infection

HPV initially infects the basal layer of epithelial cells through microabrasions in the skin or mucosa. Infection results in proliferation, division, and lateral expansion of infected cells. Subsequently, infected cells migrate to the suprabasal layers, where viral gene expression and thereby viral replication and particle formation occur. As viral particle formation continues in the upper layers of the epidermis or mucosa, viral particles are released to infect adjacent tissue.

Although HPV infection is extremely common in adolescents, infections are usually transient. More than 90% of adolescents with subclinical HPV infection become HPV negative within 9 to 12 months. A recent longitudinal study of sexually active adolescent girls demonstrated that the median time to clearance was 32 weeks for high-risk types and 24 weeks for low-risk types (Brown et al., 2005).

Clinical Manifestations

Types of Anogenital Warts

1. Condylomata acuminata: Cauliflower-shaped growths with a granular surface and finger-like projections. They usually have highly vascular cores that produce punctuated or loop-like patterns unless obscured by overlying keratinized surfaces.
2. Papular warts: Smooth, skin-colored, well-circumscribed papules that are usually 1 to 4 mm in diameter and lack finger-like projections.
3. Keratotic warts: These have a thick, horny (crust-like) layer; they resemble common warts or seborrheic keratoses.
4. Flat-topped papules: These are subclinical lesions that are difficult to detect without techniques such as treatment with a weak acetic acid solution.

Location

Typical sites for anogenital warts in women include the cervix, vagina, vulva, urethra, and anus. Typical sites in men include the inner surface of the prepuce, frenulum, corona, penile shaft, glans, scrotum, and anus. Condylomata can be multifocal (one or more lesions at one anatomical site) or multicentric (lesions at multiple separate anatomical sites).

Condylomata acuminata tend to occur on partially keratinized, non–hair-bearing (“moist”) skin; keratotic and papular warts tend to occur on fully keratinized (hair-bearing or non–hair-bearing) skin; and flat-topped warts may occur on either skin surface.

Color

Pink, red, tan, brown, or gray.

Symptoms

Usually asymptomatic but may cause pruritus, burning, pain, urethral or vaginal discharge, urethral bleeding, or postcoital bleeding.

Exacerbating Factors

Pregnancy, skin moisture, and/or vaginal or urethral discharge.

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Clinical Course

Lesions usually appear 2 to 3 months after infection, with a range of approximately 3 weeks to 8 months. However, viral latency may occur and therefore lesions may appear years after infection (Beutner and Ferenczy, 1997). The clinical course of anogenital warts is not well understood. Warts may regress spontaneously, persist, or increase in size or number. They often recur after therapy. However, over a period of months to years most anogenital warts resolve.

Differential Diagnosis

1. Micropapillomatosis labialis of labia minora: Lesions with separate bases that do not converge as do the papillae of condylomata acuminata
2. Pearly penile papules (in males): Parallel rows of small angiofibromas located at the penile corona, which are a normal finding
3. Seborrheic keratoses: Localized hyperpigmented lesions
4. Other benign genital lesions: Skin tags, fibromas, lipomas, hidradenomas, and adenomas
5. Condylomata latum: Owing to secondary syphilis, and diagnosed with dark-field examination and serological testing
6. Molluscum contagiosum: Dome-shaped lesions with central umbilication that are caused by a poxvirus
7. Granuloma inguinale (verrucous type): A rare STD caused by Calymmatobacterium granulomatis; Donovan bodies are found in crushed tissue smears
8. High-grade intraepithelial lesions and cancer: Bowen disease, Bowenoid papulosis, dysplastic nevi, VIN, VAIN, PIN, AIN, and squamous cell carcinoma

Diagnosis

Subclinical Human Papillomavirus Infection

The Hybrid Capture II assay is a hybridization and signal amplification technique that detects 13 different high-risk HPV types. PCR-based detection methods are not yet commercially available in the United States. Currently, HPV DNA testing is recommended routinely only in the context of cervical cancer screening in women, as discussed in Chapter 54.

Genital Warts

Genital warts can usually be diagnosed using direct visual inspection with a bright light and, if necessary, magnification. A speculum examination is helpful in women with external genital warts to evaluate for vaginal and cervical warts. An otoscope and small spreader is helpful to inspect the male urinary meatus. Anoscopy should be considered for men and women with recurrent perianal warts and/or a history of anoreceptive intercourse, and urethroscopy should be considered for men with warts at the terminal urethra, and terminal hematuria or an altered urinary stream. Acetowhite testing, HPV DNA testing, and biopsy are not recommended routinely for diagnosis. However, patients with anogenital warts who are not responsive to therapy or have features suggestive of neoplasia (e.g., blue or black discoloration, induration, bleeding, ulceration, increased pigmentation, rapid growth, or fixation to underlying structures) should be referred to a specialist for further evaluation and possible biopsy.

Treatment

General Considerations

The goal of therapy is to eradicate or reduce the size of clinically apparent anogenital warts. However, because anogenital warts may resolve spontaneously and because it is not clear whether treatment of anogenital warts alters the natural history of the infection or decreases future viral transmission, it is reasonable not to begin treatment unless the warts persist or enlarge. Treatment should be guided by the patient's preferences, extent and type of lesion, the provider's experience, and available resources.

General treatment considerations include eliminating or minimizing any predisposing factors and treating coexisting vaginitis and/or cervicitis. Specific treatments for external genital warts can be classified as patient-applied or clinician-applied treatments. Patient-applied therapies require that the patient can adequately visualize the lesions to be treated and can adhere to the specified treatment schedule. There is no definitive evidence that any one treatment is more effective than another. The various treatment strategies, initial treatment success rates, and reported recurrence rates are summarized in Table 66.1, and the instructions for use, and advantages and disadvantages of these strategies are presented in Table 66.2. Clinical trials of treatment strategies vary widely in terms of patient selection, type of wart treated, duration of therapy, length of follow-up, use of concomitant therapies, outcomes assessed, and overall quality. The data in the table should therefore be viewed only as a general guide to treatment efficacy.

Clinicians should be familiar with at least one clinician-applied and one patient-applied therapy. If one treatment strategy fails (e.g., if warts have not improved substantially after three provider-administered treatments or have not completely cleared after six treatments) another may be tried. However, if anogenital warts persist then patients should be referred to a specialist. The use of more than one treatment modality at the same time has not been shown to be effective and may increase the risk of side effects.

Specific Treatment Recommendations and Considerations

1. Patient-applied treatments for external genital warts (Table 66.2): If possible, the provider should apply the first treatment to demonstrate both the application technique and the warts to be treated.
2. Imiquimod 5% cream
3. Podophyllotoxin/podofilox 0.5% solution or gel
4. Clinician-applied treatments for external genital warts (Table 66.2):
5. Podophyllin resin 10% to 25%
6. Bichloracetic acid (BCA) or trichloroacetic acid (TCA) 80% to 90%
7. Cryotherapy with liquid nitrogen or cryoprobe
8. Surgical therapies
9. Treatment of cervical, vaginal, urethral, anal, and oral warts:
10. Cervical warts: Patients should be referred to a specialist for management of cervical warts, because evaluation for high-grade squamous intraepithelial lesions must be performed before treatment is initiated.

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1. Vaginal warts: Cryotherapy with liquid nitrogen (but not a cryoprobe) or TCA/BCA 80% to 90%.
2. Urethral meatus warts: Cryotherapy with liquid nitrogen or podophyllin 10% to 25%. Treated warts must be dry before contact with normal mucosa.
3. Anal warts: Cryotherapy with liquid nitrogen, TCA/BCA 80% to 90%, or surgical removal. Patients with rectal mucosal warts should be referred to a specialist.
4. Oral warts: Cryotherapy with liquid nitrogen or surgical removal.
5. Treatment considerations during pregnancy: Several factors associated with pregnancy, such as hormonal factors and relative immunosuppression, may promote growth of anogenital warts. The only treatments recommended during pregnancy are BCA/TCA, cryotherapy, electrocautery, and surgical excision.
6. Treatment considerations in the setting of immunodeficiency: Adolescents who are immunosuppressed due to HIV infection, organ transplantation, or other conditions may not respond as well as immunocompetent adolescents and may have more frequent recurrences. In addition, squamous cell carcinomas originating in or resembling genital warts occur more frequently among immunocompromised patients. Therefore, evaluation by a specialist should be considered.

TABLE 66.1 Summary of Data about Clearance and Recurrence Rates Associated with Different Treatment Options for External Genital Warts

Treatment Clearance Rate (%) Recurrence Rate (%) Data were obtained from randomized controlled trials and well-designed uncontrolled studies. Abstracted from Wiley DJ, Douglas J, Beutner K, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis 2002;35(Suppl 2):S210. Patient applied Imiquimod 27–54 13–19 Podofilox 45–88 4–38 Clinician applied Podophyllin resin 23–72 23–65 Trichloroacetic or bichloracetic acid 63–70 Cryotherapy 27–88 21 Curettage/surgical excision 35–72 19–29 Electrocautery 61–94 22 Laser therapy 23–52 60–77

Partner Evaluation

It is not clear whether treatment of sexual partners alters the natural history of HPV-related disease. Therefore, although evaluation of sexual partners is not necessary, partner evaluation provides an opportunity for the clinician to screen partners for anogenital warts and other STDs and to educate partners about HPV and genital warts.

Counseling

Providers should educate patients with anogenital warts about HPV infection, its transmission, and its clinical consequences. Key messages are as follows: Genital warts are caused by specific HPV types that are different from the types that cause cervical cancer, genital warts may recur after treatment, it is unclear whether treatment reduces transmission of HPV to partners, condom use may reduce transmission of HPV and acquisition of genital warts, and adolescents with genital warts do not need HPV testing or more frequent Pap testing. They should provide information about available treatment options for genital warts and their prognosis. Web sites that may be helpful are listed in the subsequent text. Providers should also discuss strategies to prevent HPV-related disease and other STDs; for example, abstinence, limiting number of sexual partners, avoiding tobacco, and using condoms consistently. Pap testing should be performed according to published guidelines, but it is not necessary to perform Pap testing more frequently in those with genital warts. Screening for other STDs is indicated in all sexually active adolescents.

Providers should make sure that patients being treated for external genital warts can see their warts, especially those who are using patient-applied therapies. Patients should be advised to examine the areas being treated for signs of inflammation or infection (such as redness, swelling, or discharge) regularly. They should report any signs or symptoms of infection immediately to their provider. General perineal care may promote healing, including sitz baths and keeping the area clean and dry (e.g., with the use of a hair dryer at the lowest setting). During treatment and after visible warts have resolved, follow-up visits are helpful to monitor for complications of therapy, educate adolescents about signs of recurrence, and reiterate prevention messages.

The diagnosis of HPV infection or genital warts may cause anxiety, distress, and fear of social stigmatization in adolescents. Clinicians should provide support and when necessary may refer patients to support groups or for counseling.

Human Papillomavirus Vaccines

Remarkable progress has been made recently in the development of HPV vaccines. HPV vaccines fall into two categories—prophylactic vaccines, which are designed

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to prevent primary HPV infection by inducing virus-neutralizing antibody, and therapeutic vaccines, which are designed to treat HPV-related diseases. In June, 2006, a prophylactic HPV-6, 11, 16, 18 vaccine (Gardasil, Merck & Co., Inc.) was approved by the U.S. Food and Drug Administration (FDA) for use in girls and women 9 to 26 years of age. The Advisory Committee on Immunization Practices (ACIP) recommended that the vaccine be given routinely to 11- and 12-year-old girls, with catch-up immunization of 13- to 26-year-old girls and women and immunization of 9- and 10-year-old girls at the discretion of the health care provider. An HPV-16 and -18 vaccine (Cervarix), manufactured by GlaxoSmithKline Biologicals, was submitted for regulatory review in Europe and to the FDA in the United States for approval.

TABLE 66.2 Recommended Treatment Options for External Genital Warts

Treatment Option Instructions for Use Advantages Disadvantages Patient applied Imiquimod 5% cream The cream is provided in individual packets. Apply at bedtime, leave on overnight (6–10 hr), then wash off with soap and water. Use three times per wk for a maximum of 16 wk, until all lesions have disappeared. Wash off before sexual intercourse. May be applied at home Can be applied to new warts as they appear Local erythema, erosion, itching, and burning May weaken condoms/diaphragms Takes up to 16 wk to treat warts Podophyllotoxin/podofilox 0.5% solution or gel Using a cotton swab for the solution or a finger for the gel, apply to genital warts twice daily for 3 d, followed by 4 d of no therapy. The cycle can be repeated up to 4 times if needed. Total wart area treated should not exceed 10 cm2and total volume of podofilox should not exceed 0.5 mL/d. Widely available Easy to apply May be applied at home Local erosion, burning, pain, and itching Not useful for cervical or mucosal lesions or extensive disease Clinician applied Podophyllin resin 10%–25% Provider paints the lesions with podophyllin using front or back of a cotton swab, ensures that solution has air-dried before allowing patient to resume a normal position. Treatment repeated weekly if necessary. Patient should wash off podophyllin in 1–4 hr. To avoid toxicity due to systemic absorption, <0.5 mL of podophyllin should be used or an area <10 cm2 treated per session. Widely available Easy to apply Contains mutagenic compounds; therefore, contraindicated during pregnancy, and adolescents receiving it should use effective contraception Possible toxic systemic absorption, associated with bone marrow suppression, hepatocellular dysfunction, neurologic effects, psychosis, nausea, vomiting, diarrhea, and abdominal pain Trichloroacetic acid (TCA) or bichloracetic acid (BCA) 80%–90% Provider first applies occlusive ointment to the healthy tissue surrounding lesion, or treats the area with a topical anesthetic (e.g., benzocaine topical solution). The back or front end of a cotton swab is used to apply the solution sparingly until the lesions blanch (frost). The solution should air-dry before the patient resumes a normal position. If necessary, sodium bicarbonate or talc may be applied to remove unreacted acid. Avoid contact with normal skin. Repeat weekly for up to 6 wk until warts have resolved. Widely available Inexpensive Easy to apply Safe in pregnancy Pain on application Destroys normal tissue if over-applied Cryotherapy with liquid nitrogen or cryoprobe Liquid nitrogen can be used to treat vaginal warts, but use of a cryoprobe is not recommended because of the risk of vaginal perforation or fistula formation. A cotton applicator designed for cryotherapy is placed in liquid nitrogen briefly and then quickly applied with gentle pressure for 2–3 sec to the wart to be treated as well as 2–3 mm of surrounding skin. The surface of the wart should briefly turn white and then return to its normal color. The process can be repeated every 1–2 wk. Well tolerated Useful for most wart types Safe in pregnancy No anesthesia needed Minimal risk of scarring Pain, necrosis, blistering Over-application may lead to complications while under-application may lead to poor results Surgical procedures These procedures may include excision with a scalpel, curettage, or scissors; electrosurgery; and laser therapy. Useful for extensive disease or lesions resistant to other modes of therapy Safe in pregnancy Rapid achievement of results Requires hospital setting, provider expertise, appropriate equipment, and anesthetic Expensive With surgical excision, scarring and bleeding possible Laser is not readily available and intact DNA may be liberated into air with laser vapor

These two prophylactic HPV vaccines consist of virus-like particles (VLPs), which are recombinant viral capsids that are identical to HPV virions morphologically, but do not contain viral DNA. Therefore, they cannot replicate and therefore pose no infectious or oncogenic risk. Given that more than 90% of genital warts are caused by HPV-6 and HPV-11 and that approximately 70% of cervical cancer is caused by HPV-16 and HPV-18, these vaccines could have a significant public health impact. Clinical trials have shown that they are highly immunogenic, induce HPV genotype-specific serum antibody responses, are safe, and are well tolerated. Phase III trials suggest that the quadrivalent HPV vaccine is highly effective in preventing infection and disease caused by the HPV types contained in the vaccines. In an international trial involving over 12,000 women 16 to 26 years of age, vaccine efficacy was 98% (96% confidence interval [CI] 86%–100%) against the combined incidence of HPV 16- or 18-related moderate/severe CIN, adenocarcinoma-in-situ, or invasive cervical cancer in the per-protocol group and 44% (95% CI 26%–58%) in the intention-to-treat group.(FUTURE II Study Group, 2007) Vaccine efficacy in the per-protocol group was 100% (95% CI 94%–100%) for prevention of external anogenital diseases (anogenital warts, VIN, VAIN, or cancer). (Garland et al., 2007). Antibody levels appear to remain high at least 4 years after initial vaccination. Both vaccines are given as three intramuscular injections, Gardasil at 0, 2, and 6 months and Cervarix at 0, 1, and 6 months.

Studies have shown that providers, parents, and adolescents generally find HPV vaccination to be acceptable. When recommending HPV vaccines, providers should address any specific parental or adolescent concerns. Vaccination provides an opportunity for clinicians to reinforce prevention messages that may maximize the effectiveness of HPV vaccines. For example, adolescents must understand that HPV vaccines do not protect against all HPV types or other STDs. They should still postpone sexual initiation, limit number of sexual partners, and use condoms consistently to prevent HPV and other STDs. In addition,

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physicians should reinforce the importance of continued Pap screening after vaccination. Routine screening is recommended because 30% of cervical cancer is caused by types not contained in the vaccines. In addition, vaccine efficacy may be compromised if women have been infected previously with HPV types contained in the vaccines, if they do not receive all three immunizations, or if immunity wanes over time.

Web Sites

For Teenagers and Parents

http://www.cdc.gov/std/hpv. CDC Web site that includes fact sheets about HPV for both providers and patients.

http://www.ashastd.org. American Social Health Association site on STDs including excellent information about HPV.

http://www.iwannaknow.org. American Social Health Association site designed specifically for adolescents, which includes information about HPV and other STDs.

http://www.niaid.nih.gov/factsheets/stdhpv.htm. National Institute of Allergy and Infectious Diseases fact sheet on HPV.

www.youngwomenshealth.org. Harvard Medical School site designed for adolescents and young adults, including information on HPV and other STDs.

For Health Professionals

http://www.emedicine.com/derm/topic454.htm. E-medicine chapter on genital warts.

http://www.obgyn.net/femalepatient/default.asp?page=warts_tfp. From “The Female Patient” on management of warts.

http://www.cdc.gov/std/hpv. CDC Web site with excellent fact sheets about HPV for both providers and patients.

http://www.cdc.gov/STD/treatemtent/. CDC Web site including 2006 STD treatment guidelines.

References and Additional Readings

Beutner KR, Ferenczy A. Therapeutic approach to genital warts. Am J Med 1997;102:S28.

Beutner KR, Reitano MV, Richwald GA, et al., AMA Expert Panel on External Genital Warts. External genital warts: report of the American Medical Association consensus conference. Clin Infect Dis 1998;27:796.

Boardman LA, Stanko C, Weitzen S, et al. Atypical squamous cells of undetermined significance: human papillomavirus testing in adolescents. Obstet Gynecol 2005;105:741.

Brown DR, Shew ML, Qadadri B. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis 2005;191:182.

Castellsague X, Bosch FX, Munoz N. Environmental co-factors in HPV carcinogenesis. Virus Res 2002;89:191.

Cates W. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. Sex Transm Dis 1999;26(Suppl 4):S2–S7.

Centers for Disease Control and Prevention. Guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 2006;55(RR-11):62.

Dempsey AF, Zimet GD, Davis RL, et al. Factors that are associated with parental acceptance of human papillomavirus vaccines: a randomized intervention study of written information about HPV. Pediatrics 2006;117:1486.

Garland SM, Hernandez-Avila M, Wheeler CM et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital disease. N Engl J Med 2007;356:1928.

Hagensee ME, Cameron JE, Leigh JE, et al. Human papillomavirus infection and disease in HIV-infected individuals. Am J Med Sci 2004;328:57.

Harper DM, Franco EL, Wheeler C. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004;364:1757.

Ho GYF, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423.

Kahn JA, Bernstein DI. Human papillomavirus vaccines and adolescents. Curr Opin Obstet Gynecol 2005;17:476.

Kahn JA, Rosenthal SL, Succop PA, et al. Mediators of the association between age of first sexual intercourse and human papillomavirus infection. Pediatrics 2002;109:E5.

Kahn JA, Slap GB, Bernstein DI, et al. Psychological, behavioral, and interpersonal impact of human papillomavirus and Pap test results. J Womens Health 2005;14:650.

Kahn JA, Zimet GD, Bernstein DI, et al. Pediatricians' intention to administer human papillomavirus vaccine: the role of practice characteristics, knowledge, and attitudes. J Adolesc Health 2005;37:502–510.

Kahn JA, Lan D, Kahn RS. Sociodemographic factors associated with high-risk HPV infection. Obstetrics and Gynecology 2007;110:in press.

Koustky LA, Galloway DA, Holmes KK. Epidemiology of genital HPV infection. Epidemiol Rev 1988;10:122.

Manhart LE, Koutsky LA. Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis. Sex Transm Dis 2002;29:725.

Marrazzo JM, Koutsky LA, Kiviat NB. Papanicolaou test screening and prevalence of genital human papillomavirus among women who have sex with women. Am J Public Health2001;91:947.

Moscicki AB. Cervical cytology testing in teens. Curr Opin Obstet Gynecol 2005;17:471.

Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA2001;285:2995.

Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by DNA testing in adolescent and young adult women. J Pediatr1998;132: 277.

Sinclair KA, Woods CR, Woods CR, et al. Anogenital and respiratory tract human papillomavirus infections among children: age, gender, and potential transmission through sexual abuse. Pediatrics 2005;116:815.

The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915.

Villa LL, Costa RL, Petta CA. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271.

de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology 2004;324:17.

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Wang SS, Hildesheim A. Chapter 5: viral and host factors in human papillomavirus persistence and progression. J Natl Cancer Inst Monogr 2003;31:35.

Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites and sampling techniques for detection of human papillomavirus DNA in men. J Infect Dis 2004;189:677.

Wiley DJ, Douglas J, Beutner K, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis 2002;35(Suppl 2):S210.

Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. New Engl J Med 2006;354:2645.