Jessica A. Kahn
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.
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.
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
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.
The behavioral and biological risk factors for HPV acquisition are as follows:
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).
Types of Anogenital Warts
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.
Pink, red, tan, brown, or gray.
Usually asymptomatic but may cause pruritus, burning, pain, urethral or vaginal discharge, urethral bleeding, or postcoital bleeding.
Pregnancy, skin moisture, and/or vaginal or urethral discharge.
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.
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 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.
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
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.
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
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.
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,
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.
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
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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.
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