Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, infecting approximately 6.2 million persons each year. Although most infections are self-limited and cause no clinical symptoms, persistent infection with oncogenic types of HPV can cause cervical cancer in women. HPV infection also causes genital warts and is associated with other anogenital cancers in men and women. Cervical cancer incidence rates have decreased by as much as 75 percent in the United States since the introduction of cervical cytology screening, which can detect precancerous lesions of the cervix. Despite the widespread use of such screening, however, approximately 11,000 new cases of cervical cancer will be diagnosed in the United States this year, and about 3,700 women will die from the disease (Figure 1).

In June 2006, the U.S. Food and Drug Administration approved the quadrivalent HPV vaccine (Gardasil) for use in females nine to 26 years of age. The vaccine is a mixture of type-specific virus-like particles prepared from the primary capsid proteins of two low-risk types of HPV (types 6 and 11, which are responsible for most cases of genital warts) and two high-risk types (16 and 18, which are responsible for most cases of cervical cancer). The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention recently issued guidelines recommending that females receive three doses of the vaccine, ideally at 11 or 12 years of age.

HPV Infection

Approximately 100 types of HPV have been identified; more than 40 of these types infect the genital area. Genital HPV types are categorized according to their epidemiologic association with cervical cancer. Infection with low-risk types can cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis. High-risk HPV types can cause low- and high-grade cervical cell abnormalities and anogenital cancers.

RISK FACTORS AND EPIDEMIOLOGY

The most consistent predictor of HPV infection is a person's number of sex partners (lifetime and recent). In one study, HPV infection was detected in 14.3 percent of women 18 to 25 years of age with one lifetime sex partner, in 22.3 percent with two lifetime partners, and in 31.5 percent with more than three lifetime partners. Acquisition of HPV occurs soon after initiation of sexual activity; the cumulative probability of infection is 38.9 percent 24 months after first sexual intercourse.

Transmission of HPV in the absence of penetrative intercourse (i.e., oral-genital, manual-genital, and genital-genital contact) has been reported but is much less common than with penetrative intercourse. Additional risk factors for women include immune status and the sexual behavior of their partners.

Because HPV is transmitted by sexual activity, understanding the epidemiology of HPV requires data on sexual behavior. The 2002 National Survey of Family Growth found that 24 percent of girls in the United States are sexually active by age 15. This percentage increases to 40 percent by age 16 and 70 percent by age 18. The mean number of lifetime male sex partners is 1.4 in sexually active females 15 to 19 years of age and 2.8 in women 20 to 24 years of age.

CLINICAL SEQUELAE

The primary clinical sequelae of HPV infection include cervical cancer and cervical cancer precursors, other anogenital cancers and their precursor lesions, and genital warts (Table 1).

Cervical Cancer and Precursor Lesions

Infection with high-risk types of HPV is necessary for the development of cervical cancer, but most women with high-risk HPV infection do not develop cancer. Although HPV infection usually is asymptomatic, cervical infection can result in histologic changes that are classified as adenocarcinoma in situ (AIS) or cervical intraepithelial neoplasia (CIN) grades 1, 2, or 3. Spontaneous clearance or progression to cancer in the absence of treatment varies: CIN 1 usually clears spontaneously (60 percent of patients) and rarely progresses to cancer (1 percent), but a higher percentage of CIN 2/3 progresses to cancer if not treated (more than 12 percent).

Cervical cancer screening with the Papanicolaou (Pap) test can detect cytologic abnormalities that reflect the underlying tissue changes. These abnormalities include atypical squamous cells of undetermined significance (ASC-US), atypical glandular cells, low-and high-grade squamous intraepithelial lesions, and AIS. HPV types 16 and 18 are more commonly associated with higher-grade lesions.

Vaginal and Vulvar Cancers and Precursor Lesions

HPV is associated with vaginal and vulvar cancers and vaginal and vulvar intraepithelial neoplasias. However, unlike cervical cancer, not all vaginal and vulvar cancers are associated with HPV. Most vaginal cancers and vaginal intraepithelial neoplasias III are positive for HPV, most commonly HPV 16.

HPV is associated with approximately one half of vulvar squamous cell cancers, the most common type of vulvar cancer. HPV-associated vulvar cancer tends to occur in younger women and may be preceded by vulvar intraep-ithelial neoplasia. HPV types 16 and 18 have been detected in up to 76 percent of vulvar intraepithelial neoplasias 2/3 and in 42 percent of vulvar carcinomas.

Anal Cancer

HPV is associated with approximately 90 percent of anal squamous cell cancers. Anal intraepithelial neoplasia is recognized as a precursor of anal cancer, although the natural history of these lesions (i.e., rate of progression and regression) is less clear than that for CIN. Women at high risk for anal cancer include those with high-grade cervical lesions and cervical and vulvar cancers. Men who have sex with men and persons with human immunodeficiency virus also are at risk.

Genital Warts

All genital warts are caused by HPV, and approximately 90 percent are associated with HPV types 6 and 11. The average time to development of new warts after infection with these HPV types is approximately two to three months. However, not all persons infected with HPV types 6 or 11 acquire genital warts. Genital warts can be treated, although many regress spontaneously. Recurrence of genital warts is common, whether clearance occurs spontaneously or after treatment.

TREATMENT AND PREVENTION

HPV infections are not treated; instead, treatment is directed at the HPV-associated lesions. Treatment options for genital warts and cervical, vaginal, and vulvar cancer precursors include local approaches that remove the lesion (e.g., cryotherapy, electrocautery, laser therapy, surgical excision). Genital warts also may be treated with topical pharmacologic agents. Treatment of HPV-related lesions may reduce infectiousness but probably does not eliminate it.

Although the use of condoms may reduce the risk of HPV transmission, abstaining from sexual activity is the only sure way to prevent infection. For persons who are sexually active, those in a monogamous relationship with an uninfected partner are least likely to become infected. Genital HPV infection is so prevalent that most partners of infected persons are infected already, and no prevention or treatment strategies are recommended.

Most cervical cancers and related deaths can be prevented by detection of precancerous changes using the Pap test. In addition to the screening recommendations presented in Table 2, the American Cancer Society and the American College of Obstetricians and Gynecologists (ACOG) recommend the routine use of the Digene Hybrid Capture 2 High-Risk HPV DNA test in addition to regular Pap testing in women 30 years and older. If both tests are negative, women should be rescreened no more frequently than every three years. In addition, ACOG and the American Society of Colposcopy and Cervical Pathology recommend that HPV DNA testing be used to triage women with equivocal ASC-US Pap test results.

Quadrivalent HPV Vaccine

The availability of the quadrivalent HPV vaccine offers an opportunity to decrease the burden of HPV infection and its sequelae, including cervical cancer and its precursors, other anogenital cancers, and genital warts. The vaccine is licensed for use in females nine to 26 years of age. In this age group, clinical trials indicate that the vaccine is safe and immunogenic. Trials assessing the effectiveness of the vaccine in men and in women older than 26 years are underway.

Quadrivalent HPV vaccine is administered intramuscularly in three separate doses. The second dose should be given two months after the first dose, and the third dose should be given six months after the first dose. If the vaccine schedule is interrupted, the series does not need to be restarted. If the series is interrupted after the first dose, the second dose should be administered as soon as possible, and the second and third doses should be given at least 12 weeks apart. If only the third dose is delayed, it should be administered as soon as possible.

AGE AT VACCINATION

Because HPV is sexually transmitted and is often acquired soon after the initiation of sexual activity, vaccination ideally should occur before this time. The recommended age for vaccination is 11 to 12 years; however, the vaccine can be administered to girls as young as nine years. Catch-up vaccination is recommended for females 13 to 26 years who have not been vaccinated.

The recommendation for routine vaccination of girls 11 to 12 years of age is based on several considerations, including studies suggesting that quadrivalent HPV vaccine is safe and effective in adolescents and that high antibody titers are achieved after vaccination at age 11 to 12; data on HPV epidemiology and age of initiation of sexual activity; and the high probability of HPV infection within several years of the onset of sexual activity. The vaccine has been proven to provide protection for at least five years without evidence of waning protection. Long-term follow-up studies are underway to determine the duration of protection beyond five years.

Although routine vaccination is recommended at 11 to 12 years of age, most females 13 to 26 years also can benefit from vaccination. Females who are not yet sexually active can be expected to receive the full benefit of vaccination. Although sexually active females may be infected with one or more vaccine HPV types, type-specific prevalence studies suggest that only a small percentage have been infected with all four of the HPV vaccine types.

The vaccine does not seem to protect against persistent infection, cervical cancer precursor lesions, or genital warts caused by an HPV type with which vaccine recipients are already infected at the time of vaccination. However, these women would be protected against disease caused by the other vaccine HPV types. Therefore, although overall vaccine effectiveness would be lower when administered to sexually active women, and effectiveness would decrease with older age and an increasing number of sex partners, most sexually active women will derive some benefit from vaccination.

CERVICAL CANCER SCREENING AFTER VACCINATION

Cervical cancer screening recommendations have not changed for women who receive HPV vaccine. HPV types in the vaccine are responsible for approximately 70 percent of cervical cancers, but women who are vaccinated could subsequently be infected with a carcinogenic HPV type for which the quadrivalent vaccine does not provide protection. Furthermore, women who were sexually active before vaccination could have been infected with a vaccine HPV type before vaccination. Physicians who administer quadrivalent HPV vaccine should educate vaccine recipients about the importance of continued cervical cancer screening.