Human papillomavirus (HPV) is one of the most common sexually transmitted infections (STIs). More than 170 types of HPV have been classified and more than 40 types of HPV can infect the genital tract of humans.[1,2,3] Genital HPV types are divided into two groups based on whether they have an association with cancer. Infections with low-risk types (non-oncogenic) are not associated with cancer but can cause genital warts and benign or low-grade cervical cellular changes. Infections with high-risk types (oncogenic), most notably HPV types 16 and 18, can cause low-grade cervical cellular changes, high-grade cervical cellular changes (moderate to severe Pap test abnormalities), and cancer of the cervix; in addition, some high-risk HPV types have been associated with cancers of the vulva, vagina, anus, penis, and oropharynx. Most HPV infections, whether caused by low-risk or high-risk types, are transient, asymptomatic, and have no clinical consequences. Estimates on the incidence and prevalence of HPV infection are limited because HPV infection is not a reportable infection in any state (genital warts are reportable in a select number of states). In addition, most HPV infections are asymptomatic or subclinical, and therefore not diagnosed. Available HPV-related data primarily focuses on the clinical sequelae of HPV infection, such as genital warts and genitourinary cancers.
Incidence and Prevalence
It is estimated that most sexually active men and women will acquire genital HPV infection at some point in their lives, but approximately 90% of these infections are clinically silent and most infections resolve spontaneously. Because HPV is not a reportable disease in the United States, precise yearly statistics on the incidence (new HPV infections) are not available. However, the Centers for Disease Control and Prevention (CDC) estimates there are approximately 14.1 million new HPV infections in the United States each year. More information is known regarding HPV prevalence (persons living with HPV infection), particularly based on data from the National Health and Nutrition Examination Survey (NHANES). In the United States, an estimated 79 million women aged 14 to 59 years are infected with HPV, with the highest prevalence among those aged 20 to 24 years.[5,7] In addition, a substantial number of genitourinary cancers and anogenital warts are attributable to HPV infection. For example, in 2009, an estimated 35,000 new HPV-associated cancers and 355,000 new cases of anogenital warts were associated with HPV infection.[8,9] In the past decade, genital warts has consistently accounted for 300,000 or more visits to an out-patient health care facility (Figure 1). In a separate analysis, the CDC estimated an average of 30,700 annual cancers attributable to HPV during the years 2008-2012, with approximately 60% of these cancers involving females. Notably, in this CDC analysis, the rates of cervical carcinoma were higher among blacks than among whites, and among Hispanics than non-Hispanics. In addition, higher rates of HPV-associated cancer were seen among persons living in the southern region of the Unites States compared with those living in other regions.
Impact of HPV Vaccine on HPV Prevalence
The prevalence of infection with high-risk types has drastically decreased with the availability of effective HPV vaccines. A recent study analyzed 14 to 34 year-old females in the NHANES study group and compared rates of vaccine-targeted strains between the pre-vaccine era (2003-2006) and 4 years of the vaccine era (2009-2012). This study demonstrated a 64% decrease in vaccine-targeted HPV prevalence among females aged 14 to 19 years and a 34% decrease among those aged 20 to 24 years; there was not a significant decrease in women aged 25 to 29 but only 14.7% had received the HPV vaccine (Figure 2). These findings are somewhat dynamic as the number of types in the HPV vaccine used in the United States has expanded from 4 to 9. Even without the expanded types in the HPV vaccine, the overwhelming trend is towards a decrease in the prevalence of infections by high-risk types of HPV in vaccinated populations.
Impact of HPV Vaccine on HPV-Related Disease
The availability of effective HPV vaccines has led to a decline in some but not all sequelae of HPV infections among women in the United States.[10,14] In a meta-analysis of 20 eligible studies, investigators showed that in countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased by 68% between the pre-vaccination and post-vaccination periods and anogenital warts decreased by 61% in girls 13-19 years of age. In the United States, the prevalence trends for anogenital warts varies by age and sex (Figure 3).  Among females aged 15–19, HPV prevalance was stable during 2003–2007, but then significantly declined during 2007–2010. Among females aged 20–24 years, anogenital wart prevalence significantly increased during 2003–2007, was stable during 2007–2010, then began to decrease during 2009–2010. Prevalence in females 25-39 years of age (persons unlikely to have been vaccinated) significantly increased throughout the time period. For males aged 15-39 years, the anogenital wart prevalence for each 5-year age group increased from 2003-2009, but no increases were observed for 2010. Rates of precancerous lesions declined following the introduction of HPV vaccination; an analysis of the New Mexico HPV Pap Registry from 2007-2014 showed significant declines in all stages of cervical intraepithelial neoplasia (CIN) for women aged 15-19 years. Data from the CDC HPV-IMPACT Project, a sentinel surveillance project, also demonstrated dramatic declines in cervical precancer incidence from 2008-2012 for women aged 18-20 years, with some sites also demonstrating significant declines among women aged 21-29 years. Of note, screening recommendations changed during this time period so declines in disease may reflect both reduced screening and impact of vaccination. During the same time there was a significant decline in prevalence of HPV 16- and 18-related precancer among adult women who received at least 1 dose of HPV vaccine.
Key risk factors associated with acquisition of genital HPV infection include higher number of sexual partners and lower education level. Investigators have evaluated potential risk factors associated with cervical cancer, including oral contraceptives, multiple pregnancies, tobacco smoking, nutrition (vitamins C and E, carotenoids, xanthophylls), immunosuppression, prior herpes simplex virus 2 infection, or Chlamydia trachomatis infection. These factors may possibly play a secondary role in progression to cervical cancer, but none consistently demonstrate the same strength of association as seen with high-risk HPV infection.
In the United States, direct annual medical costs associated with genital HPV infection, including treatment of genital warts, precancers and cancers, and screening for cervical cancer, are estimated to be $1.7 billion.