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Human Papillomavirus Infections and Prevention
Abstract
Human papillomavirus (HPV) is the most common sexually transmitted infection (STI) worldwide and is the etiologic agent of cervical cancer, the majority of anogenital and oropharyngeal cancers, and genital warts. In the United States, vaccination to prevent HPV infection was first introduced in 2006 and is now routinely recommended for adolescent males and females aged 11 to 12 years to prevent morbidity and mortality from cervical and anogenital cancers and genital warts. Initial studies since vaccine implementation have demonstrated a reduction in prevalence of HPV vaccine types, genital warts, and cervical cancer precursors, despite moderate vaccine coverage rates.
Clinical Vignette
A 12-year-old healthy girl presents to her pediatrician’s office for a well child visit prior to 7th grade entry. Her physical exam is normal, and she has no complaints. The pediatrician discusses with her mother that she should receive her routine adolescent vaccinations at today’s visit. Her mother expresses concern about the human papillomavirus (HPV) vaccine, stating that she is worried that her daughter may exhibit more risk-taking sexual behaviors if she is vaccinated. She is also worried about the safety of the vaccine, due to reports she has heard on social media. The pediatrician responds that she understands the mother’s concerns but that she strongly recommends the vaccine. She informs the girl’s mother that studies have shown effectiveness at reducing infection with HPV types that cause cervical cancer and precursors to cervical cancer, but the vaccine must be given prior to sexual activity for it to be effective. The pediatrician reassures her that studies have not demonstrated increased risk-taking behaviors in vaccinated adolescents and that the vaccine is highly safe, with the most common reactions being fever and local reactions. The girl’s mother ultimately consents to the vaccine, and the girl tolerates it without any significant adverse events.
Etiology
HPV is a nonenveloped, double-stranded deoxyribonucleic acid (DNA) virus with an icosahedral nucleocapsid composed of structural proteins L1 and L2. The L1 protein comprises 85% of the nucleocapsid and is the basis for the current HPV vaccine. Viral proteins E6 and E7 are implicated in malignant cellular transformation through inactivation of proteins encoded by host tumor-suppressor genes p53 and retinoblastoma (RB), respectively.
There are more than 200 types of HPV, and different types demonstrate tropism for specific tissues. They can be classified as high risk, indicating association with cancer, or low risk, which are not associated with malignancy. HPV types 1 to 4 are low-risk types that cause skin warts. HPV types 6 and 11 are low-risk types that cause 90% of genital warts, as well as respiratory tract papillomas. Types classified as high risk cause premalignant lesions and may progress to cause cervical and other anogenital cancers, as well as head and neck cancers. High-risk types 16 and 18 cause the majority of cervical and other cancers. Other high-risk types include types 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59.
Geographic Distribution and Magnitude of Disease Burden
HPV infection occurs worldwide and is the most common STI. Globally, approximately 500,000 cases of cervical cancer are caused by HPV every year, representing approximately 7% of all cancers of women. Cervical cancer is the fourth most common cause of cancer mortality in women worldwide and is the second most common cause of cancer mortality in women in developing countries. In addition, HPV causes most oropharyngeal, vulvar, vaginal, penile, and anal cancers.
In the United States, approximately 79 million people are actively infected with HPV, with more than 14 million new infections occurring every year. HPV causes approximately 35,000 cancers annually in the United States, of which 21,000 occur in females and 14,000 occur in males. HPV causes approximately 11,000 cases of cervical cancer every year, with a mortality rate of 4000/year. Cervical cancer incidence has been decreasing steadily since the 1970s with the advent of screening. Invasive cervical cancer incidence and mortality rates are higher in Black and Hispanic women as compared with white women. Oropharyngeal cancers are currently the most common HPV-associated malignancy in the United States, with 13,000 cases attributable to HPV annually. HPV is additionally responsible for 6000 anal cancers among men and women per year.
Approximately 350,000 cases of genital warts and 1000 cases of recurrent respiratory papillomatosis (RRP) occur every year in the United States. Direct medical costs related to HPV disease, detection, and management are estimated to be $8 billion annually, second in cost only to human immunodeficiency virus (HIV) among STIs.
Since the introduction of HPV vaccine in 2006, there has been a significant reduction in the proportion of high-grade cervical lesions caused by HPV types 16 and 18, which are included in all three US Food and Drug Administration (FDA)-approved vaccines, as well as the overall incidence of high-grade cervical lesions in women aged 15 to 24 years. Due to the prolonged time between HPV infection and development of cancer, decreases in cancer incidence have not been documented at this time but are likely to be seen in the future.
Risk Factors for Infection
HPV causes cutaneous and mucosal infections. Primary HPV infection occurs in the basal layer of the epidermis. Minor trauma of the epidermis allows HPV to access the basal layer, where replication initially occurs. Infectious virions are then assembled and released from the squamous cells of the epidermis, which can then infect others. Naturally thin mucosal layers, such as occur in the cervix or anus, are particularly susceptible to infection ( Fig. 16.1 ). Infection may result from an infectious contact or autoinoculation. Minor trauma may not be clinically apparent and can result from normal sexual intercourse or other skin-to-skin contact activities.
The lifetime risk of cervical HPV infection in women is estimated to be as high as 80%. Sexual behavior influences risk of infection, with increased risk noted in individuals with young age at sexual initiation, increasing number of sex partners, and increasing number of partner’s sex partners. Sexual intercourse, genital-to-genital contact, and contact with HPV-contaminated fomites can all lead to anogenital HPV transmission. Oral sex is associated with oropharyngeal acquisition. In the United States, more than 50% of men and women acquire HPV infection within 5 years of initiation of sexual activity. Men who have sex with men are at increased risk for infection and for developing anogenital cancer. Other factors that have been associated with HPV infection include alcohol use, smoking, hormonal contraceptives, inconsistent condom use, uncircumcised male partner, bacterial vaginosis, and coinfection with other STIs, including HIV.
Clinical Presentation
Most HPV infections are asymptomatic, and many associated lesions are self-limited. However, persistent HPV infections, most notably anogenital and head and neck lesions, can lead to cancer. Risk factors for persistent infection include infection with high-risk HPV types, infection with multiple types, high viral load, host genetic susceptibility, immune compromise, higher parity, smoking, and infection with other STIs.
Warts
Cutaneous HPV infection causes common skin warts, plantar warts, and flat warts. Mucosal infection with low-risk types, most commonly types 6 and 11, causes genital warts (see Fig. 57.1 ). If mothers have genital warts or asymptomatic genital HPV infection, newborns may be exposed to the virus during the birth process. Infection of the neonatal respiratory tract can result in a condition known as juvenile-onset RRP, which is benign but associated with significant morbidity. Respiratory papillomas most commonly occur in the laryngeal area, and affected children generally present before age 5 with hoarseness, noisy breathing, and symptoms of airway obstruction.
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