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Am Fam Physician. 2021;104(2):152-159

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With more than 200 types identified, human papillomavirus (HPV) commonly causes infections of the skin and mucosa. HPV infection is the most common sexually transmitted infection in the United States. Although most HPV infections are transient and subclinical, some lead to clinical manifestations ranging from benign papillomas or warts to intraepithelial lesions. In some patients, persistent infection with high-risk mucosal types, especially HPV-16 and HPV-18, causes anal, cervical, oropharyngeal, penile, vaginal, and vulvar cancers. Most HPV-related cancers are believed to be caused by sexual spread of the virus. A history of multiple sex partners; initiation of sexual activity at an early age; not using barrier protection; other sexually transmitted infections, including HIV; an immunocompromised state; alcohol use; and smoking have been identified as risk factors for persistent HPV infections. Screening for HPV infection is effective in identifying precancerous lesions and allows for interventions that can prevent the development of cancer. Use of condoms and dental dams may decrease spread of the virus. Vaccination is the primary method of prevention. The nonavalent HPV vaccine is effective in preventing the development of high-grade precancerous cervical lesions in noninfected patients. Vaccination is ideally administered at 11 or 12 years of age, irrespective of the patient's sex. In general, a two-dose series is recommended if administered before 15 years of age; however, individuals who are immunocompromised require three doses.

There are more than 200 types of human papillomavirus (HPV), a DNA virus that infects cutaneous and mucosal epithelial cells. HPV is spread by direct skin-to-skin contact and has tropisms for cutaneous or mucosal epithelial cells.1 A small subset of HPV types can cause cutaneous warts.2 The approximately 40 types that infect mucosal surfaces are typically spread through sexual contact, including vaginal, anal, or oral sex, and can be divided into low-risk and high-risk types based on their associated cancer risk. Low-risk types cause warts, whereas the 15 high-risk types cause cervical intraepithelial neoplasia (CIN) and squamous cell carcinomas of the anogenital tract and oropharyngeal mucosa.3,4 Vertical or horizontal spread of HPV can occur during the perinatal period and is associated with oral infections and respiratory papillomatosis.5,6 Concomitant cervical and anal infections have been demonstrated in women without a history of anal intercourse and may be a result of autoinoculation.7


Human Papillomavirus

Vaccination has been demonstrated to reduce the prevalence of vaccine-type HPV in females, anogenital warts, and precancerous cervical lesions.

According to a 2018 Cochrane review, vaccinating women, with or without HPV exposure, between 15 and 26 years of age decreases the risk of cervical intraepithelial neoplasia 2 and 3, with a number needed to treat of 39.

On June 12, 2020, the U.S. Food and Drug Administration approved adding the prevention of head and neck cancers caused by HPV as an indication for the nonavalent HPV vaccine (Gardasil 9).

HPV = human papillomavirus.

Clinical recommendation Evidence rating Comments
Limiting the number of lifetime sex partners, delaying first intercourse until a later age, and consistently using condoms reduce the risk of HPV infection.13,14 C Mixed-quality randomized controlled trials of disease-oriented outcomes
Smoking and alcohol cessation should be recommended to reduce the risk of HPV persistence and the development of HPV-related malignancies.15,16 C Two case-control studies
Vaccination should be recommended to prevent the development of high-grade precancerous cervical lesions in women.57,63,64 C Consistent findings from a Cochrane review of randomized controlled trials of disease-oriented outcomes; evidence-based practice guideline
HPV vaccination is ideally administered at 11 or 12 years of age and may be administered as early as nine years of age, irrespective of the patient's sex.In immunocompetent individuals immunized before 15 years of age, a two-dose series is indicated. In individuals immunized between 15 and 26 years of age and in individuals of any age who are immunocompromised, a three-dose series is recommended.57,62 C Evidence-based practice guidelines
HPV vaccination is not routinely recommended in individuals 27 years or older. Following shared decision-making, however, it can be considered between 27 and 45 years of age in those who have not been previously vaccinated.57 C Evidence-based practice guideline
In patients 21 to 29 years of age, cervical cancer screening should be performed every three years using cervical cytology alone. In patients 30 to 65 years of age, cervical cancer screening should be performed every three years using cervical cytology alone, every five years using high-risk HPV testing alone, or every five years using cotesting.3941 C Consistent findings from randomized controlled trials; evidence-based practice guidelines
RecommendationSponsoring organization
Do not perform cervical cytology (Pap test) or HPV screening in immunocompetent women younger than 21 years.American Society for Colposcopy and Cervical Pathology
Do not perform annual cervical cytology (Pap test) or annual HPV screening in immunocompetent women with a history of negative screening.American Society for Colposcopy and Cervical Pathology
Do not perform low-risk HPV testing.American Society for Clinical Pathology

Epidemiology and Prevalence

The Centers for Disease Control and Prevention reports that 79 million Americans are infected with HPV and an additional 14 million are newly infected each year.3 Data from early HPV vaccine trials suggest that the lifetime prevalence of the infection is 85% in women and 91% in men who have had at least one sex partner.8

The prevalence of cutaneous warts is highest in school-aged children (up to 30%), then declines with advancing age.2 HPV infection is the most common sexually transmitted infection in the United States. Genital warts occur in 1% of sexually active adults.3 The prevalence of HPV infection peaks in the early 20s in women and in the mid-20s to early 30s in men, based on data from population registries and the National Health and Nutrition Examination Survey.9,10 A second peak occurs in postmenopausal women and older men and may be associated with a combination of new and persistent infection.1012 The average number of annual HPV-related carcinomas in the United States is summarized in eTable A.


Risk Factors


Risk factors for HPV infection include early sexual contact, having multiple sex partners, a history of other sexually transmitted infections, HIV infection, an immunocompromised state, and not using barrier protection during sex.3,13,14


Persistent oral and genital HPV infections are associated with alcohol use and smoking.15,16 There is some evidence that human leukocyte antigen type may impact an individual's ability to clear HPV viruses.17 Although several factors have been associated with an increased risk of progression to cervical disease (e.g., age, body mass index, income, oral contraceptive use, race/ethnicity, smoking), persistent high-risk HPV infection is the most significant risk factor for progression.18,19

Pathogenesis and Subtypes

Infection with a low-risk HPV type does not preclude infection with a concomitant high-risk type. One study demonstrated that 31% of genital warts contain both low- and high-risk types of HPV.20

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