Human papillomavirus infection

The human papillomavirus (HPV) is a nonenveloped DNA virus that infects the cutaneous and mucosal epithelium. There are more than 200 known types of HPV. Transmission usually occurs through direct contact (e.g., sexual or nonsexual contact between skin and/or mucosal surfaces). Vertical transmission is uncommon. Most HPV infections are asymptomatic. Clinical manifestations depend on the HPV type and include cutaneous warts, anogenital warts, and laryngeal papillomas. Infection with high-risk mucosal types can cause HPV-related cancers, e.g., cervical cancer, anal cancer, and oropharyngeal cancers. Diagnosis of HPV infection is based on disease manifestation and ranges from clinical diagnoses (e.g., cutaneous warts) to HPV testing (e.g., in patients with abnormalities detected on cervical cancer screening). Most HPV infections in immunocompetent individuals resolve spontaneously within 2 years. Management is based on clinical manifestations, and options include observation, topical pharmacotherapy, cryotherapy, laser therapy, and surgical excision. The HPV vaccine is the most effective preventive measure against anogenital warts and HPV-related cancers and is indicated for all individuals between 11 and 12 years of age, ideally before the first sexual intercourse. In individuals with cutaneous warts, minimizing skin-to-skin transmission can help prevent autoinoculation and transmission of infection to others. Recurrence of HPV infections is common.

Specific HPV-related diseases (e.g., cutaneous warts, anogenital warts, cervical cancer) are detailed separately.

Human papillomavirus ^[1][2]

• Double-stranded, circular, nonenveloped DNA virus with an icosahedral capsid
• There are > 200 known types of HPV; some infect the cutaneous epithelium and others infect the mucosal epithelium.
• Routes of transmission include: ^[3][4]
  • Direct contact (e.g., sexual activity, autoinoculation)
  • Fomites ^[5]
  • Vertical transmission (rare)

Genital HPV infection is the most common sexually transmitted infection. ^[1]

Risk factors for HPV infection ^[3]

• Damaged skin/mucous membranes (e.g., maceration, trauma) ^[6][7]
• Immunodeficiency (e.g., due to HIV infection, chemotherapy)
• Additional risk factors for genital/mucosal HPV infections include:
  • Unprotected sex
  • Higher number of lifetime sexual partners
  • Early age at first sexual activity
  • Lack of circumcision in male individuals ^[1]
  • History of other sexually transmitted infections

• HPV expresses the following oncoproteins
  • E6 → inhibition of p53 protein → inhibition of the intrinsic apoptotic pathway and inhibition of p21 protein
  • E7
    • Inhibition of retinoblastoma protein (pRb) → increased activity of E2F-family of transcription factors
    • Inhibits p21 and p27 (CDK inhibitors) → increased activity of cyclin-dependent kinase

6 comes before 7 and P comes before R: E6 inhibits P53 and E7 inhibits pRb

• Most HPV infections are asymptomatic. ^[1]
• HPV infection can cause various diseases depending on specific HPV type and site of infection. ^[3]

HPV types 1, 2, and 4 are commonly associated with cutaneous warts. HPV types 6 and 11 are commonly associated with anogenital warts. ^[1][2][5]

Most HPV infections are asymptomatic and resolve spontaneously. Persistent infection with a high-risk HPV type (especially HPV types 16 and 18) is associated with an increased risk of HPV-related cancers, most of which are squamous cell cancers. ^[1][2][3]

• Cutaneous warts and anogenital warts are usually diagnosed clinically. ^[7][10]
• HPV testing may be performed as part of any of the following: ^[7][10]
  • Cervical cancer screening (primary HPV testing and HPV/Pap cotesting)
  • Management of abnormalities detected on cervical cancer screening
  • Follow-up after treatment of high-grade cervical lesions
  • Anal cancer screening
  • Testing of biopsy samples from suspicious malignant or premalignant lesions
• For further information, see respective articles (e.g., “Cutaneous warts,” “Anogenital warts,” “Cervical cancer screening”).

HPV testing is only indicated to evaluate for high-risk HPV infections. HPV testing is not recommended in the evaluation of patients or partners of patients with anogenital warts. ^[10]

• Epidermal hyperplasia and hyperkeratosis
• Koilocytes
  • Pathognomonic of an infection with HPV
  • Dysplastic squamous cells characterized by well-defined, clear, balloon-like, perinuclear halo and hyperchromasia
• Papillomatosis (i.e., elongated rete ridges of the epidermis that point towards the center of the wart)

• There is no cure for HPV infections.
• Most HPV infections in immunocompetent individuals resolve spontaneously within 2 years.
• Management is based on clinical manifestations of HPV; options include observation, topical pharmacotherapy, cryotherapy, laser therapy, and surgical excision.
• For further information, see respective articles (e.g., “Cutaneous warts,” “Anogenital warts,” “Invasive cervical cancer”).

Recurrence of cutaneous and anogenital warts after treatment is common, as the surrounding tissue may continue to harbor HPV infection. ^[7]

Risk factor modification

• Advise patients to minimize skin-to-skin transmission of HPV (e.g., by avoiding direct contact with warts). ^[11]
  • Use appropriate footwear in public areas (e.g., locker rooms, public showers).
  • Keep skin clean and dry.
• Counsel patients on safe sex practices to minimize sexual transmission of HPV. ^[3][10][12]
  • Delay initiation of sexual activity.
  • Limit number of sex partners.
  • Use barrier contraception consistently. ^[13]
• Counsel patients on smoking cessation and minimizing alcohol consumption. ^[3][10]

Barrier contraception does not provide complete protection from HPV infection, as uncovered areas such as the anus, vulva, and scrotum may still transmit infection. ^[10][13]

Infection with one HPV type does not protect against infection with another type. Simultaneous or consecutive infection with multiple HPV types is possible. ^[1]

Vaccination ^{[10][12][14][15]}

• HPV vaccine: The human papillomavirus 9-valent vaccine protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, which cause anogenital warts and HPV-related cancers. ^[3][14][16]
• Vaccine schedule ^{[14][17][18][19]}
  • Routine immunization
    • All individuals between 11 and 12 years of age, preferably before first sexual intercourse
    • Minimum age for the first dose: 9 years
  • See “ACIP immunization schedule” for dosing, catch-up immunization, and recommendations for special patient groups (e.g., immunocompromised individuals).
• Contraindications
  • Pregnancy (pregnancy testing is not required before vaccination) ^[10][12][20]
  • Severe allergic reaction (e.g., anaphylaxis) following a previous HPV vaccine dose

The HPV vaccine protects against HPV infection and associated conditions (e.g., anogenital warts and HPV-related cancers). ^[13][21]Offer vaccination to all eligible patients, regardless of sexual orientation or practices and including those already exposed to HPV through sexual contact. ^[1][22]