Human papillomavirus (HPV)

Overview

Human papillomavirus (HPV) is a common sexually transmitted infection (STI). There are more than 100 subtypes of HPV, which are categorised into high-risk and low-risk types. Oncogenic, high-risk HPV infection (e.g., HPV types 16 and 18) causes the majority of cervical, penile, vulvar, vaginal, anal, and oropharyngeal cancers and precancers, whereas other HPV infection (e.g., HPV types 6 and 11) causes genital warts and recurrent respiratory papillomatosis.

HPV infections are common and most infections do not result in clinically visible genital tract lesions. Cancers from HPV can be prevented with vaccination.

Disease epidemiology

From 2019 data, it was estimated that 620,000 new cases of cancer in women and 70,000 in men were attributed to HPV globally. Cervical cancer, which ranked as the fourth leading cause of cancer and cancer-related deaths in women in 2022, accounted for approximately 660,000 new cases and around 350,000 deaths worldwide. Cervical cancers make up more than 90% of HPV-related cancers in women. In Singapore, cervical cancer is the 10^th most common cancer among women.

The highest rates of cervical cancer incidence and mortality are observed in low- and middle-income countries, underscoring significant disparities resulting from limited access to national HPV vaccination, cervical screening, treatment services, and broader social and economic factors.

The prevalence of the virus is higher among women with HIV, men who have sex with men (MSM), individuals with compromised immune systems, those with co-infections of other STIs, individuals receiving immunosuppressive medications, and children who have experienced sexual abuse.

Pathogen(s)

Human papillomavirus (HPV).

Transmission

Transmission can occur during oral, vaginal, and anal sex and other intimate skin-to-skin contact. HPV 6 and 11 are transmitted predominantly by epithelial contact. HPV can spread even when a person with infection has no signs or symptoms.

Incubation period: 2 to 3 months, with a range of 1 to 20 months for genital warts

Infectious period: Unknown

Clinical features

HPV infection occurs as:

• Clinical lesions: Condylomata acuminata, papular and flat warts

• Condyloma acuminata: Exophytic, filiform, cauliflower-shaped warts, HPV 6 and 11 in more than 90% of cases

• Multifocal: Usually 5 to 15 lesions, in areas of trauma during sex, 1 to 10 mm diameter, may coalesce, especially in immunosuppressed individuals and in the presence of diabetes mellitus

• Coinfection: With oncogenic “high-risk” HPV e.g. HPV 16 and 18

• Oncogenic HPV: Mostly give rise to subclinical lesions, intraepithelial neoplasia (IN), and anogenital cancer

• Subclinical Lesions: Only visible after application of acetic acid and magnification

Latent HPV infection defined when HPV DNA can be demonstrated in absence of clinical or histological evidence of infection.

Risk factors

Risk factors include:

• Onset of sexual intercourse at an early age

• Unprotected sex or inconsistent condom use if the relationship is not monogamous

• Having multiple sex partners

• Persons who exchange sex for money or drugs

• History or current presence of other STIs

• Long term consumption of combined oral contraceptive pills

• Smoking

• Immunosuppression (innate or acquired), including HIV infection

Diagnosis

A clinical diagnosis is made from recognition of characteristic lesions.

• Subclinical mucosal warts can be identified by turning white (acetowhite) after application of 5% acetic acid for three minutes. This can be applied onto discrete as well as suspected sub-clinical lesions; the mechanism for this aceto-whitening effect is not clear. One hypothesis is that acetic acid causes a reversible coagulation of some epithelial and stromal proteins. Note that this whitening effect may also occur in areas of abrasions or non-specific inflammation and may also be seen in other infections such as candidiasis, and thus is not specific for HPV infection.

• Skin biopsy is indicated for atypical cases, cases where the benign nature of papular or macular lesions is unclear. Features which may raise suspicion include pigmentation, depigmentation, pruritus, immunodeficiency, and history of intraepithelial neoplasia. Biopsy may also be indicated when the lesions do not respond to or worsen during standard therapy.

• If a clinical diagnosis has been made, HPV testing is not recommended to confirm anogenital wart diagnosis.

Screening for HPV in females can be found in the national guidelines.

Treatment and management

Treatment is directed to the macroscopic (e.g., genital warts) or pathologic precancerous lesions caused by HPV. While subclinical genital HPV infection typically clears spontaneously, treatment can be given to remove visible exophytic warts. No treatment, however, is completely satisfactory in eliminating HPV infection.

It is important to perform meatoscopy for meatal warts, proctoscopy for anal warts, and speculum examination with cervical cytology/colposcopy for female genital warts.

Precancerous lesions are detected through cervical cancer screening; HPV-related precancer should be managed based on national guidelines.

Follow-up:

• Provide clear information: causes, treatment, outcomes, and possible complications

• Advise smoking cessation for recalcitrant warts

• Regular cervical cytology (PAP smears) for females

• Condoms: with new partners till clearance is achieved; regular partner already exposed

• Long latency periods mean that only one partner in a relationship may manifest warts

• Current partners and recent partners within 6 months should be assessed for HPV and other STIs

Precaution, prevention, and control

All women who have had sex should undergo screening for cervical cancer from the age of 25. According to the national cancer screening guidelines, the recommended screening interval is as follows:

Age 25 to 29 years: Pap smear screening once every 3 years. Primary HPV testing is not recommended for women in this age group.

Age 30 to 69 years: HPV testing once every 5 years.

Prevention of HPV:

• Not having sex

• Consistent and correct use of condoms when engaging in sexual activity

• Limit the number of sex partners

• Undergo cervical cancer screening regularly

• HPV vaccines are recommended to all females between ages 9 to 26 years

Three HPV vaccines are available for prevention:

• A bivalent vaccine (Cervarix), which protects against HPV 16 and 18

• A quadrivalent vaccine (Gardasil-4), which protects against HPV 6, 11, 16, and 18

• A nonavalent (9-valent) vaccine (Gardasil-9), which protects against HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58

Management of sexual contacts:

• Patients should inform current partners about having genital warts because the types of HPV that cause warts can also be transmitted to partners.

• Partners should be counselled on the possibility of having HPV despite no visible signs of warts; therefore, HPV testing of sex partners of persons with genital warts is not recommended.

• Partners might benefit from a physical examination to detect genital warts and tests for other STIs.      

• No recommendations can be made regarding informing future sex partners about a diagnosis of genital warts because the duration of viral persistence after resolution of warts is unknown.

Notification

HPV is not a notifiable disease. Please refer to the Infectious Disease Notification for more information. 

Resources

Refer to Academy of Medicine Singapore for information about cervical cancer screening.

Refer to the Department of Sexually Transmitted Infections Control (DSC)'s website for more information about HPV.

References

• Academy of Medicine, Singapore. Report of the Screening Test Review Committee. 2019.

• Centers for Disease Control and Prevention. STI treatment guidelines: Human Papillomavirus (HPV) infections. 2021.

• Department of Sexually Transmitted Infections Control (DSC). STI management guidelines 7^th edition. 2021.

• World Health Organization. Human papillomavirus and cancer. 2023.