Anogenital HPV Infection

Anogenital human papillomavirus infection is the commonest sexually transmitted infection worldwide. HPV is a non-enveloped, double-stranded DNA virus of the Papillomaviridae family, with over 200 genotypes and about 40 infecting the anogenital tract.

Classification:

• Low-risk types (6 and 11): cause over 90% of anogenital warts (condylomata acuminata) and recurrent respiratory papillomatosis.
• High-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59): cause cervical, vaginal, vulvar, anal, penile and oropharyngeal cancers. Types 16 and 18 account for about 70% of cervical cancers, and HPV 16 is the dominant type in anal and oropharyngeal cancer.

Epidemiology and natural history:

• Most sexually active people acquire HPV at some time (lifetime risk above 80%), with highest prevalence in those aged 18 to 25.
• Transmission is through skin-to-skin and mucosal contact during vaginal, anal or oral sex, and condoms offer partial protection only.
• About 90% of infections clear within 2 years through cell-mediated immunity. Persistent infection with high-risk types leads to precancerous lesions, with a progression time to cervical cancer of 10 to 20 years (faster in immunosuppression).
• Perinatal transmission can cause juvenile-onset respiratory papillomatosis.

Risk factors for persistence and progression: HIV infection (CD4 count below 200), immunosuppression after transplantation, smoking, long-term oral contraceptive use, multiparity, co-infection with chlamydia or herpes, and early age at first intercourse.

Disease spectrum:

• Subclinical and latent infection (no lesions).
• Anogenital warts.
• Precancer: cervical intraepithelial neoplasia (CIN 1 to 3), vaginal and vulvar intraepithelial neoplasia, anal intraepithelial neoplasia, penile intraepithelial neoplasia (including erythroplasia of Queyrat).
• Invasive cancer: cervix (the principal burden, over 600,000 cases yearly), anus, vulva, vagina, penis and oropharynx.

Men who have sex with men and people with HIV have a markedly higher risk of anal cancer (incidence 30 to 100 per 100,000 per year, compared with about 1 to 2 in the general population).

Most infections are asymptomatic and detected on screening.

Anogenital warts:

• Soft, flesh-coloured, pink or pigmented papules and cauliflower-like growths, which may be flat, papular, keratotic or pedunculated, single or multiple.
• Sites: vulva, introitus, vagina, cervix, perineum and perianal skin, penis (shaft, glans, foreskin, frenulum), scrotum, urethral meatus and anal canal. Intra-anal warts occur mainly after receptive anal sex.
• Symptoms are usually itching, bleeding, discomfort, and cosmetic and psychological distress. Large lesions may cause obstruction or interfere with intercourse. Urethral warts cause haematuria and altered stream.
• Pregnancy and immunosuppression produce larger, more numerous and treatment-resistant warts.

Precancerous and cancerous disease:

• Cervical intraepithelial neoplasia is asymptomatic and found through screening. Abnormal bleeding (postcoital, intermenstrual), discharge and pelvic pain suggest invasion.
• Anal intraepithelial neoplasia may cause itching, bleeding or a mass, and is usually silent.
• Vulvar disease presents with chronic itching, raised pigmented or white patches, and ulcers.
• Anal cancer presents with bleeding, pain, mass, itching, change in bowel habit and tenesmus.

Differential diagnosis of warts:

• Condylomata lata of secondary syphilis (flat, moist, grey-white), molluscum contagiosum, skin tags, pearly penile papules and vestibular papillae (normal variants), Fordyce spots, seborrhoeic keratosis, lichen planus, bowenoid papulosis, and squamous cell carcinoma.

Red flags: pigmented, indurated, ulcerated, fixed or bleeding lesions, lesions refractory to treatment, immunosuppression, and age over 40 with new warts, all of which need biopsy.

Warts are diagnosed clinically. Biopsy is indicated when there is diagnostic uncertainty, pigmented or indurated lesions, ulceration, bleeding, fixation, treatment failure, or immunosuppression.

HPV testing:

• Routine HPV DNA testing for warts is not recommended, since low-risk types are implicated and the result does not change management.
• High-risk HPV testing is used within cervical screening.

Cervical screening:

• Primary HPV testing (with cytology triage for 16/18 and other high-risk positives) every 5 years for ages 25 or 30 to 65. Cytology alone every 3 years for ages 21 to 29, or co-testing every 5 years.
• Abnormal results lead to colposcopy with application of acetic acid 3 to 5% and Lugol iodine, directed biopsy and endocervical curettage. Management follows histology (CIN 2 or 3 requires treatment).
• Immunocompromised people (HIV): screening begins at diagnosis, annually for 3 years, then every 3 years if normal (annual cytology in some protocols).

Anal screening:

• Anal cytology and high-resolution anoscopy with biopsy for high-risk groups (people with HIV, men who have sex with men, women with prior high-grade vulvar or cervical lesions, transplant recipients). Digital anorectal examination annually is advised in high-risk groups.

Other diagnostics:

• Acetowhite changes with 5% acetic acid are non-specific and not recommended for diagnosing subclinical infection in the penis.
• Screening for coexisting sexually transmitted infections: HIV, syphilis serology (with condyloma lata), chlamydia, gonorrhoea, hepatitis B.
• Examination of the urethral meatus and anal canal (anoscopy) when warts are at the meatus or perianal region, respectively.
• Pregnancy test before certain treatments.

Prevention

• HPV vaccination is the primary prevention, and is effective at preventing infection, warts and precancer when given before exposure. The 9-valent vaccine (types 6, 11, 16, 18, 31, 33, 45, 52, 58) is given as 2 doses (0 and 6 to 12 months) for ages 9 to 14, and 3 doses (0, 1 to 2 and 6 months) from age 15 and in immunocompromised people. Vaccination is recommended up to age 26 routinely, and through shared decision-making to age 45. Single-dose schedules are used in many programmes and appear effective.
• Condom use reduces transmission (up to about 70% of risk), smoking cessation, and screening for cervical and anal cancer.
• Vaccination after treatment of CIN 2 or 3 reduces recurrence.
• Not recommended: vaccination during pregnancy (defer until postpartum, though inadvertent doses are not harmful).

Treatment of anogenital warts No treatment is clearly superior and none eradicates the virus. About 20 to 30% of warts clear without treatment within 3 months, and recurrence occurs in 20 to 50%. Choose according to site, number and size, patient preference and resources.

• Patient-applied therapies (external warts):
• Podophyllotoxin 0.5% solution or 0.15% cream, applied twice daily for 3 days, followed by 4 days of rest, for up to 4 to 5 cycles. Total area under 10 cm2 and daily volume under 0.5 mL. Avoid in pregnancy.
• Imiquimod 5% cream, applied at night three times weekly, washed off after 6 to 10 hours, for up to 16 weeks. Imiquimod 3.75% cream daily for up to 8 weeks. Avoid in pregnancy.
• Sinecatechins 15% ointment, applied three times daily for up to 16 weeks.
• Clinician-applied therapies:
• Cryotherapy with liquid nitrogen, repeated every 1 to 2 weeks, with clearance in 60 to 90%. It is safe in pregnancy.
• Trichloroacetic acid or bichloroacetic acid 80 to 90% applied weekly, a safe option in pregnancy. Protect surrounding skin with petroleum jelly.
• Podophyllin resin 10 to 25% in tincture of benzoin, applied weekly and washed off after 1 to 4 hours (not in pregnancy).
• Surgical: tangential shave excision, curettage, electrosurgery, CO2 laser ablation, or excision under local anaesthetic. Best for extensive, large or resistant lesions, with immediate clearance, but risk of scarring. Intraurethral warts: cryotherapy, laser or topical 5-fluorouracil under urology care. Intra-anal warts: cryotherapy, TCA, or electrocautery by experienced clinicians.
• Other: intralesional interferon alpha, topical 5-fluorouracil 5%, and cidofovir 1% gel for refractory warts in immunosuppressed patients. Intralesional Candida antigen or MMR vaccine has been used.
• Recurrent or resistant warts: biopsy, treatment change, immune function assessment.
• Pregnancy: defer treatment where possible, use cryotherapy, TCA or surgery. Warts may regress postpartum. Caesarean delivery is reserved for obstructing warts or heavy bleeding, and not for preventing neonatal transmission.

Treatment of precancerous lesions

• Cervix: CIN 2 and 3 by loop electrosurgical excision procedure (LEEP) or cold knife conisation, cryotherapy or thermal ablation in low-resource settings (screen-and-treat). CIN 1 is observed. Follow-up with HPV testing at 6 to 12 months, then annually until negative twice.
• Anus: high-grade anal intraepithelial neoplasia is treated with infrared coagulation, targeted ablation, or topical imiquimod 5% or 5-fluorouracil 5%, with surveillance by high-resolution anoscopy.
• Vulva and penis: excision, laser ablation, or topical imiquimod 5% for high-grade intraepithelial neoplasia, with long-term surveillance.

Treatment of invasive cancer

• Cervical cancer: surgery or chemoradiation according to stage. Anal cancer: chemoradiotherapy with mitomycin C and 5-fluorouracil or capecitabine with 50 to 59 Gy radiotherapy. Other sites per tumour-specific care.

Counselling and partner management

• Explain that HPV is common, that warts and abnormal smears do not signify infidelity, that infection may have been acquired years earlier, and that the virus is often cleared. Partners do not need routine testing but should be examined for warts and offered vaccination and screening.
• Encourage condom use during the active treatment period. Address psychosexual impact, and screen for other sexually transmitted infections.
• Follow-up at 2 to 4 weeks during treatment, with reassessment after 3 months of treatment without response.