Nutshell Series 6: Human Papilloma Virus Disease

Causative Organism

Human Papillomavirus

Clinical Manifestations

The principal clinical manifestations of mucosal HPV infection are genital, anal and oral warts; cervical intraepithelial neoplasia (CIN);vulvar intraepithelial neoplasia(VIN);vaginal intraepithelial neoplasia (VAIN); anal intraepithelial neoplasia (AIN); squamous cell cancers; and cervical adenocarcinomas.

A subset of oropharyngeal cancers are caused by HPV. Oral, genital and anal warts (condylomaacuminata) are usually flat, papular  or pedunculated growths on the mucosa or epithelium. The lesions may measure a few millimetres to 1–2 cm in diameter. Most warts area symptomatic, but warts can be associated with genital itching or discomfort.

No characteristic symptoms are associated with CIN, which is often asymptomatic but can manifest with bleeding. Cervical cancer also can be asymptomatic or may manifest with bleeding, pain or a palpable mass.

No characteristic symptoms are associated with VAIN ,VIN and AIN; these lesions are often asymptomatic, but can manifest with bleeding or itching ,and external lesions may be visible or palpable. Similarly, squamous cell cancers at these sites also can be asymptomatic or it may manifest with bleeding, pain or a visible/palpable mass.

Diagnosis

• Diagnosis of genital and oral warts is made by visual inspection and can be confirmed by biopsy, although a biopsy is needed only if the diagnosis is uncertain, the lesions do not respond to standard therapy, or warts are pigmented, indurated, fixed, bleeding or ulcerated.
• No data support the use of HPV testing for the diagnosis or management of visible genital or oral warts.
• The same cytology (Pap test) and colposcopic techniques with biopsy are used to detect CIN among HIV-seronegative and HIV-seropositive patients
• The genitalia and anal canal should be inspected carefully for visual signs of warts, intraepithelial neoplasia or invasive cancer.
• A digital examination of the vaginal, vulvar and perianal regions and the anal canal to feel for masses should be performed as part of routine evaluation.
• AIN, VAIN and VIN are recognized through visual inspection, including high-resolution anoscospy, colposcopy, and biopsy as needed.

Prevention

Preventing the First Episode of HPV Infection

Indications for HPV Vaccination

• HIV-infected; aged 13–26 years

Table 1: Vaccination Schedules

Vaccination Schedules
For Females • HPV recombinant vaccine quadrivalent (types 6, 11, 16, 18) 0.5 mL IM at 0, 1–2, and 6 months or • HPV recombinant vaccine bivalent (types 16, 18) 0.5 mL IM at 0, 1–2, and 6 months	For Males • HPV recombinant vaccine quadrivalent (types 6, 11, 16, 18) 0.5 mL IM at 0, 1–2, and 6 months

IM=intramuscular

Drug Therapy

Treating Genital and Oral Warts

• HIV-infected patients may have larger or more numerous warts, may not respond well to therapy for genital warts, and may have more recurrence after treatment than HIV-negative individuals.
• More than one treatment option maybe required for refractory or recurrent lesions. Intra-anal, vaginal or cervical warts should be treated and managed by a specialist.

Table 2:Patient-applied and Provider-applied Therapy

Patient-applied Therapy For uncomplicated external warts that can be easily identified and treated by the patient: • Podophyllotoxin (e.g. podofilox 0.5% solution or 0.5% gel): Apply to all lesions twice daily for 3 consecutive days, followed by 4 days of no therapy; repeat weekly for up to four cycles until lesions are no longer visible. or • Imiquimod 5% cream: Apply to lesions at bedtime and remove in the morning on 3 non-consecutive nights a week until lesions are no longer seen, for up to 16 weeks. Each treatment should be washed with soap and water 6–10 hours after application. or • Sinecatechins 15% ointment: Apply to the area three times daily for up to 16 weeksuntil warts are not visible.

Provider-applied Therapy For complex or multicentric lesions, lesions inaccessible to patient-applied treatments, or patient/ provider preference: • Cryotherapy (liquid nitrogen or cryoprobe): Apply until each lesion is thoroughly frozen; repeat every 1–2 weeks for up to 4 weeks until lesions are no longer visible. Some specialists allow the lesion to thaw, and then freeze a second time in each session. • TCA or BCA cauterization:  Using an 80–90% aqueous solution, apply to warts only and allow the area to dry until a white frost develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate or liquid soap to remove un-reacted acid. Repeat treatment weekly for up to 6 weeks until lesions are no longer visible. • Surgical excision or laser surgery can be performed for external or anal warts. • Podophyllin resin 10–25% in tincture of benzoin: Apply to lesions (up to 10 cm2 of skin area),  then wash off a few hours later; repeat weekly for up to 6 weeks until lesions are no longer visible.

Treatment of CIN and Cervical Cancer

• HIV-infected women with CIN should be managed by a clinician with experience in colposcopy and treatment of cervical cancer precursors and according to the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines.
• Women with satisfactory colposcopy and biopsy-confirmed high-grade CIN can be treated with either ablation (i.e. cryotherapy, laser vaporization, electrocautery, diathermy, and cold coagulation) or excisional methods (e.g. loop electrosurgical excision procedure [LEEP], laser conization, cold knife conization).
• Women with unsatisfactory colposcopy should be treated only with excisional methods.
• In patients with recurrent high-grade CIN, diagnostic excisional methods are recommended.
• Hysterectomy is acceptable for the treatment of recurrent or persistent biopsy-confirmed high-grade CIN.

Treatment of VIN and Vulvar Cancer and of VAIN and Vaginal Cancer

• Treating VIN/VAIN should be individualized in consultation with a specialist and dependent upon the patient’s medical condition and the location and extent of the disease.
• Various treatment modalities are available for VIN, including local excision, laser vaporization, ablation, and imiquimod therapy.
• Treatment options for VAIN include topical 5-fluorouracil (5-FU), laser vaporizationwith CO₂laser, and excisional procedures with electrosurgical loops or a scalpel excision.
• Management of vulvar and vaginal cancer must be individualized in consultation with a specialist.

Treatment of AIN and Anal Cancer

• The most commonly used treatment for anal cancer is combination radiation and chemotherapy.
• Treatment decisions are based on assessment of the size and location of the lesion and the grade of histology.

Managing Treatment Failure

• For persistent or recurrent genital warts, re-treatment with any of the modalities previously described should be considered.
• Biopsy should be considered to exclude VIN. Genital warts often require more than one course of treatment.
• Recurrent cytologic and histologic abnormalities after therapy for CIN should be managed according to the ASCCP guidelines.
• There is no consensus on the treatment of biopsy-proven recurrent VIN and surgical excision can be considered.

Considerations with Regard to Starting ART

• There are no data to indicate that decisions about initiation of antiretroviral therapy (ART) should be influenced by the presence of HPV-related oral, anal or genital disease.
• No evidence indicates that ART should be instituted or modified solely for the purpose of treating CIN or AIN.
• The diagnosis of CIN or AIN in HIV-infected individuals should not be considered an indication for initiation of ART.

Considerations during Pregnancy

• HIV-infected pregnant women with genital warts or anogenital HPV-related neoplasia are best managed by an interdisciplinary team of specialists (such as an OB/GYN and an infectious disease physician).
• Pregnancy may be associated with an increased frequency and rate of growth of genital warts.
• Podophyllin and podofilox should not be used during pregnancy.
• No change in obstetrical management is indicated for women with HPV infection unless extensive condylomata are present that might impede vaginal delivery or cause extensive bleeding.
• All pregnant women should have a Pap test at their initial prenatal visit unless a normal cervical cytology result has been obtained within the past year.
• Pregnant women with abnormal cervical cytology results should undergo colposcopy and cervical biopsy of lesions suspicious for high-grade disease or cancer.
• Vaccination with commercially available HPV vaccine is not recommended during pregnancy.
• Pregnant women with suspected cervical cancer should be referred to a gynaecologic oncologist for definitive diagnosis, treatment and delivery planning. Vaginal delivery is not recommended for women with invasive cervical cancer.

References

1. Vaccine 2014;32;9:1079-1085
2. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Last accessed on 17th April 2014.