HPV Infections

James W. Myers

Emmanuel Okon

INTRODUCTION

Human papillomaviruses (HPV) are icosahedral nonenveloped dsDNA viruses belonging to the family papillomaviruses. HPVs are the commonest cause of sexually transmitted infection in the world and the third most common cause of cancer in women world-wide.

Clinical manifestations of infection include anogenital disease and other types of disease (e.g., respiratory papillomatosis and focal epithelial hyperplasia of the oral cavity). An association exists between oncogenic HPV infection and squamous intraepithelial lesions of the cervix, anus, vulva, penis, and vagina. Fifteen percent of HPV infections will progress to cervical intraepithelial neoplasia or carcinoma within 2 to 3 years if left untreated. Risk factors for persistent infection include multiple sexual partners, age of first intercourse, history of STDs, and smoking. Sixty-five percent of sexual contacts will develop an infection. Most people who become infected with HPV do not even know they have it.

CLINICAL MANIFESTATIONS

Genital HPV infections can be divided into low-risk infections (genital warts) and high-risk infections (cervical and other cancers).
The presence of genital warts is not an indication for HPV testing, a change in the frequency of Pap tests, or cervical colposcopy.
Incubation period: 3 weeks to 8 months (3 months average).
Up to 90% will clear the infection in about 2 years. Genital warts usually clear with treatment in about 6 months. Up to 30% clear spontaneously in 4 months. A minority of those infected will go on to malignant disease.
Genital warts appear as a small bump or groups of bumps in the genital area. They can be small or large, raised or flat, or shaped like a cauliflower.
Warts can appear within weeks or months after sexual contact with an infected partner—even if the infected partner has no signs of genital warts.
HPV testing is not indicated for partners of persons with genital warts.
HPV transmission—4.9 from penis to cervix, and 17.4 from cervix to penis events per 100 person months.
If left untreated, genital warts might go away, remain unchanged, or increase in size or number. They will not turn into cancer.
Cervical cancer usually does not have symptoms until it is quite advanced. For this reason, it is important for women to get regular screening. The interval between infection and cancer is about 10 to 20 years. Given a peak prevalence of HPV infection in women in their early 20s, screening is most effective for those patients between 30 and 40 years of age.
Other HPV-related cancers might not have signs or symptoms until they are advanced and hard to treat. These include cancers of the vulva, vagina, penis, anus, and head and neck.
RRP (recurrent respiratory papillomatosis) causes warts to grow in the throat. It can sometimes block the airway, causing a hoarse voice or troubled breathing.
- Follows exposure during a vaginal birth.
- May first appear between 6 months and 10 years of age.
- Adults may get it from oral-genital contact.
- Treatment: endoscopic cryotherapy or laser surgery

DIAGNOSIS

Diagnostic Tests^a	Findings
Clinical evaluation	Speculum examination is needed for anogenital warts + Anoscopy for women with perianal and perineal warts.
Acetic acid	3%-5% acetic acid is applied, used to delineate disease prior to biopsy. Look for characteristic acetowhite appearance.
Cytology	Pap smear to detect HPV disease in the cervix, vagina, and sometimes in the anus, especially in homosexual men and women with HPV genitourinary tract lesions. Look for koilocytes + nuclear atypia + delayed maturation.
Histology	Biopsy is indicated in atypical cases and when the benign nature of the lesion is unclear, that is, Bowenoid or giant condylomas. Look for papillomatosis accompanied by the characteristic features of acanthosis, parakeratosis, hyperkeratosis, and koilocytosis.
Molecular-based methods	Two HPV DNA detection tests, the Hybrid Capture II (Digene Corporation) and the Cervista HPV HR and HPV 16/18 (Hologic Inc.) assays, are approved by the U.S. Food and Drug Administration (FDA) for the triage of ASC-US Pap smears and for the primary screening of cervical cancer in combination with cytology.
^aSee the Internet Resources table for an excellent algorithm for screening with Pap smears and HPV detection tests available from the American Society for Colposcopy and Cervical Pathology.

No recommended uses of the HPV test to diagnose HPV infection in sex partners have been established. HPV infection is commonly transmitted to partners but usually goes away on its own.

TREATMENT

The response to treatment will depend on the following:
- Duration of lesions more than 1 year.
- >10 lesions
- Dry skin heals less often than moist lesions.
- Tobacco smoking and contraceptive use are adverse factors as well.
The natural history of genital warts is usually benign, but recurrence of genital warts within the first several months after treatment is common.
Treatment of genital warts can reduce HPV infection, but whether the treatment results in a reduction in risk for transmission of HPV to sex partners is unclear. The duration of infectivity after wart treatment is not clear at this time.
Examination of sex partners is not necessary for the management of genital warts because reinfection plays no role in recurrences !

Self-Applied Therapies
Treatment	Mechanism of Action	Directions	Adverse Reactions
Podofilox (podophyllotoxin)	Unknown? Mitotic toxin.	Apply with a cotton-tipped applicator (solution) or finger (gel) q 12 hours for 3 days, then none for 4 days. May repeat in 1 week for up to four cycles.	Chemical burns, neurologic, hematologic, and febrile complications, sometimes leading to death, and allergic sensitization. Therefore, areas larger than 10 cm² should not be treated. Total volume should be >0.5 mL/day. Contraindicated in pregnancy.
Imiquimod	Induces the production of interferon-α and other cytokines. Likely mechanism of action involves binding to the toll-like receptors 7 and possibly 8 of dendritic cells	Three times/week at bedtime. Apply until gone or up to 16 weeks maximum. Wash with soap and water, 6-10 hours after application.	Itching and burning sensations, erythema, erosions, and swelling. Safety not established in pregnancy. Might weaken condoms and vaginal diaphragms. Lactation safety unknown.
Polyphenon E, or sineatechin ointment	Contains green tea catechins. These compounds have some antiviral and anticarcinogenic activities.	Apply a 0.5 cm strand of ointment with a finger three times a day on the lesions until complete disappearance, but for no more than 16 weeks. Do not wash off.	Erythema, pruritus, pain, and ulceration. Contraindicated in pregnancy. Might weaken condoms too. Efficacy in HIV not established. The red stain of the substance and its frequency of administration are potential drawbacks.

Provider-Applied Therapies:
Treatment	Directions	Side Effects.
Podophyllin resin	Apply with a cotton-tipped applicator (1-2 mL). No open lesions. Allow to air dry and then wipe off after 1-4 hours. May repeat in 1 week.	Similar to podofilox. Pregnancy category X
Trichloroacetic acid	Trichloroacetic acid in a 10%-90% solution is used topically at weekly intervals. Commonly used by gynecologists for the treatment of genital warts.	The application is painful and can cause ulcers. The unreacted acid should be removed with talcum powder or bicarbonate of soda. Safe in pregnancy.
5-Fluorouracil	It is used topically as a 5% cream applied daily. Best results with intraurethral warts. Rarely used.	It is used topically as a 5% cream applied daily. Unsafe in pregnancy
Cryotherapy	Lesions are frozen every 1 or 2 weeks with liquid nitrogen or cryoprobe.	Burning, which resolves within a few hours, and ulceration, which heals in 7-10 days with little or no scarring. Safe in pregnancy.
Conventional surgery or electrosurgery.	Refer to a specialist	Recurrences, and scarring, typically limited to some skin discoloration.