HPV (human papillomavirus), the most common sexually-transmitted infection (STI), is a highly prevalent condition associated with significant morbidity and mortality. For this reason, it is important for health-care providers as well as susceptible individuals to understand its methods of transmission, risk factors, clinical manifestations and current treatments. More than half of all sexually active women have been infected at some point with one or more of the HPV types that infect the anogenital tract 1,2. Men are infected at similar rates and with similar serious consequences.
Risk Factors for HPV
Risk factors for HPV are similar to those for all sexually-transmitted infections. Genital infections are acquired primarily from sexual contact, most often during vaginal and anal sexual intercourse. The single most important risk factor for HPV infection is the number of lifetime sexual partners, and the number of lifetime partners each of those partners has had previously. Age is an important factor, with first exposure and disease most common between ages 15 and 25. Rates of infection go down as age goes up1. The incubation period after exposure varies from 3 weeks to 8 months, on average from 2 to 4 months3. Newborns can be infected as they pass through the birth canal of an infected mother. It appears that, in patients with intact immune systems, most genital HPV infections are resolved spontaneously by the body's defenses. In contrast, immunosuppressed individuals (e.g., HIV patients, post-transplant patients, patients with autoimmune disorders) have more severe and frequent HPV disease, from extensive, hard-to-eradicate warts to anogenital cancers. Up to 92% of HIV-positive men who have sex with men will develop anogenital warts. HPV can evade immune detection and attack in several ways, such as inducing a low level of inflammation (a red flag to the immune system). This trait increases the ability of the infection to progress to malignancy1.
HPV is a double-strand DNA virus of the Papovaviridae family. Approximately 120 types of the virus have been identified. Of these, at least 40 infect the male and female genitalia. (Others cause conditions such as common and plantar warts.) Genital HPV types are classified as low-risk and high-risk based on their potential effect in the host. Low-risk types (commonly 6, 11, 42, 43, and 44) are associated with condyloma or anogenital warts2. Most of these infections are asymptomatic and benign. In these infections, the viral genomes do not invade the host's chromosomes but stay on the surface of the epithelium (skin or mucous membrane). Many of these infections resolve spontaneously within 12 to 24 months 3.
High-risk HPV types are associated with the appearance of abnormal cells, called "dysplasia," on the surface of anogenital organs, such as the cervix or anal canal. These abnormal cells may progress to cervical or other cancers, including anal, penile, vulvar, and vaginal cancer 4. Although anogenital cancers can come from infection with more than 20 HPV types, more than 70% of these cancers come from only two types: HPV-16 or HPV-18. The genomes of these types invade and are integrated with the chromosomes of the host cells 2,3. However, infection alone cannot cause a progression to cancer; other events at the cellular level, not clearly understood at this point, must occur to produce genetically unstable cells which become invasive1.
An individual may acquire more than one type of HPV, either at the same time or at different times. The risk of acquiring a new type is not reduced by a previous HPV infection with a different type5.
Avoiding HPV Infection
The only sure way to avoid HPV infection is to abstain from sexual activity. However, risk can be greatly reduced by later onset of sexual activity and fewer lifetime sexual partners. Latex condoms may reduce but not eliminate the risk. Vaccines have been introduced in recent years, and are being shown to be safe, well-tolerated, and highly effective in the prevention of type-specific HPV infection3. The two vaccines currently available are Gardisil and Cervarix. Both protect against the HPV types that cause 70% of cervical cancer4; Gardisil also protects against the types that cause 90% of genital warts in both males and females. Several studies have shown high acceptance of the vaccines among adolescents, young adults, and their parents3. The ideal time to immunize is in early adolescence, before the onset of sexual activity. Immunizing boys as well as girls would enhance "herd" immunity and further reduce infection. A limitation of the vaccines is that they only cover a few HPV types. Therefore, women who have received the vaccine need to continue routine cervical cancer screening4. In addition, health-care workers have an important role to play in providing their patients, especially adolescents and sexually-active young adults, with ongoing counseling about reducing risks and undergoing routine screening for all sexually-transmitted infections.
Screening for HPV
In women, regular Pap tests can detect cervical changes associated with high-grade HPV virus before they become cancerous. Current recommendations from the American Cancer Society and the US Preventative Services Task Force are to begin Pap screening three years after first vaginal intercourse, no later than age 21. The US Preventive Services Task Force recommends the following: "screening ... every year with the regular Pap test or every 2 years using the newer liquid-based Pap test. Beginning at age 30, women who have had 3 normal Pap test results in a row may get screened every 2 to 3 years. Women older than 30 may also get screened every 3 years with either the conventional or liquid-based Pap test, plus the human papilloma virus (HPV) test. This test detects viral DNA/RNA and specifies the type in the sample being tested.
Women 70 years of age or older who have had 3 or more normal Pap tests in a row and no abnormal Pap test results in the last 10 years may choose to stop having Pap tests. Women who have had a total hysterectomy (removal of the uterus and cervix) may also choose to stop having Pap tests, unless the surgery was done as a treatment for cervical cancer or pre-cancer. Women who have had a hysterectomy without removal of the cervix should continue to have Pap tests6."
Recommendations from the American Cancer Society and the American College of Obstetricians and Gynecologists vary slightly from those of the USPS Task Force.
Treatment is directed at the type of lesions, either benign (i.e., genital warts) or pathologic (i.e., precancerous) caused by the infection. As stated above, subclinical infection usually clears spontaneously and does not require treatment. This includes infection diagnosed by colposcopy, acetic acid application, or by laboratory tests for HPV DNA.
Clinical Manifestations and Diagnosis: Genital Warts Caused by HPV
Genital warts are usually asymptomatic; however, if they become large enough, they may be annoying, unsightly, painful, or itchy. They are usually small (less than 5mm across), flat or slightly raised, and appear individually or in groups on the genital mucous membranes - around the opening to the vagina in women, on the penis in men, in the anal opening in both men and women. The warts can sometimes come together to form a larger mass, which can resemble a cauliflower. In these cases, patients are usually very symptomatic and motivated to have the lesions treated.
Warts are usually diagnosed on physical exam, if the patient has not brought them to the attention of the provider. Further testing is usually unnecessary, unless the appearance is unusual (e.g. the warts are pigmented or a darker color than the surrounding skin), bleeding, ulcerated, or indurated (hardened); or they do not respond to standard treatment or worsen during treatment. Further testing is also recommended in immunosuppressed individuals4.
Treatment of Genital Warts Caused by HPV
Treatment of warts is to relieve symptoms and remove the lesions. Left untreated, warts can resolve on their own, stay the same, or become larger and/or more numerous.
There are a number of treatment regimens for genital warts. The preference of the patient, available resources, convenience, adverse effects, and experience of the provider should all be considered when choosing a treatment. There have been many studies comparing treatment regimens, but there is no conclusive evidence that one treatment is superior to others. Most cases respond within three months of initiating treatment. In addition, it is acceptable for an individual to decide to wait and see if the condition will improve and resolve on its own4.
Treatments for external warts are classified as patient-applied or provider-applied. Patient-applied therapies include podofilox 0.5% solution or gel, imiquimod 5% cream, and sinecatechin ointment, a green-tea extract. Patients must comply with the treatment regimen and be able to reach all the warts. Mild to moderate pain or irritation may occur with these compounds. With imiquimod and sinecatechin, there may also be local inflammatory responses such as ulceration, erosion, or vesicles3,4.
Provider-applied therapies include cryotherapy with liquid nitrogen or cryoprobe; podophyllin resin, and trichloroacetic or bichloroacetic acid. All of these treatments usually need to be repeated weekly or biweekly for a period of time that depends on the extent of the lesions. Podophyllin is contraindicated during pregnancy but the other treatments can be used safely. Lastly, and usually reserved for large or numerous warts, is surgical removal. This may be with electrocautery or laser, scissor or shave excision, or curettage (scraping). It requires substantial clinical training, special equipment, and a longer visit with local anesthesia 3,4.
Clinical Manifestations, Diagnosis, and Treatment: Precancerous and Cancerous Lesions
Cervical cancer is the second most common cancer in women worldwide, and the third most deadly. HPV infection is almost certainly a precursor to this disease 1, being found in 94-99.7% of all cervical and other anogenital carcinomas. Early detection and treatment is crucial in the prevention of invasive carcinoma. Once a woman has had an abnormal Pap smear, she is at higher risk for the development of cervical cancer, and is managed according to guidelines for abnormal results. Patients with abnormal routine Pap smears showing atypical squamous cells (cells forming the surface of the cervix) of undetermined significance or ASC-US, low-grade squamous intraepithelial lesion or LSIL, and high-grade squamous intraepithelial lesion or HSIL are followed according to fixed protocols or algorithms. Women with ASC-US or LSIL are followed with more frequent Pap tests for several years or until results are normal for a period of time, or with a procedure called a colposcopy. In this procedure, the health-care provider uses a lighted magnifying instrument called a colposcope to examine the tissues of the vagina and the cervix. Colposcopy is not painful, has no side effects, and can be done safely during pregnancy. If an abnormal area is seen on the cervix during the colposcopy, a small amount of tissue is removed and sent to the lab for a test called a biopsy, which can identify pre-cancerous or cancerous lesions7. (Information regarding colposcopy management and follow-up care is available from the American Society for Colposcopy and Cervical Pathology at their website, http://www.asccp.org.) In addition, HPV DNA typing is usually done in these cases to identify the type of HPV and whether it is a cancer precursor or not.
High-grade intraepithelial lesions require more aggressive diagnosis and treatment to remove them. "Cone biopsy" refers to a therapy used to diagnose and remove abnormal tissue on the cervix. Other methods available to remove abnormal tissue include electrocauterization, cryosurgery, laser vaporization, and surgery, and depend on the site and extent of the HSIL lesions.
In summary, HPV is an extremely common sexually-transmitted infection. Most cases are benign, asymptomatic, and self-limited. However, infection with high-risk HPV types, particularly in susceptible individuals, causes significant morbidity and mortality as a precursor to anogenital cancers, including cervical cancer. Screening recommendations, diagnosis, and treatment regimens for anogenital HPV infections are complicated and change frequently. Clinicians must resort to protocols or algorithms to help them choose the correct sequence of diagnostic tests and treatments, in order to minimize over-treatment while assuring treatment of those cases that are at high risk for becoming invasive cancers.
References
1. Ahmed AM, Madkan V, Tyring SK (2006). Human papillomaviruses and genital disease. Dermatologic Clinics 24:2.
2. Lee PK, Wilkins KB (2010). Condyloma and other infections including human immunodeficiency virus. Surgical Clinics of North America 90(1).
3. Leung AKC, Kellner JD, Davies HD (2005). Genital infection with human papillomavirus in adolescents. Advances in Therapy 22(3):187-97.
4. Sexually transmitted diseases treatment guidelines, 2010. Morbidity and Mortality Weekly Report, 59:RR-12, December 17, 2010. Available at: http://www.cdc.gov/mmwr.
5. Thomas KK, Highes JP, Kuypers JM et al (2000). Concurrent and sequential acquisition of different genital human papillomavirus types. The Journal of Infectious Diseases 182:1097-102.
6. U.S. Preventive Services Task Force. Screening for Cervical Cancer. Available at: http://www.uspreventiveservicestaskforce.org/uspstf/uspscerv.htm.
7. American Cancer Society. Cervical Cancer: Prevention and Early Detection. Available at: http://www.cancer.org/Cancer/CervicalCancer/MoreInformation/CervicalCancerPreventionandEarlyDetection/cervical-cancer-prevention-and-early-detection-find-pre-cancer-changes.
This article has been reviewed by a member of the Wellness Partners Editorial Board.
Posted February 2011
