(Published January 2009)

Introduction to HPV-Related Diseases

Impact

• Genital HPV infection is the most commonly diagnosed sexually transmitted infection in the United States, on the basis of estimates from HPV DNA testing.¹
• HPV infection is now known to be necessary to development of cervical cancer.²
• Virtually all cervical cancers are associated with persistent infection with high-risk types of HPV.³
• High-risk HPV also is associated with external genital warts and cancer of the penis, vagina, vulva, anus, and oropharynx.⁴
• More than half of all cases of invasive cervical cancer and death from cervical cancer occur in women who infrequently or never received proper screening.^5,6
• In the United States in 2007, there were an estimated 11,150 cases of cervical cancer and 3,670 deaths.³
• Cervical cancer screening in the United States is estimated to cost $3.4 billion annually.⁷
• Almost 900,000 women have an abnormal Pap test result associated with HPV 16, one of the high-risk types, each year in the United States.^8,9

Incidence and Prevalence

• Approximately 6.2 million new HPV infections occur in the United States each year.¹⁰
• At any given time, about 26.8% of women 14–59 years old have an HPV infection.¹¹
• The lifetime risk of HPV infection is about 75% for sexually active individuals.¹²
• HPV prevalence varies by age and is highest for young women.¹³
• New HPV infection is common in young women.¹⁴
• In one study of female college students, 39% of those who initially had a negative result for HPV DNA tested positive two years later.¹⁴

Transmission

• Sexual intercourse is the primary route of transmission for HPV.
• HPV is transmitted through direct genital contact rather than body fluids, like most sexually transmitted infections (STIs).^14,15
• Intercourse is not necessary for infection; transmission through non-penetrative sexual contact has been documented. The primary mode of transmission is through genital skin-to-skin contact.^14,16
• Genital contact in the absence of intercourse is a plausible means for HPV transmission, but the risk associated with this contact is much lower than that for intercourse.^15,17
• The virus also can be transmitted through oral-genital contact.^14,16
• Receptive anal intercourse is strongly associated with HPV infection.¹⁷
• HPV is not thought to survive for long on inanimate objects, making transmission by means of such objects unlikely. 15 However, it is possible that transmission could occur through objects shared in the short term, such as sex toys.

Natural History

• Progression to precancer occurs when infection with high-risk HPV types persists over time.
• Only a small minority of women who test positive by HPV DNA assay have concurrent microscopic cervical abnormalities; however, when tested one to three years later, as many as 25% to 40% of these women will have developed such abnormalities.¹⁸
• In most cases, HPV infection—with low- or high-risk types—is cleared by the immune system.
• In a study of female college students, more than 90% of women infected with high-risk HPV had cleared the infection when tested 24 months later.¹⁹
• Studies have shown that viral clearance is not often followed by subsequent reinfection with the same genotype.¹⁸
• Less than half of women who develop HPV infection with a high-risk type will have persistence of the same high-risk HPV type 12 months later.¹
• The average episode of HPV infection lasts four to 20 months.¹
• Persistent infection has been defined as detection of the same high-risk HPV genotype two or more times within a given interval of time; however, the duration of time that defines “persistence” is not yet agreed upon.¹⁸
• HPV type 16 persists longer than other types and also is especially carcinogenic, with a risk of cervical intraepithelial neoplasia-3 (CIN-3) of 40% at five years.¹⁸
• There are currently no data on the natural history of high-risk HPV infection in men.¹⁵

HPV Types

• More than 120 types of HPV have been identified.^22,23
• About 40 types can infect the genital tract.²
• Approximately 13 to 19 types are considered high risk, meaning that persistent infection with these types is associated with an increased risk of cervical, anogenital, and other cancers. (The number considered high risk types has varied in different studies).^21-23
• The most important high-risk types are 16 and 18. Type 16 alone causes 50% of all cases of cervical cancer. Type 18 causes another 20% of all cases.²¹
• Low-risk HPV types, the most important of which are 6 and 11, are associated with external genital warts, or condylomata acuminata, and with low-grade cervical lesions.²⁴ Approximately 12 HPV types have been classified as low-risk types.²

Risk Factors for HPV Infection

• The most consistent predictors of HPV infection are measures of sexual activity, such as:¹⁷
  • Lifetime number of partners
  • Younger age at sexual debut
  • Lack of condom use
  • Partner with a history of multiple partners
• In a study of female college students, the strongest risk factor for incident infection was having a main regular sexual partner who had six or more lifetime partners (adjusted relative risk of 10.1).¹⁹
• Because the virus is transmitted by skin-to-skin contact, condoms do not completely prevent infection. According to one study, however, women whose partners used condoms consistently were 70% less likely to acquire an HPV infection than women whose partners did not use condoms consistently.¹⁴

Role of Persistent Infection in Progression to Invasive Cervical Cancer

• The current etiologic model for the development of invasive cervical cancer highlights infection with high-risk HPV types as a necessary, but not sufficient, cause of cervical cancer. This model also incorporates the role of co-factors, such as smoking, nutritional deficiencies, oral contraceptive (OC) use, and parity status in the development of cancer.
• Persistent infection with high-risk types of HPV is necessary for the progression of high-grade lesions to invasive cancer.¹
• Certain HPV types (e.g., type 16) are more likely to induce progression toward malignancy.²
• Smoking is clearly associated with neoplastic progression.^2,17 Some, but not all, studies have demonstrated a longer persistence of infection among ever smokers than non-smokers.²⁵
• Recent studies have suggested that condom use reduces the risk of high-grade cervical lesions and increases HPV clearance.²⁶
• Women with human immunodeficiency virus (HIV) have prolonged HPV persistence, even if their CD4 counts are normal.²⁷
• Some studies have suggested that OC use and the presence of other STIs may act as co-factors in neoplastic progression, persistence of HPV infection, or both.¹ However, OC use may be a proxy for the behaviors associated with increased risk of HPV infection, which were listed previously. There is insufficient evidence to recommend that women who have infection with a high-risk HPV type should discontinue OC use.
• Persistence of infection with high-risk HPV leads to abnormal clonal progression in the cervical epithelium and eventually may lead to invasive cervical carcinoma.¹⁸
• Researchers believe that carcinoma develops from infections that persist with continued viral replication within the squamous epithelium.¹
• Infection with HPV type 16 tends to persist longer than infection with other HPV types.¹

References

1. Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006;24(Suppl 1):S4-15.
2. Munoz N, Castellsague X, de Gonzalez AB, Gissmann L. HPV in the etiology of human cancer. Vaccine. 2006; 24(Suppl 3):S1-10.
3. American Cancer Society. Cancer Facts and Figures. 2007. Available at: www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed March 20, 2007.
4. Parkin DM, Bray F. Chapter 2: the burden of HPV-related cancers. Vaccine. 2006;24(Suppl 3):S11-25.
5. Anhang R, Goodman A, Goldie SJ. HPV communication: review of existing research and recommendations for patient education. CA Cancer J Clin. 2004;54:248-59.
6. National Institutes of Health. Consensus development conference statement: cervical cancer. April 1–3, 1996. Accessed September 12, 2008.
7. Insinga RP, Glass AG, Rush BB. The health care costs of cervical human papillomavirus-related disease. Am J Obstet Gynecol. 2004 ;191(1):114-20.
8. Davey DD, Neal MH, Wilbur DC, Colgan TJ, Styer PE, Mody DR. Bethesda 2001 implementation and reporting rates: 2003 practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med. 2004;128(11):1224-9.
9. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention; Advisory Committee on Immunization Practices. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices. MMWR. 2007;56(RR-2):1-24.
10. Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36:6-10.
11. Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE. Prevalence of HPV infection among females in the United States. JAMA. 2007;297(8):813-9.
12. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102:3-8.
13. Schiffman M, Kjaer SK. Natural history of anogenital human papillomavirus and neoplasia. J Natl Cancer Inst Monogr. 2003;31:14–9.
14. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218-26.
15. Centers for Disease Control and Prevention. Human Papillomavirus: HPV Information for Clinicians. November 2006.
16. Hernandez BY, Wilkens LR, Zhu X, Thompson P, McDuffie K, Shvetsov YB. Transmission of human papillomavirus in heterosexual couples. Emerg Infect Dis. 2008; 14:888-92.
17. Burchell AN, Winer RL, de Sanjose S, Franco EL. Epidemiology and transmission dynamics of genital HPV infection. Vaccine. 2006;24(Suppl 3):52-62.
18. Moscicki A-B, Schiffman M, Kjaer S, Villa LL. Updating the natural history of HPV and anogenital cancer. Vaccine. 2006;24(Suppl 3):42-51.
19. Ho GYF, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338:423-8.
20. Lacey CJN, Lowndes CM, Shah KV. Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine. 2006;24(Suppl 3):35-41.
21. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsagué X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518-27.
22. de Villiers EM, Gunst K, Stein H, Scherübl H. Esophageal squamous cell cancer in patients with head and neck cancer: prevalence of human papillomavirus DNA sequences. Int J Cancer. 2004;109:253-8.
23. zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000;92:690-8.
24. Soper D. Reducing the health burden of HPV infection through vaccination. Infect Dis Obstet Gynecol. 2006;14:1-5.
25. Giuliano AR, Sedjo RL, Roe, DJ, Harris R, Baldwin S, Papenfuss MR, et al. Clearance of oncogenic human papillomavirus (HPV) infection: effect of smoking (United States). Cancer Causes Control. 2002;13:839-46.
26. Hogewoning CJ, Bleeker MC, van den Brule AJ, Voorhorst FJ, Snijders PJ, Berkhof J, et al. Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial. Int J Cancer. 2003;107:811-6.
27. Moscicki AB, Ellenberg JH, Farhat S, Xu J. Persistence of human papillomavirus infection in HIV-infected and -uninfected adolescent girls: risk factors and differences, by phylogenetic type. J Infect Dis. 2004;190:37-45.