Epidemiology of Human Papillomaviruses

Most HPV-infected individuals eliminate the virus without developing recognizable symptoms or complications. Nevertheless, genital HPV is a public health concern because persistent infection with certain types can lead to cervical cancer in some women. Genital HPV infections are categorized according to their differential risk for progression to cervical cancer. Infection with one or more of 10-15 low-risk HPV types can produce benign or low-grade cervical epithelial changes and genital warts. In contrast, infection with one or more of 15-20 high-risk HPV types can produce not only low-grade cervical abnormalities but also high-grade abnormalities that are precursors to cervical and other genital cancers. Although infection with high-risk types appears “necessary” for the development of cervical cancer, infection per se is not “sufficient” because cancer does not develop in the majority of infected women.

Incidence and Prevalence of HPV

The complexity and variability of the natural history of HPV infection make it difficult to gather precise estimates of the epidemiology of HPV infection. The vast majority of HPV infections are asymptomatic and >90% of infections clear within 2 years [Ho, NEJM 1998]. A number of infections persist, potentially leading to precancers or even invasive cervical cancer, while other infections are subclinical or asymptomatic, latent infections, which may reactivate later in life. Thus, it is often difficult to ascertain whether a newly-detected infection is recently-acquired or long-standing. Estimates of the prevalence of HPV infection reflect the “sum total” of infections that are newly-acquired, clearing, clinically-diagnosed, persistent, and subclinical/latent.

Another challenge is that prevalence estimates vary according to the study population (e.g., general population vs. college students or STD clinics with younger, more sexually-active populations), age-range of the populations studied, ethnicities, study design, specimen sampled, and the sensitivity of the HPV detection methods.

Moreover, in contrast to certain other infectious diseases, clinicians are not required to report cases of HPV infection to public health departments. Because of these limitations and complexities, epidemiologic estimates likely represent a rough approximation of the true scope and magnitude of the public health burden posed by HPV.

United States

HPV is thought to be the most commonly occurring STD in the U.S. About 20 million (or 15% of the 15-49 year old population) are currently infected with HPV, with 6.2 million people infected every year (Figure 9). At least 50% of sexually-active men and women will acquire genital HPV infection at some point in their lives, and at least 80% of these women will have acquired genital HPV by 50 years of age [CDC Fact Sheet].

Figure 9. Epidemiology of HPV Infection in the U.S.

Hierarchy of Clinically-apparent and Subclinical Infections

Genital warts (condylomata acuminata or condylomas) represent the “tip of the iceberg” of HPV infection (Figure 10). Of the estimated 148 million 15-49 year-olds in the U.S. in 2004: 1.5 million (1%) had clinically-apparent genital warts; 20.7 million (14%) had subclinical infection detected by colposcopy (5.9 million or 4%) and nucleic acid assays (14.8 million or 10%); 88.8 million (60%) were HPV negative but had antibodies to genital papillomaviruses, a likely indication of prior HPV infection [Koutsky, 1997].

Figure 10. Hierarchy of Clinically-apparent & Subclinical Human Papillomavirus Infections: U.S. Adults 15-49 Years of Age (2004)

This leaves only about 37 million people (or 25% of the population) that are likely to have never been infected with this virus.

Adolescents and Young Adults

The incidence and prevalence of genital HPV infection are especially high among adolescent and young-adult females as they initiate sexual activity and become exposed to HPV for the first time. In the U.S., about 9.2 million 15-24 year-olds are currently infected, representing almost half of all individuals currently infected with HPV (see Figure 9). Moreover, an estimated 4.6 million new cases of HPV are acquired every year among 15-24 year olds, representing nearly three quarters (74%) of all incident infections.

The high rate of HPV infection in young women is evident in epidemiologic studies evaluating the cumulative incidence of newly-acquired HPV infections over time. For example, in a Seattle study of college-aged virgins who were HPV negative at time of study entry and then became sexually-active by engaging in penetrative sex with a male partner, greater than 50% acquired a new genital HPV infection by 4 years after first sexual intercourse [Winer, 2003] (Figure 11).

Figure 11. Cumulative Incidence of HPV Infection Among College Students in the U.S.

In this study, the minimum time period between first sexual exposure and detection of HPV DNA was less than 1 month.

Age-specific Prevalence in Women

As a result of the high rate of newly-acquired HPV infections in young women, the prevalence of HPV infection increases dramatically between ages 15 and 24, reaching 28-46%. After reaching a peak in late adolescence/early adulthood (20-24 years), the prevalence of HPV declines with increasing age [Burk, Sex Transm Dis, 1996] (Figure 12).

Figure 12. Age-specific Prevalence of Gental HPV Infection in a Cohort of Sexually-active Inner City Women, age 18-50 years (n=439)

The high rate of genital HPV infection in younger women is thought to reflect newly sexually-active women being exposed to HPV for the first time (newly-acquired infections), with infection clearing over time in most women. The prevalence of HPV declines in older women, presumably due to the acquisition of protective immunity following infection earlier in life and/or reduced exposure to HPV over time, perhaps as a result of less-frequent sexual activity.

Men

HPV infection appears to be very common in men, though it has not been studied as extensively as in women. Although HPV DNA can be detected at various anogenital sites, including the penis, urethra, scrotum, or anus, as well as in urine and semen, it is not clear which anatomic sites or specimens are optimal to test [Baseman & Koutsky, 2005]. Genital HPV infection ranges from 16–45%, depending on the anatomic sites or specimens tested.

Changes over Time

Sensitive assays for the detection of HPV infection have been developed only in the last few decades, so it is unclear whether the rate of HPV infection has changed over time in the U.S. There is indirect evidence, however, based on first office visits to physicians for genital warts (data compiled by the CDC) that the incidence of clinically-diagnosed HPV infection has increased dramatically over time. One explanation for this trend is that today people are more likely than those in previous generations to have multiple sex partners during their lives, a consequence of becoming sexually-active earlier yet marrying later and divorce being more common.

Economic Burden

Total direct costs associated with HPV infection and cervical HPV-related disease include routine screening for cancer prevention, follow-up of abnormal Pap smears, detection of cervical intraepithelial neoplasia (CIN), and treatment of warts and invasive cervical cancer. Each year in the U.S. approximately $3.5 billion is spent on cervical HPV-related disease [Insinga, 2004] (Figure 13).

Figure 13. Estimated Total Annual Healthcare Costs for Cervical HPV-related Disease

In the U.S., annual health care costs for cervical HPV-related disease are greater than for other common STDs, except HIV/AIDS (Table 6).

Table 6. Total Annual Healthcare Costs of STDs in the U.S.

Transmission of HPV

The transmission of genital HPV occurs predominantly via sexual contact. However, non-sexual routes also have been suggested (such as through fomites or vertical transmission). These latter routes are considered to be uncommon (Figure 14).

Figure 14. Routs of HPV Transmission

Genital contact, usually through sexual intercourse, with an infected partner appears to be necessary for HPV transmission. HPV infects the epithelium presumably via mechanical abrasion, resulting in microscopic tears in the mucosa or skin. Most HPV infections have no signs or symptoms; therefore, most infected persons are unaware they are infected, yet they can transmit the virus to a sex partner. Other types of genital contact, in the absence of penetrative intercourse (oral-genital, manual-genital, and genital-genital contact), may lead to HPV infection, but these routes of transmission are less common than sexual intercourse. For instance, a study of college-aged women in Seattle reported a two-year genital HPV incidence rate of 39% among sexually-active women and only 8% among women who had not engaged in penetrative vaginal intercourse [Winer, 2003].

It has been hypothesized, but not adequately documented, that HPV transmission may occur via inanimate objects (fomites) such as environmental surfaces and clothing. Rarely, mother-to-newborn or vertical transmission may occur, in which HPV infection is acquired by a newborn baby after passing through the mother’s infected genital tract. Vertical transmission of HPV may lead to recurrent respiratory papillomatosis (RRP), benign epithelial growths in the respiratory tract [Bonnez, 2005].

Risk Factors for Acquisition of HPV

Risk factors for acquiring HPV most commonly are proxies for the likelihood that a sexual partner is infected. In addition to sexual behavior, other potential risk factors include smoking, oral contraceptive (OC) use, nutritional factors, and immune status; however, their role is unclear because it is difficult to distinguish between factors that truly increase the risk of HPV infection from those that merely facilitate the detection of previously-acquired latent or subclinical HPV disease.

Sexual Behavior

Women

A greater number of sexual partners, both lifetime (Figure 15) and recent, increases a woman’s risk of acquiring HPV infection [Burk, JID, 1996].

Figure 15. Prevalence of HPV Infection in Women as a Function of Lifetime Number of Sexual Partners

Similar to infection with other STDs, having sex with a new partner may be an even stronger risk factor for genital HPV infection than both lifetime and recent number of sexual partners, since a woman’s risk of HPV infection is influenced by the sexual history of her male partner. College-aged women with male sex partners who had at least one prior partner had a 5-fold increased risk of genital HPV infection compared to those whose male partners had no prior partners. Women whose male partners had an unknown number of prior sex partners had an 8-fold increased risk for acquiring genital HPV infection. Moreover, women who had known a new sex partner for at least 8 months before initiating a sexual relationship were less likely than those who had sex earlier to acquire genital HPV infection [Winer, 2003]. This is perhaps due to the fact that the elapsed time allowed for spontaneous clearance of HPV infection (which has a median duration of 8 months) in male partners who might have been infected from a previous sexual relationship.

Men

Similar to women, greater lifetime number of sex partners, and greater number of sex partners in the last year increase a man’s risk for acquiring HPV infection. In contrast to women, while young age (25-29 years) has been suggested to increase risk for HPV infection in men, this relationship does not appear to be as consistent in men as it is in women.

Uncircumcised males have an increased likelihood of acquiring HPV infection; however, the mechanisms by which removal of the foreskin protects against HPV infection are not yet clear [Castellsague, 2002]. One possibility is that circumcision increases the probability of maintaining good penile hygiene; another is that the glans of a circumcised penis has a thicker, cornified epithelium, which makes it more resistant to small abrasions and less susceptible to HPV entry.

Evidence suggests that latex condoms provide a barrier to particles the size of HPV. Although HPV infections are primarily located on areas of the penis covered by a condom they also may occur on other uncovered sites such as the scrotum, groin, base of the penis, and anus. In women, HPV may be found on the outside of the vulva, which can come into contact with the genital skin of a man using a condom, so even consistent and correct use of condoms may not offer complete protection.

Condom use may afford some degree of protection in reducing the risk of HPV-associated diseases, including warts in men and cervical neoplasia (cervical cancer precursors and invasive cancer) in women [Manhart & Koutsky, 2002]. Moreover, for women and men, use of condoms reduces the risk of acquiring genital herpes and chlamydia, both of which may be cofactors for the development of cervical cancer.

Table 7. Risk Factors for HPV Infection

Adolescents

Both young age and young age at first sexual intercourse are risk factors for acquisition of HPV, perhaps because of biological, behavioral, and emotional changes that occur during adolescence [ACOG Committee Opinion #301, 2004].

One biologic change that has been identified is the environment of the cervix, which may be more permissive for HPV infection in adolescent females than older women. In addition, adolescents who engage in sexual intercourse at a young age are more likely than those who wait until an older age to have multiple sexual partners, to have had unwanted sex, and less likely to use barrier protection. In the U.S. in 2003, 28% of girls in the 9th grade and 62% of girls in the 12th grade reported having had sexual intercourse [Grunbaum, MMWR, 2004] (Figure 16).

Figure 16. Percentage of U.S. High School Students Reporting Sexual Debut (Intercourse), 2003

Although approximately two-thirds of adolescents self-reported using condoms, only 45% used condoms consistently. In addition, although many adolescents reported that they have had only 1 sexual partner, 14.4% of all high school students (including 18% of females and 22% of males in the 12th grade) who participated in the CDC Youth Risk Behavior Survey already had four or more sexual partners during their lifetime.

Depending on their level of maturity, some adolescents may not be able to comprehend the consequences of risky behaviors. Alcohol or drug use that impairs judgment can increase the likelihood of engaging in sexual intercourse without a condom, with multiple partners, or with high-risk partners.

Lifestyle/Other Risks

Oral contraceptive use and smoking may increase the risk of HPV infection/detection, although the available data are still inconclusive and controversial. It is difficult to discern whether OC use or smoking are true, independent risk factors for HPV infection, or merely surrogate markers for high-risk sexual behaviors (e.g., acquisition of a new partner, lifetime number of sexual partners) that predispose individuals to HPV infection [Baseman & Koutsky, 2005].

The immune status of the host appears to have a significant impact on the ability to detect genital HPV infection. Studies in women with HIV infection, undergoing dialysis, or after a kidney transplant, demonstrate that HPV detection is particularly common with immune suppression. It is not clear, however, whether impaired immune status plays a significant role in acquisition of HPV or whether it primarily affects the body’s ability to clear or suppress latent infection [Koutsky, 1997].

References

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Burk RD, Ho GY, Beardsley L, et al. Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women. J Infect Dis. 1996;174(4):679-689.

Burk RD, Kelly P, Feldman J, et al. Declining prevalence of cervicovaginal human papillomavirus infection with age is independent of other risk factors. Sex Transm Dis 1996;23(4):333-341.

Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. New England Journal of Medicine 2002;346(15):1105-1112.

Centers for Disease Control and Prevention Fact Sheet. Genital HPV Infection.1-5.

Chesson HW, Blandford, JM, Gift TL, et al. The estimated direct medical cost of sexually transmitted diseases among American youth 2000. Perspectives on Sexual Health and Reproductive Health. 2004,36(1):11-19

Grunbaum JA et al. MMWR Surveill Summ 2004;53(2):1-96.

Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. New England Journal of Medicine 1998;338(7):423-428.

Insinga RP, Glass AG, Rush BB. The healthcare costs of cervical human papillomavirus-related disease. Am J Obstet Gynecol. 2004;191(1):114-20.

Koutsky L. Epidemiology of genital human papillomavirus infection. Am J. Med. 1997;102(5A):3-8.

Manhart LE, Koutsky LA. Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis. Sexually Transmitted Diseases 2002;29(11):725-735.

Winer RL, Lee SK, Hughes JP, et al. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157(3):218-226.

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