Epidemiology of human papillomavirus infections

Author
Joel M Palefsky, MD
Section Editor
Martin S Hirsch, MD
Deputy Editor
Allyson Bloom, MD
Disclosures: Joel M Palefsky, MD Grant/Research/Clinical Trial Support: Merck and Co [HPV infection
(Quadrivalent and nonavalent HPV vaccines)]; Hologic [HPV infection (HPV assay)]. Consultant/Advisory Boards:
Merck [HPV infection (Quadrivalent and nonavalent HPV vaccines)]; TheVax [HPV infection (therapeutic HPV
vaccine)]; Hera Therapeutics [HPV infection (HPV therapeutics)]. Martin S Hirsch, MD Nothing to disclose. Allyson
Bloom, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2015. | This topic last updated: Sep 25, 2014.
INTRODUCTION Papillomaviruses are double-stranded DNA viruses that constitute the
Papillomavirus genus of the Papillomaviridae family. These viruses are highly species specific;
human papillomaviruses (HPV) infect only humans. There are more than 100 types of HPV, which
can be subdivided into cutaneous or mucosal categories based upon their tissue tropism.
The epidemiology and disease associations of HPV infections will be reviewed here. The clinical
manifestations, diagnosis, treatment, and prevention of these infections and their association with
malignancy are discussed separately. (See "Virology of human papillomavirus infections and the
link to cancer" and "Recommendations for the use of human papillomavirus vaccines".)
TISSUE TROPISM Different human papillomavirus (HPV) types have a propensity to infect
different body sites (table 1).
Cutaneous Certain HPV types have a predilection for cutaneous epithelium and are found in
plantar warts, common warts, flat warts, and butcher's warts [1]. HPV types associated with plantar
and common warts include type 1 and types 2 and 4, respectively. Flat warts are most often caused
by HPV types 3 and 10, while butcher's warts (common warts that tend to occur in meat, poultry,
and fish handlers) are most often associated with HPV types 7 and 2 [2].
Bowen's disease, a form of high-grade intraepithelial neoplasia, has both genital and extragenital
forms [3]. It can occur on the fingers, toes, palms, feet, and on the genital mucosa. Multiple HPV
types have been isolated from these lesions; including HPV types 16, 18, 31, 32, 34, and others
[1,3,4].
Epidermodysplasia verruciformis is a rare, probably autosomal recessive condition, characterized
by the appearance of HPV-induced wart-like lesions early in childhood, with malignant
transformation in approximately half of patients during adulthood, often in skin surfaces with sun
exposure. Multiple HPV types have been isolated from these lesions, but HPV types 5 and 8 appear
to have the most malignant potential in these individuals [5].

Anogenital epithelium HPV types with a predilection for anogenital keratinized skin and
mucous membrane infection also exist. Common sites for infection include: the penis, scrotum,
perineum, anal canal, perianal region, vaginal introitus, vulva, and cervix. The major manifestations
of anogenital HPV include:
Genital warts (condyloma acuminatum) Condylomata acuminata (also known as genital or
venereal warts) are benign anogenital warts, caused most often by HPV types 6 and 11 [6,7].
(See "Condylomata acuminata (anogenital warts) in adults".)
Squamous intraepithelial lesions and/or carcinoma of the vagina, vulva, cervix, anus or penis
HPV infection has been clearly linked to all or nearly all squamous intraepithelial lesions and
cancers of the cervix and anus. HPV is also linked to a subset of penile, vulvar, and vaginal
cancers. Of the 14 most common oncogenic HPV types associated with these cancers, HPV
16 is the most common and associated with the highest risk of progression to cancer [2,4,6,810].
The presence of a cervical transformation zone is not necessary for oncogenic HPV to infect the
female genital tract. As a result, the prevalence of oncogenic HPV subtypes in the vagina is similar
in women who have and have not undergone hysterectomy [11]. Similarly, HPV may infect not only
the anal canal in the anal transformation zone, but also more distal sites, including the keratinized
skin of the anal verge and perianal region [12,13]. (See "Virology of human papillomavirus infections
and the link to cancer" and "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis,
and prevention" and "Anal squamous intraepithelial lesions: Diagnosis, screening, prevention, and
treatment" and "Vaginal intraepithelial neoplasia" and "Vulvar intraepithelial
neoplasia" and "Carcinoma of the penis: Epidemiology, risk factors, staging, and prognosis".)
Other mucosal surfaces An increasing body of evidence suggests a relationship between HPV
infection, particularly with HPV type 16, and squamous cell carcinoma of the oral cavity, especially
in those less than 50 years of age [14,15]. Infection of the respiratory mucosa with HPV types 6 and
11 also occurs, particularly but not exclusively in young children and infants [6].
DETECTION OF HPV HPV infection can be detected by several molecular methods, but only
testing of cervical cytological or biopsy specimens is currently clinically available. Staining of
histology specimens for HPV antigens such as capsid proteins or early region proteins such as E6
or E7 (ie, from tumor resection) can also be performed, but their clinical utility is uncertain and these
tests are not readily available. In the United States, there are no FDA-approved tests clinically
available to detect HPV infection of oropharyngeal, anal, or male genital specimens. There are also
no FDA-approved serological or blood tests to detect HPV infection.
HPV testing on cervical specimens and molecular testing methods are discussed in detail
elsewhere. (See "Cervical cancer screening tests: Techniques for cervical cytology and human
papillomavirus testing", section on 'HPV testing' and "Virology of human papillomavirus infections
and the link to cancer", section on 'Detecting HPV'.)
DISEASE ASSOCIATIONS
Nongenital warts Cutaneous human papillomavirus (HPV) infections are widespread throughout
the general population. Warts occur in 10 percent of children, with a peak incidence between the
ages of 12 and 16 [16]. Nongenital warts are not confined solely to the pediatric population; as
many as 3.5 percent of adults have nongenital warts at any given time [6]. Common warts represent

up to 71 percent of all cutaneous warts followed in frequency by plantar warts and flat warts (34 and
4 percent, respectively) [2]. Cutaneous warts can present in patients in ages ranging from 2 to 80
years. Only 16 percent of patients are over the age of 35, but in one report accounted for 11
referrals per 1000 patients annually [17].
Genital warts Population-based studies in sexually active individuals suggest that the burden of
genital warts is high, with a prevalence ranging from 1 percent in the United States to approximately
10 percent in Scandinavian countries [16,18-20]. The peak prevalence occurs in persons between
the ages of 17 and 33 years of age, and the peak incidence is in those from ages 20 to 24 years.
The incidence of HPV infection was evaluated in 8702 women who were enrolled in the placebo
arms of two randomized trials of HPV quadrivalent vaccine [21]. Approximately 3 percent developed
genital warts over four years. In a multinational cohort of 2487 healthy men, 4.5 percent developed
genital warts over a median of 18 months [22]. Risk factors for genital warts in women and men
included baseline and incident infection with HPV types 6 and 11, acquisition of new sexual
partners, and a higher number of sexual partners.
Men and women with anogenital warts frequently experience psychological distress and disruption
of sexual relationships [23,24]. (See "Condylomata acuminata (anogenital warts) in adults".)
Cervical cancer Worldwide, an estimated 500,000 cases of invasive cervical carcinoma are
diagnosed annually [25]. Cervical carcinoma was the most frequent malignancy among women in
developing countries until it was surpassed by breast cancer in the early 1990s [4]. (See "Virology
of human papillomavirus infections and the link to cancer" and "Cervical intraepithelial neoplasia:
Terminology, incidence, pathogenesis, and prevention" and "Invasive cervical cancer: Epidemiology,
risk factors, clinical manifestations, and diagnosis".)
Evidence linking HPV to cervical carcinoma is extensive [2,4,8,26], with HPV 16 accounting for
approximately 50 percent of cases and HPV 18 for 20 percent [27]. The epidemiology of high-risk
types can be illustrated by the following observations:
A study of paraffin-embedded samples representing 10,575 cases of invasive cervical cancer
from 38 countries spanning five continents demonstrated that the most common HPV types
were 16, 18, 31, 33, 35, 45, 52 and 58; HPV types 16 and 18 represented 71 percent of the
cases overall.
A pooled analysis of 11 case-control studies from nine countries involving 1918 women with
histologically confirmed squamous-cell cervical cancer and 1928 controls was performed to
better determine the risk associated with various HPV genotypes [28]. HPV DNA was found in
90 percent of the women with cervical cancer and 13 percent of controls. Fifteen HPV types
were classified as high risk (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and
82).
The prevalence of antibodies against HPV 16, the most commonly identified high-risk type,
was evaluated in almost 1600 men and women attending sexually transmitted diseases clinics
in the United States [29]. The seroprevalence of HPV 16 was 19 percent in men and 30
percent in women.
The high frequency of infection with high-risk types illustrates the potential significance of
vaccination efforts against HPV. (See "The life cycle, natural history, and immunology of human
papillomaviruses".)

A detailed discussion of other risk factors for cervical cancer is found elsewhere. (See "Invasive
cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on
'Epidemiology and risk factors'.)
Anal cancer Although a relatively uncommon cancer, the incidence of anal cancer in the United
States has increased substantially in the last three decades [30]. Most of these cases are
attributable to HPV infection, with similar high-risk types as found in cervical cancer, particularly 16
and 18 (see above). The epidemiological link of HPV infection to anal cancer is discussed in detail
elsewhere. (See "Classification and epidemiology of anal cancer", section on 'Human
papillomavirus infection'.)
Cancer of the external genitalia HPV is also linked to penile, vulvar, and vaginal cancers.
Unlike cervical and anal cancer, however, not all cancers of the external genitalia are associated
with HPV infection. In contrast to HPV-negative cancers, which are often associated with chronic
inflammation or lichen sclerosis, HPV-associated penile and vulvar cancers occur at a younger age,
exhibit basaloid instead of keratinizing pathology, do not have p53 mutations, and are associated
with sexual risk factors [31,32].
The epidemiological link of HPV infection to these cancers is discussed in detail elsewhere.
(See "Carcinoma of the penis: Epidemiology, risk factors, staging, and prognosis", section on
'Human papillomavirus infection' and "Vulvar cancer: Clinical manifestations, diagnosis, and
pathology", section on 'Epidemiology and risk factors'and "Vaginal cancer", section on
'Epidemiology and risk factors'.)
Oropharyngeal cancer HPV infection may also play a role in the pathogenesis of squamous cell
carcinomas of the head and neck. However, there are currently no clinically available tests for
detection of oropharyngeal HPV infection. Furthermore, it is as yet uncertain what the actual risk for
cancer of an individual HPV infection is and whether detecting infection would be clinically useful.
The available data on oropharyngeal HPV infection highlight that it is associated with sexual risk
factors, that it is not as common as genital HPV infection, and that detecting oropharyngeal HPV
infection at a single time-point likely has little value in assessing the risk for cancer development.
Like penile and vulvar cancer, oropharyngeal cancers consist of two broad categories of disease:
HPV-associated and non-HPV-associated. HPV-associated oropharyngeal cancers are primarily
found in the oropharynx and base of the tongue and tonsil [33-35]. HPV has also been linked to
cancer of the larynx [36]. (See"Human papillomavirus associated head and neck cancer".)
HPV-related oropharyngeal cancers occur in a younger population than the non-HPV-associated
cancers and are primarily associated with sexual risk factors [37,38]. In contrast, the non-HPVassociated cancers are associated primarily with alcohol and tobacco use and often have p53
mutations. In the United States, the incidence of HPV-associated cancers has been rising and the
incidence of non-HPV-associated cancers has been declining, such that the incidence of the former
now exceeds that of the latter [30,38]. In an age and gender-matched case-control study of 130
patients with newly diagnosed squamous cell carcinoma of the head and neck, oropharyngeal
malignancy was associated with high-risk sexual behaviors, oropharyngeal HPV infection, and HPV
16 seropositivity [33].
The prevalence of oropharyngeal HPV is generally lower than that of anogenital HPV infection
[35,39-41]. The prevalence of oropharyngeal HPV infection was evaluated in a cross-sectional

study of 5579 women and men who provided an oral sample for HPV DNA sampling [35]. The
overall prevalence of any HPV DNA was 6.9 percent, and the prevalence of HPV type 16 was 1
percent. HPV prevalence was approximately threefold more common in men compared with women
(10.1 versus 3.6 percent), consistent with the observed sex distribution for HPV-associated
oropharyngeal cancer. Oropharyngeal HPV prevalence has been associated with a greater number
of sexual (including oral sex) and open-mouthed kissing partners in both men and women, as well
as with older age and smoking [35,39,42,43].
Similarly, the incidence of oropharyngeal HPV is lower than that of anogenital HPV infection. In a
study of 1626 men aged 18 to 70 years (88 percent men who have sex with women only) without a
prior history of HPV-associated disease and with a median follow-up of 13 months, 4.4 percent
acquired an oropharyngeal infection with any HPV type and 1.7 percent with an oncogenic HPV
type [44]. The incidence of oropharyngeal HPV infection was 5.6 and 2.5 cases per 1000 personmonths for any and oncogenic types, respectively, and was constant across all age groups. In
multivariate analysis, acquisition of a new oncogenic oropharyngeal HPV infection was associated
with former or current smoking and single/divorced/separated/widowed marital status, but not with
number of sexual partners or oral sex partners. Of the infections with enough longitudinal follow-up,
45 of 81 (56 percent) oral infections with any type and 18 of 24 (75 percent) infections with
oncogenic types spontaneously cleared, at a median of six to seven months.
There is emerging evidence that HPV vaccination can also protect against oropharyngeal HPV
infection [45]. (See "Recommendations for the use of human papillomavirus vaccines", section on
'Oral disease'.)
Recurrent respiratory papillomatosis Recurrent respiratory papillomatosis (RRP) is the most
common benign laryngeal tumor in children and is thought to be caused by HPV acquired during
passage through the birth canal of an infected mother [46]. HPV 6 and 11 are the types most
commonly involved. The incidence is uncertain but has been estimated at 4.5 per 100,000 children
and 1.8 per 100,000 adults in the United States. Although benign, substantial morbidity arises from
obstruction of the larynx by the warts, and many affected children require multiple ablative
procedures [46,47]. In addition, the papillomatous lesions can rarely grow aggressively, spread into
the lungs, and undergo malignant transformation.
This condition is discussed in further detail elsewhere. (See "Hoarseness in children: Etiology and
management", section on 'Papillomatosis (HPV)'.)
RISK FACTORS FOR INFECTION Human papillomavirus (HPV) is spread from skin surface to
skin surface. Close personal contact is assumed to be of importance for the transmission of
cutaneous warts [2], while anogenital warts and HPV infection of the cervix are primarily transmitted
by genital-genital, oral-genital, anal-genital, or oral-anal contact [2,26]. However, HPV types
typically isolated from common warts (types 1 and 2) have been isolated from anogenital warts in
children, and infection of the respiratory tract mucosa (recurrent respiratory papillomatosis) is
thought to occur during passage of the fetus through an infected birth canal. (See "Hoarseness in
children: Etiology and management", section on 'Papillomatosis (HPV)'.)
The most consistent predictor of genital HPV infection has been sexual activity [48,49]. Most studies
have been performed in young women in whom the following findings have been noted:

The risk of HPV infection in women is directly related to the number of male sex partners
[18,48,50-55] and to the male partners' number of female sex partners [48].
As with other sexually transmitted infections, sex with a new partner is a stronger risk factor
than sex with a steady partner [51,54]. In a prospective cohort study of young women in San
Francisco, for example, the relative hazard was 10.1 per new partner per month [54].
Both vaginal and anal intercourse are major risk factors for HPV infection [48]. Although penetrating
vaginal intercourse is not required for transmission [51], the prevalence of HPV infection is much
lower among virgins (4 versus 22 percent in sexually active women in a report from Sweden) [53].
In one study of adolescent females with no reported history of sex, genital HPV infection was noted
in 8 percent and was associated with intravaginal cleansing, but this observation could simply
reflect unreported or nonpenetrating sexual activity [56,57]. Anal intercourse is likely an efficient
means of spread of HPV to the anal canal but it is similarly not required for transmission; other
types of contact may also play a role in transmission, such as spread through fingers or toys, or
from other genital organs infected with HPV [51,58,59].
Among heterosexual couples, type-specific concordance (ie, both partners infected with the same
HPV type) is common, almost 25 percent in one series [60]. Additionally, among discordant
heterosexual couples, female to male transmission may occur at a higher rate than male to female
transmission [61]. Transmission in either direction is typically asymptomatic [18,62].
In several studies of women, the presence of anti-HPV antibodies, indicative of prior infection, has
been associated with a decreased risk of subsequent infection with HPV of the same type,
particularly for type 16, suggesting the potential for protective immunity following natural infection
[63-65]. However, the extent and duration of such protection is unknown, and many women do not
develop antibodies following infection [66-68].
EPIDEMIOLOGY IN FEMALES A meta-analysis in 157,879 women with normal cervical cytology
demonstrated that the worldwide point-prevalence of human papillomavirus (HPV) is approximately
10 percent [69]. The highest regional prevalence was found to be in Africa, where 22 percent of
women had evidence of HPV infection. The most common types worldwide were HPV 16 and 18,
both of which are preventable by vaccination. (See "The life cycle, natural history, and immunology
of human papillomaviruses".)
The prevalence of cervical HPV infection decreases sharply in women after the age of 30 [70].
Those with persistent infection are at the highest risk for the development of high-grade squamous
intraepithelial lesions or invasive cervical cancer [70]. (See 'Cervical cancer' above.)
United States The estimated prevalence of anogenital tract HPV infections in the United States
is 20 million, with an annual incidence of 5.5 million. It has been estimated that 75 to 80 percent of
sexually active adults will acquire a genital tract HPV infection before the age of 50 [71]. Two
longitudinal studies have also demonstrated that acquisition of cervical HPV infection also predicted
acquisition of an anal HPV infection [72,73].
Genital HPV infection is common in young sexually active women in the United States, as illustrated
by the following observations among different age groups [48,50,51,74-76]:
The National Health and Nutrition Examination Survey (NHANES) assessed the prevalence
of HPV infection in the United States by collecting vaginal swabs for HPV DNA in 1921 women

[74]. The overall prevalence was 27 percent and was highest among females aged 20 to 24
years (45 percent). The prevalence of the specific types contained within the quadrivalent HPV
vaccine (ie, types 6, 11, 16, and 18) was 17, 7, 16, and 7 percent, respectively [77]. (See "The
life cycle, natural history, and immunology of human papillomaviruses".)
In a series of 312 urban adolescent girls (mean age 16) with a median of two years of sexual
activity and four lifetime sex partners, cervical HPV was detected in 64 percent using
polymerase chain reaction (PCR)-based testing [50]. Another study demonstrated that the
one-year cumulative incidence of initial HPV infection in 244 female college students was 29
percent after their first male sexual partner [75].
A prospective study evaluated 608 female college students at six-month intervals for three
years; the evaluation included cervicovaginal lavage that was tested for HPV DNA [48]. At
entry, 26 percent were HPV-positive. Among those who were HPV-negative, 43 percent
acquired HPV during the three-year follow-up. A similar rate of new disease acquisition (32
percent in two years) was noted in another report of 603 female university students [51]. Longterm follow-up of a subset of these patients with HPV infection at baseline (n = 156)
demonstrated persistence of the same HPV type in 4.8 percent (over an average of four
years) in association with pathologic changes [78].
In a review of over 3800 women 18 to 40 years of age, the overall HPV prevalence was 39
percent [52]. Detection of high-risk and low-risk HPV genotypes declined with increasing age.
In a seroepidemiologic study of injection and noninjection drug users (median age 24 years),
HPV 16 seroprevalence was 38 percent and HPV 18 seroprevalence was 42 percent [79].
The above data reflect the overall prevalence of HPV infection. However, many sexually active
young women have sequential infections with different oncogenic types of HPV. These infections
are usually detected transiently, although they frequently produce reversible cytologic changes.
There may be racial differences in the type and turnover of HPV infection in women [80-82]. These
differences are illustrated by the findings of a longitudinal study of 467 college-age women in the
United States [80]. The overall incidence of HPV infection was similar between black and white
women, but black women had a slightly higher incidence of infection with high-risk HPV types. Two
years after the incident high-risk HPV infection, more black women had persistent infection (56
versus 24 percent of white women). These findings might contribute to the higher incidence of
cervical cancer in black women in the United States. (See "Invasive cervical cancer: Epidemiology,
risk factors, clinical manifestations, and diagnosis", section on 'Incidence and mortality'.)
Among older women, the prevalence of HPV detection may be related more to reactivation of
infection acquired previously than to new, recent infections. In a cohort of over 800 women aged 35
to 60 years, the attributable risk for high-risk HPV detection associated with a history of more than
five lifetime sexual partners was greater than that associated with a new sexual partner among
women older than 50 years (87 versus 8 percent) [83]. In contrast, among women 35 to 49 years,
the attributable risks associated with lifetime and recent sexual partners were the same (28
percent). That this reflects reactivation of infection in older women is only one interpretation of the
data, but raises important questions about the cause and importance of reactivation HPV [84,85].
Reactivation has also been proposed as a major source of newly detected HPV infection among
HIV-infected women. In a prospective study of 1848 HIV-infected women (the Womens Interagency
HIV Study), more than half of the women with newly detected cervical HPV infection had reported
no new sexual partners since the prior visit [86].

Studies of anal HPV infection in women suggest that it is far more common than originally thought
[87-89]. In studies of high-risk women, including HIV-infected women and women with a history of
commercial sex work or injection drug use, anal HPV infection is more common than cervical HPV
infection [90]. In studies of lower-risk women, the prevalence and incidence of anal HPV infection is
similar to that of cervical HPV infection [72,88]. Women with a history of vulvar or cervical highgrade squamous intraepithelial lesions or cancer are also at increased risk of anal HPV infection
and HPV-related disease. In one study of women with cervical or vulvar high-grade squamous
intraepithelial lesions, 12 percent had an anal squamous intraepithelial lesion and 9 percent had an
anal high-grade squamous intraepithelial lesion [91]. In these studies anal intercourse was not a
consistent risk factor for either anal HPV infection or anal squamous intraepithelial lesions.
Despite the frequency of anal HPV infections in women, they are often detected only transiently
[87,92]. In one study of 431 sexually active women, half of whom had incident anal HPV infections,
more than 58 percent became HPV DNA test-negative over a 15-month period of follow-up [87].
This observation may help explain why the incidence of anal cancer is much lower than that of
cervical cancer [93].
Worldwide There appears to be geographic variation in the distribution of HPV genotypes. For
example, in an HPV prevalence study conducted in 13 areas from 11 countries (Nigeria, India,
Vietnam, Thailand, Korea, Colombia, Argentina, Chile, the Netherlands, Italy and Spain), 15,613
sexually active women (15 to greater than 65 years of age) with normal cervical cytology were
selected for HPV screening by polymerase chain reaction (PCR) [94]. HPV positive women in
Europe were significantly more likely to be infected with HPV 16 than were those in sub-Saharan
Africa (OR 2.6).
A study of HPV prevalence was performed in Uganda in a cohort of 1275 sexually active women
aged 12 to 24 years seeking health services at a local clinic [95]. The prevalence of HPV and HIV
infections was 75 and 9 percent, respectively. Among high-risk types, the most frequently detected
were HPV 52 (13 percent), HPV 51 (12 percent), HPV 18 (11 percent), and HPV 16 (11 percent).
In contrast, in a study of 2185 sexually active women recruited from universities in the United
Kingdom, the prevalence of high-risk HPV infection, detected by testing of self-collected vaginal
swabs, was 19 percent [96]. While HPV 16 was the single most common type detected, most of the
women were infected with at least one nonvaccine HPV type.
EPIDEMIOLOGY IN MALES Factors associated with prevalent human papillomavirus (HPV)
infection in men include HIV infection, current and past sexual behavior, number of sex partners,
absence of condom use, prior sexually transmitted diseases, race, ethnicity, and circumcision status
[97-103]. Natural history studies demonstrate that uncircumcised men have slower rates of HPV
clearance compared with circumcised men [104].
In a systematic review of articles published from 1990 to 2006, HPV prevalence in men ranged from
1 to 73 percent [62]. This wide range of prevalence was attributed to a combination of factors,
including the anatomic sites sampled, number of specimens processed, and methods of detection
used. A consistent finding among demographic groups is an association of increased sexual activity
and high-risk HPV genotypes.
Men who have sex with men The burden of anogenital HPV infection among men who have
sex with men (MSM) is high [101,103,105], including among teenaged and young MSM under 30

years [106,107]. In a meta-analysis of 53 observational studies, the pooled prevalence for anal
infection with any HPV type and any high-risk HPV type in HIV-uninfected MSM was 64 and 37
percent, respectively [103]. The largest of these studies evaluated 1218 HIV-uninfected MSM
between the ages of 18 and 89 years in four American cities [105]. Demographic data and
information on sexual practices were collected and specimens from the anal canal were tested for
the presence of HPV infection by polymerase-chain reaction. The following findings were noted:
The overall prevalence of anal HPV infection was 57 percent.
Prevalence did not vary across age groups.
The most common HPV type was HPV 16, a high-risk type for anal cancer.
In a multivariate analysis, anal HPV infection was independently associated with a history of
receptive anal intercourse (odds ratio 2) and with more than five sex partners during the preceding
six months (odds ratio 1.5). Another study that assessed the baseline prevalence of penile, scrotal,
perineal and intra-anal HPV infections among 602 HIV-uninfected MSM found anal infections to be
the most common site of involvement (42 percent) [101].
Among men with HIV infection, the prevalence of anal HPV infection appears to be even higher.
(See 'Effect of HIV infection on HPV' below.)
Heterosexual men HPV genital infection is common among heterosexual men, as shown by the
findings of the human papillomavirus in men (HIM) study, which follows a large prospective cohort
of HIV-uninfected men from the United States, Mexico, and Brazil:
Among 3326 heterosexual men, the prevalence of genital HPV of any type was 53 percent
[108]. Almost one-third of study participants were infected with oncogenic HPV types. Factors
associated with oncogenic HPV infection included smoking, heavy alcohol use, and a higher
numbers of female sexual partners, whereas condom use was associated with a reduced
likelihood of HPV infection.
The 12-month incidence of genital HPV among 1159 men (about 90 percent of whom were
heterosexual) was 39 and 27 percent for any type and oncogenic types, respectively [109].
The overall median time to clearance of HPV infection was 7.5 months, although it was one
year for HPV type 16.
Other smaller studies of men in the United States have shown comparable HPV rates and
associated factors [110-112]. These rates may differ in various regions of the world. A study of 776
heterosexual HIV-uninfected men in rural Uganda reported a high incidence of oncogenic genital
HPV infection (33 cases per 100 person years) [113]. The risk of infection decreased with age,
married status, and circumcision; condom use had no association. In another study of 3463
heterosexual men from Latin America, North America, Africa, Europe, and Asia, the prevalence of
genital HPV was 21 percent for any type, although fewer types were tested for in this study [100].
Neither condom use nor circumcision was associated with HPV infection. The prevalence of HPV
was lowest in Asia and highest in Africa.
Few studies have evaluated the frequency of anal HPV infection in heterosexual men, but it
appears to be less than that of genital HPV infection. In a study that included 1305 heterosexual
men, anal infection with any HPV type was detected in 12 percent, over half of whom carried an
oncogenic type [99]. Approximately 50 percent of the heterosexual men with anal HPV infection had
the same HPV type detected on genital sampling. Risk factors for anal HPV infection included

increased lifetime number of female sex partners, shorter duration of relationship with the current
sex partner, and past diagnosis of hepatitis B infection.
The high rates of infection in these study populations suggest that strategies for the prevention of
HPV infection also need to target men. (See "Recommendations for the use of human
papillomavirus vaccines", section on 'Recommendations for HPV immunization in males'.)
Effect of circumcision A meta-analysis of 23 studies was performed to assess the association
between circumcision and HPV DNA [114]. Circumcised men were less likely to have prevalent
genital HPV infection than uncircumcised men (OR, 0.57, 95% CI 0.45-0.71). There was weak
evidence that circumcision was associated with decreased HPV incidence or increased HPV
clearance.
Effect of HPV sampling sites The epidemiology of HPV may also be affected by the specific
genital sites that are sampled within studies; this issue is most controversial among males because
of conflicting data on optimal HPV detection.
A systematic analysis of optimal HPV sampling in the prevalence study cited above evaluated the
site-specific prevalence of infection (eg, urethra, glans penis/coronalsulcus,
penile shaft/prepuce, scrotum, perianal region, anal canal, semen, and urine) [115]. HPV detection
was highest at the penile shaft (50 percent) and lowest in the urethra and in semen (10 and 5
percent, respectively). Another prevalence study of 379 males also demonstrated a wide range of
infection rates depending on the site sampled (eg, 6 percent in semen to 52 percent on the penile
shaft) [116].
The findings were different in the incidence study [111]. Sampling of the glans, penile shaft, and
scrotum demonstrated that genital infection in men is multifocal and that there is no clear
preferential site for infection. HPV DNA was also detected under fingernails; however, it is unclear
as to whether this observation has significant implications for transmission.
EFFECT OF HPV VACCINE Bivalent and quadrivalent human papillomavirus (HPV) vaccines
are available for the prevention of HPV genital infection in women and men; the bivalent vaccine is
effective against HPV types 16 and 18 and the quadrivalent vaccine is effective against HPV types
6, 11, 16, and 18. Clinical trial data have demonstrated efficacy against acquisition of vaccineassociated HPV types with declines in incident and persistent cervical and vulvovaginal infection
and abnormalities in women [117-119]. The quadrivalent vaccine has also been shown to be
effective in men at reducing persistent external genital and anal HPV infection as well as lesions
that occur at these sites, including condyloma and squamous intraepithelial lesions [120]. No trials
have directly evaluated the efficacy of the bivalent vaccine in men or for anal disease in women.
However, in a post-hoc analysis of women who had participated in a trial of the bivalent vaccine,
there were fewer persistent anal HPV infections in the vaccinated group compared with the placebo
group [121].
Several studies have reported declining HPV prevalence and incidence of HPV-related disease
following the introduction of HPV vaccination [122-131]. As an example, in the United States, the
prevalence of HPV 6, 11, 16, and 18 in cervical samples from females aged 14 to 19 years
decreased by 56 percent, from 11.5 percent in the pre-vaccine era (2003 to 2006) to 5.1 percent in
the post-vaccine era (2007-2010) [126]. This observation was made in the setting of estimated
vaccine coverage with at least one dose of 25 to 49 percent among adolescent girls between 2007

and 2010 [132]. In Australia, the 2007 implementation of a national program to administer the
quadrivalent vaccine to women aged 12 to 26 years led to high rates of vaccine coverage,
particularly among females under 18 years old [122-125]. In one study of the cervical cytology
registry in Victoria, Australia, there was a progressive decrease in the incidence of high-grade
cervical squamous intraepithelial lesions among girls 18 years of age or younger in the two years
after the vaccination program compared with the four years preceding it [122]. HPV vaccination is
also associated with decreases in the burden of genital warts. In a study of nearly 400,000 females
born between 1989 and 1999 in Denmark, vaccination was associated with a substantially lower
risk of developing genital warts (229 cases among 248,403 vaccinated versus 2241 cases among
151,367 unvaccinated individuals after an average of 3.5 years of follow-up) [133]. Declines in the
incidence of genital warts have also been temporally associated with vaccine availability in both
young women and heterosexual men in Australia [124,125] and in the United States [134].
Although many of these studies did not formally link individual vaccination status or implicated HPV
type with disease occurrence, they suggest an association between widespread vaccination and
population decreases in HPV-related disease that is consistent with the efficacy observed in clinical
trials of the HPV vaccines and that may reflect vaccine-associated herd immunity.
(See "Recommendations for the use of human papillomavirus vaccines", section on
'Efficacy' and "Recommendations for the use of human papillomavirus vaccines", section on
'Efficacy'.)
Routine HPV immunization is recommended by multiple guideline committees for female
adolescents and adults 9 to 26 years of age and male adolescents and adults 11 to 21 years of age;
HPV vaccine is most effective when given before the onset of sexual debut.
(See "Recommendations for the use of human papillomavirus vaccines", section on
'Recommendations for HPV immunization in females' and "Recommendations for the use of human
papillomavirus vaccines", section on 'Recommendations for HPV immunization in males'.)
VIRAL INTERACTIONS BETWEEN HIV AND HPV HIV and human papillomavirus (HPV)
infections appear to affect the epidemiology of these two viruses bidirectionally.
Effect of HIV infection on HPV Several studies have shown that HPV infection is more common
among HIV-infected than uninfected men and women [103,135-138]. In a study of 486 heterosexual
South African couples followed for up to 24 months, new HPV infection was detected more
frequently in HIV-infected women (57 versus 27 events per 1000 person-months) and men (80
versus 52 events per 1000 person-months) compared with HIV-uninfected individuals [137].
Furthermore, HIV infection was independently associated with a decreased likelihood of clearance
of HPV infection over time.
Another study evaluated the concordance of HPV infection among 254 heterosexually active
couples and the impact of HIV coinfection on the prevalence of HPV [136]. The following
observations were made:
HPV detection was significantly more common among HIV-infected women than among HIVuninfected women (68 versus 31 percent, respectively).
Similarly, HPV detection was significantly more common among HIV-infected men than
among HIV-uninfected men (72 versus 43 percent, respectively).

HIV coinfection in one partner had a significant impact on the prevalence of HPV infection in
the other partner. For example, HIV-uninfected male partners of HIV-infected women had a
greater prevalence of HPV than did HIV-uninfected male partners of HIV-uninfected women
(58 percent versus 32 percent, respectively).
Concordance of the same HPV genotypes was more commonly found among couples where
one or both partners were HIV-infected, compared with HIV-uninfected couples.
Among men who have sex with men (MSM), HPV prevalence is similarly increased in the setting of
HIV infection [103,139-141]. In a meta-analysis of 53 studies, the pooled prevalence of anal HPV
infection was considerably higher in HIV-infected men (93 and 74 percent for any type and any
high-risk type, respectively, compared with 64 and 37 percent in HIV-uninfected MSM) [103].
The use of effective antiretroviral therapy (ART) may attenuate the risk of HPV infection and
persistence among HIV-infected patients [138,142-144], although data are conflicting [145]. As an
example, in a study of 652 HIV-infected women, among whom the baseline prevalence of high-risk
HPV was 42 percent, ART use and HIV RNA suppression for more than two years were each
independently associated with a lower risk of high-risk HPV infection [142]. Sustained HIV RNA
suppression was also marginally associated with clearance of high-risk HPV infection (OR 1.02,
95% CI 1.001-1.04). Other studies have not shown an association between ART use and decreased
HPV risk [146]. The effect of ART on the risk of HPV-associated neoplasia is discussed elsewhere.
(See "Preinvasive and invasive cervical neoplasia in HIV-infected women", section on 'Highly active
antiretroviral therapy' and "Anal squamous intraepithelial lesions: Diagnosis, screening, prevention,
and treatment", section on 'HIV infection'.)
Effect of HPV on HIV acquisition The first evidence for an association between HPV infection
and increased risk of HIV acquisition came from studies of MSM. In a cohort of HIV-uninfected
MSM, infection with more than one anal HPV type was significantly associated with HIV
seroconversion (adjusted hazard ratio [HR] 3.5; 95% CI 1.210.6) [147]. Subsequent studies
suggest that penile HPV infection is also a risk factor for subsequent HIV infection [148]. HIVuninfected men in Kenya (n = 2168) who were participating in a randomized trial of male
circumcision underwent HPV DNA sampling of their glans/coronal sulcus and were followed up for
42 months for evidence of HIV acquisition [148]. Approximately 50 percent of the men had evidence
of HPV DNA at baseline. After controlling for subsequent circumcision status, baseline herpes
simplex virus type 2 serostatus, and other sexual risk factors, those men who were infected with
HPV at baseline had a significantly higher risk of HIV acquisition compared with men without HPV
infection (HR 1.8; 95% CI 1.1-2.9).
In contrast, in a case-control study of 44 men who acquired HIV infection and 787 HIV-uninfected
men who had been followed in a circumcision trial, penile HPV acquisition was not associated with
HIV acquisition after controlling for other HIV transmission risks [149]. However, an association
between clearance of HPV infection and subsequent HIV infection was observed in this study and
postulated to be related to changes in local immune responses that might predispose to HIV
infection.
The presence of HPV infection also appears to be associated with an increased risk of HIV
acquisition among women. In a meta-analysis of prospective studies of women who underwent HPV
testing, HIV acquisition was associated with baseline HPV infection of any and high-risk type (HRs
2.06 [95% CI 1.44-2.94] and 1.99 [95% CI 1.54-2.56], respectively) when compared with no

baseline HPV infection [150]. Of note, several included studies did not assess or adjust for sexual
behavior or other coincident sexually transmitted infections, which are significant potential
confounders in the association between HPV and HIV. In a separate study of women from
Zimbabwe, clearance of cervical HPV infection was associated with risk of HIV acquisition [151],
similar to the association with clearance of penile HPV infection described in the study above.
Whether HPV infection itself predisposes to subsequent HIV infection or is simply a marker of
increased HIV risk remains unknown. It is also unclear whether prevalent HPV infection or the
immune response associated with clearing that HPV infection, or both, plays a role in potentiating
HIV acquisition.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The
Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10 th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
Basics topics (see "Patient information: Human papillomavirus (HPV) vaccine (The Basics)")
Beyond the Basics topics (see "Patient information: Human papillomavirus (HPV) vaccine
(Beyond the Basics)" and "Patient information: Genital warts in women (Beyond the
Basics)" and "Patient information: Cervical cancer screening (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Human papillomaviruses are double-stranded DNA viruses that only infect humans.
(See 'Introduction' above.)
Different human papillomavirus (HPV) types have a propensity to infect different body sites.
As examples, HPV types 1, 2, and 4 have a predilection for cutaneous epithelium while HPV
types 6, 11, 16, and 18 have a predilection for mucous membrane infection. (See 'Tissue
tropism' above.)
Cutaneous infection with HPV types 1 and 2 is frequently associated with plantar or common
hand warts. Mucocutaneous infection with HPV types 6, 11, 16, and 18 is often associated
with genital warts and precancerous and cancerous lesions of the cervix, vulva, vagina, penis,
anus, and oropharynx. Evidence linking HPV to cervical carcinoma is extensive, with HPV 16
accounting for approximately 60 percent of cases and HPV 18 for 10 percent. (See 'Disease
associations' above.)
Close personal contact is assumed to be of importance for the transmission of cutaneous
warts, while anogenital and cervical infection are primarily transmitted through sexual contact.
Both of these represent transmission from one epithelial surface to another. As with other
sexually transmitted infections, persons with multiple sex partners are at greater risk for HPV
infection compared with those in a monogamous relationship, and individuals with a new sex

partner are at greater risk than those with a long-term sex partner. (See 'Risk factors for
infection' above.)
The worldwide prevalence of HPV infection among females is approximately 10 percent. The
highest regional prevalence is in Africa, where 22 percent of women have evidence of HPV
infection. Worldwide, the most serious HPV infections are caused by high-risk types HPV 16
and 18, both of which are preventable by vaccination. (See 'Epidemiology in females' above.)
Rates of anal cancer are rising among men and women in the United States. Studies in men
who have sex with men (MSM) and heterosexual men demonstrate that HPV infection is
highly prevalent among men, including high-risk type HPV 16. Some observational studies
suggest that male circumcision is associated with lower rates of HPV infection than those
observed in uncircumcised men. (See 'Epidemiology in males' above.)
Bivalent and quadrivalent HPV vaccines are available for the prevention of HPV genital
infection in women and men; the bivalent vaccine is effective against HPV types 16 and 18
and the quadrivalent vaccine is effective against HPV types 6, 11, 16, and 18. Clinical trial
data have demonstrated efficacy against acquisition of vaccine-associated HPV types with
declines in incident and persistent HPV infections and decreasing rates of cervical and anal
squamous intraepithelial lesions. (See 'Effect of HPV vaccine' above and "Recommendations
for the use of human papillomavirus vaccines".)
HPV detection is more common among HIV-infected men and women than among men and
women who are HIV-uninfected. Among HIV-uninfected men and women, HPV infection is
associated with an increased risk of HIV acquisition compared with those without HPV
infection. (See 'Viral interactions between HIV and HPV' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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