Review

Genital human papillomavirus infection in men

Jeffrey M Partridge, Laura A Koutsky

Genital human papillomavirus (HPV) infection, globally one of the most common sexually transmitted infections, is Lancet Infect Dis 2006; 6: 21–31
associated with cancers, genital warts, and other epithelial lesions. Although a consistent and coherent picture of the JMP is a research assistant and
epidemiology and pathogenesis of genital HPV infections in women has developed over the past two decades, less is LAK is a professor at the
Department of Epidemiology,
known about these infections in men. Available data suggest that, as with women, most genital HPV infections in
University of Washington HPV
men are symptomless and unapparent, and that HPV16 is probably the most frequently detected type. In Research Group, University of
populations of similar age, the prevalence of specific HPV types is usually lower in men than in women. Whether Washington, Seattle, WA, USA.
this observation relates to lower incidence or shorter duration of infection in men than in women has not yet been Correspondence to:
determined. Seroprevalence of specific anti-HPV antibodies also seems to be lower in men than in women of similar Dr Laura A Koutsky, University of
Washington HPV Research
age, a difference that might be due to lower viral load, lower incidence or duration of infection or lower antibody
Group, 1914 N 34th Street, Suite
responses, or both, in men compared with women. Differences in sexual behaviour may also be important predictors 300, Seattle, WA 98103, USA.
of genital HPV infection. With the anticipated availability of prophylactic HPV vaccines in the near future, it Tel +1 206 616 9784;
becomes increasingly important to understand the incidence and duration of HPV infections in men to develop cost- fax +1 206 616 9788;
kouts@u.washington.edu
effective approaches to prevention through a combination of immunisation and promotion of risk-reduction
strategies.

Introduction from 11 case-control studies by the International Agency

Genital human papillomavirus (HPV) is a common for Research on Cancer, HPV types 40, 42, 43, 44, 54, 61,
sexually transmitted infection. The well-established 70, 72, 81, and CP6108 are also classified as low-risk
causal link between specific types of HPV and cervical types.7 HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,
cancer that has developed over the past two decades has 59, 68, 73, and 82 are termed high-risk types and are
driven a strong preventative research agenda in associated with pre-malignant high-grade squamous
women,1–7 leading to the development and testing of new intraepithelial lesions and cancers of the uterine cervix,
cervical cancer screening tests and prophylactic HPV vagina, vulva, anus, and penis. At present, HPV types 26,
vaccines. Results from randomised controlled clinical 53, and 66 are thought by some to be carcinogenic.
trials of prophylactic vaccines against HPV16, HPV16
and HPV18, and HPV types 6, 11, 16, and 18 virus-like Pathogenesis and manifestations
particles (VLPs) have showed high level efficacy for HPVs are strictly epitheliotropic and preferentially infect
preventing infection and precancerous cervical lesions squamous epithelial cells rather than columnar,
among young women.8–11 Whether similar protective cuboidal, or transitional epithelial cells.13 Outcomes of
effects will be seen in men remains to be determined.
There is much interest in characterising genital HPV
infections in men because of their association with
anogenital cancers and genital warts, as well as the role
of men in transmitting HPV to their sex partners.
Although phase III HPV vaccine trials are currently
being done in adolescent boys and young men, some
researchers are uncertain about the value of vaccinating
boys and young men. This perception is due in part to
the fact that compared with women, less is known about
the incidence, duration, and host response to HPV
infections in men. We therefore reviewed the current
knowledge about the epidemiology of genital HPV
infections in men.

Human papillomavirus
HPV is a non-enveloped, icosahedral virus containing a
double-stranded circular DNA genome of approximately
8000 basepairs.12 PCR techniques have been successfully
used to identify over 90 genotypes of HPV. HPV6 and
HPV11, which are associated with condylomata
acuminata (genital warts) and low-grade squamous
intraepithelial lesions of the cervix, are referred to as Figure 1: Genital warts on the penile shaft of a 20-year-old African-American man
benign or low-risk HPV types. On the basis of evidence Photograph courtesy of the Cincinnati STD/HIV Prevention Training Center, Cincinnati, OH, USA.

http://infection.thelancet.com Vol 6 January 2006 21

 Review
HPV infection in men range from unapparent infection
to squamous cell carcinomas. Gillison and Shah13
proposed that cancers causally linked to genital HPVs
were likely to have the following characteristics:
(1) squamous cell in origin; (2) HPV DNA in tumour cell
nuclei with expression of viral oncogenes; (3) located at
anatomic sites of exposure by direct contact;
(4) stimulate development of serum antibodies to HPV
E6 and E7 proteins; (5) association with sexual
behaviour; and (6) rates in immunosuppressed
individuals and in individuals with previous HPV-
related malignancies that are greater than expected.
Genital warts (figure 1) are a very common sexually
transmitted disease (STD) with an annual prevalence
estimated to be 1% of the sexually active population of
those aged 15–49 years in the USA.14 Genital warts are
associated with HPV6 or HPV11 infections, with
70–100% of exophytic genital wart tissue containing
one of these types.15–18 Cook and colleagues19 reported
that among all men with genital warts the most
common site was on the shaft; however, uncircumcised
men were more likely than circumcised men to have
warts detected on the distal penis. A retrospective study
done in England and Wales reported a 390% increase
in clinical attendance for genital warts from 1971 to
1994, with the ratio of male to female infections
decreasing from 1·85/1 to 1·34/1 during the same
period.20 Studies of genital warts done in Europe and
the USA have further shown that peak genital wart
incidence in both sexes occurs in the 20–24-year age
group.20–22
1968–1972
1993–1997
Alberta, Canada
Israel (Jewish)
Osaka Prefecture, Japan
Denmark
Estonia
Finland
Iceland
Norway
Slovakia
Slovenia
Zaragoza, Spain
Geneva, Switzerland
S Thames Region, England, UK
Hawaii, USA (white)
Penile cancer Cervical cancer
2 1 0 10 20 30
Incidence per 100 000
Figure 2: Age-adjusted incidence of cervical and penile cancers in countries with tumour registries during the
years 1968–1972 and 1993–1997
Data from the International Agency for Research on Cancer.42
22
Recurrent respiratory papillomatosis is a rare but
highly morbid condition characterised by the recurrent
growth of wart-like lesions in the respiratory tract. Most
recurrent respiratory papillomatosis seems to be caused
by perinatal transmission of HPV6 or HPV11.23
Although the papillomas primarily occur in the larynx,
on and around the vocal cords, they may spread
downward and affect the trachea, bronchi, and
occasionally the lungs. The incidence is approximately
4 per 100 000 in the paediatric population, with
approximately seven of every 1000 children born to
mothers with vaginal condylomata developing paediatric
recurrent respiratory papillomatosis.24,25
Studies of perinatal transmission from mother to
infant have reported a wide range (1–79%) of HPV DNA
prevalence in infants.26–31 From a large, well-designed
study of HPV infections in infants, Smith and co-
workers32 reported a prevalence of only 1·6% based on
testing oral or genital specimens. HPV type-specific
concordance between specimens obtained from mothers
and their infants was rare, at less than 1%.32 Thus, HPV
DNA detected in genital and oral specimens of
newborns and toddlers is more likely to be from
contamination than from infection.
Although HPV infection is thought to be
predominantly sexually transmitted in adolescents and
adults, non-sexual routes of transmission are
possible.33,34 Sonnex and colleagues35 studied whether
individuals with genital warts also carry HPV on their
fingers, and if so, whether there was concordance
between the finger and genital infections. In this small
study, cytobrush samples were taken from the genital
lesions, the tips of the fingers, and the tips of the
fingernails of 14 men. HPV DNA was detected by PCR
in 13 of 14 (93%) genital samples and nine of 14 (64%)
finger and fingernail samples. Of the men with positive
genital samples, four of 13 (31%) were positive for the
same HPV type (HPV6) on their finger sample.
HPV infects all anogenital sites, and has an important
part in the development of cancers at these sites.36
Although HPV DNA is nearly always detected by
sensitive PCR assays in cervical cancer specimens,
detection has ranged from only 42% to 80% in more
recent studies of penile tumours, with HPV16 identified
as the most common type.37–41 HPV DNA positivity varies
substantially by histological subtype, with non-invasive
tumours more likely than invasive tumours to be
positive. Similar observations have been made for vulvar
tumours.23,37 The implications of these findings include
two possibilities: (1) a smaller proportion of penile
cancers than cervical cancers is HPV related; or
(2) specimens from penile cancers are more likely than
cervical cancer specimens to be compromised for PCR-
based testing because they are more likely to be detected
at a later stage of diagnosis, and thus contain more
inflammatory and necrotic debris. In addition, it has
been suggested that penile tissue is less susceptible to
http://infection.thelancet.com Vol 6 January 2006
 Review

the oncogenic potential of HPVs.23,37 This observation is

1·6
supported by the fact that even in countries with at least Men
1·4 Women
40 years of widespread Papanicolaou screening and

Incidence per 100 000

treatment of precancerous lesions, the incidence of
cervical cancer remains many times higher than the
incidence of penile cancer (figure 2). Although the exact
mechanism is unclear, one hypothesis is that a relatively
large transformation zone in the cervices of women of
reproductive age (ie, the area of columnar epithelium
that is susceptible to metaplasia and transformation into
squamous epithelium) allows frequent attachment and
entry of HPV into replicating metaplastic cells. Three
types of histologically similar lesions that display the
features of carcinoma in situ in the male external
genitalia have been described: Bowen’s disease,
erythroplasia of Queyrat, and bowenoid papulosis.43 All
have a strong association with HPV infection, most
commonly with HPV16.37
HPV infection is associated with anal cancer and
precursor lesions such as anal intraepithelial
neoplasia.44–48 Currently, anal cancer represents about
4% of all lower gastrointestinal cancers in the USA;
however, the incidence is increasing in both men and
women (figure 3). In 1973, no cases of anal cancer were
reported in men aged less than 40 years in the USA,
whereas in 2000, a small number of incident cases were
reported in men aged 25–39 years (figure 4), possibly
related to the HIV epidemic in men who have sex with
men that began in the early 1980s.50 Daling and
colleagues48 suggest that the temporal increase in
prevalence of exposures—eg, HPV and HIV infection,
cigarette smoking, anal intercourse, and the lifetime
number of sex partners—may account for the
increasing incidence. The clinical and pathological links
between anal cancer and HPV were reported in a large
study by Frisch and co-workers.51 This study found that
squamous cell carcinomas of the anal region that were
positive for HPV types 16, 18, 31, or 33, especially those
detected in young men, were associated with anal
intercourse. The investigators also reported that
approximately 90% of anal cancers among women, 58%
among heterosexual men, and 100% among
homosexual men were positive for high-risk HPV
DNA.46 Chin-Hong and co-workers52 reported that urban
1·2
1·0
0·8
0·6
0·4
0·2
0
1975 1980 1985 1990 1995 2000
Year
Figure 3: Anal cancer incidence by selected years in men and women in USA
Data from the US National Cancer Institute.49
that HPV does not have a causal role.13,55–58 Others
conclude that high-risk HPV infection may contribute to
a subset of prostate cancers.59,60
Several groups report a causal role for HPV, especially
HPV16, in head and neck cancers.61–70 Recently, Smith
and colleagues71 did a case-control study of 201 patients
with head and neck cancer and 333 controls, and
reported a significant positive association between the
presence of high-risk HPV DNA and head and neck
cancer, which persisted after adjusting for alcohol and
tobacco use (odds ratio 2·6, 95% CI 1·5–4·2).71 Overall,
approximately 20% of head and neck cancers are positive
for HPV DNA.72
In summary, as with vulvar cancers, only about half to
three-quarters of penile cancers are HPV DNA positive.
Anal cancer in men who have sex with men is nearly
always HPV positive (as is cervical cancer in women),
whereas only about 60% of anal cancers in heterosexual
men are HPV positive. These data suggest that epithelial
site of infection and perhaps frequency of exposure are
important factors in determining the risk of HPV-related
cancer in men. Genital warts are common among
sexually active young men, although, as has been found
with women, most HPV infections are symptomless and
unapparent,73 and therefore are only detected when
7
1973
2000
6
Incidence per 100 000

HIV-negative men who have sex with men have high 5

rates of anal HPV infection across all age groups. Before 4
the HIV epidemic, anal cancer incidence among men 3
who have sex with men was estimated to be as high as
2
35 per 100 000.53 This is similar to the incidence of
1
cervical cancer before the widespread introduction of
cervical cytology screening. A high rate of HPV-related 0
d)

anal cancer among men who have sex with men is not
9

85

ste
–2

–3

–3

–4

–4

–5

–5

–6

–6

–7

–7

–8

ju
25

30

35

40

45

50

55

60

65

70

75

80

ad

unexpected because the anus resembles the cervix in

e-
ag
ll (

that both anatomic sites have an HPV-susceptible

a
er

Age (years)
Ov

transformation zone.54
Reports of an association between HPV and prostate Figure 4: Anal cancer incidence in US men (1973 and 2000) by age group
cancer are inconsistent. Some investigators conclude Data from the US National Cancer Institute.49

http://infection.thelancet.com Vol 6 January 2006 23

 Review

molecular tests for HPV DNA or RNA are used.
Currently, HPV DNA testing of genital specimens
obtained from men is done in research studies only. Due
to the reality of uncertain benefits, there are no widely
accepted recommendations for HPV DNA testing of
specimens obtained from men in clinical settings.
Treatment options for HPV-related cancers,
precancerous lesions, and genital warts are similar for
men and women. The choice of a particular option (eg,
surgery, cryotherapy) is determined by location, size,
and type of lesion, and by preference of the provider and
patient.74 Whether or not treatment reduces infectivity is
not known, thus treatment of HPV infections detected
only by molecular methods is not recommended.
Molecular detection of HPV infections in men
Detection method
Given the well-established low sensitivity and low
specificity of clinical and histological techniques for
detecting HPV infections in men,75,76 the inability to
efficiently propagate the virus in culture,12 and the
relatively low sensitivity of serological testing for HPV
antibodies,77,78 detection of genital HPV infection in men
(as with women) is currently done using signal
amplification methods such as hybrid capture, or target
amplification such as PCR-based assays. The Hybrid
Capture II system (HC2; Digene Corporation,
Gaithersburg, MD, USA), which is a signal amplification
system, is used in combination with Papanicolaou tests
in many clinics that offer cervical cancer screening.79 This
system consists of two probe cocktails for the separate
identification of low-risk and high-risk HPV types (only
the probes for high-risk types are clinically useful).
Limitations of the HC2 system include the inability to
identify specific HPV types, lack of specificity in
determining the presence of a high-risk versus a low-risk
HPV infection, and a lower analytical but not necessarily
clinical sensitivity compared with PCR.79 PCR methods
include primer systems that target a consensus (broad
spectrum) of HPV types or target specific HPV types.
Although they differ in design, several different
consensus primer systems target the L1 region of the
HPV genome because it is the most conserved. Several
studies compared the sensitivities of these different PCR
systems.80–83 Results from these studies showed that
sensitivity increased slightly in the primer order
GP5+/6+, PGMY09/11, SPF1/2. Comprehensive reviews
of detection methods have been done.79,84
Specimen collection
Comparison of results across studies is limited by
variation in specimen collection technique. Hippelainen
and colleagues85 suggested that inadequate sample
collection was responsible for a large proportion of

Sites tested Sampling technique PCR method Betaglobin

insufficiency
Kataoka et al, Urethra, biopsy of aceto- Urobrush (Medscand) for urethral specimens Separate primer cocktails for HPV16/18 and types 6, 11, and 33. Typing by type- 0%
1991100 white epithelium specific probes
Hippelainen et al, Glans, sulcus, urethral Accellon Multi biosampler swab (Medscand) MY09/MY11 consensus primers for HPV types 1, 6, 11, 16, 18, 31, 33. Typing by 26%
199385 meatus, preputium, meatus restriction enzymes
Bosch et al, Glans coronal sulcus, distal Saline-wetted cotton-tipped swab MY09/MY11 consensus primers (25 type-specific probes) 21%
1996101 urethra
Wikstrom et al, Glans, coronal sulcus, inner Cytobrush GP5+/GP6+ generic primers. Positives analysed by specific primers to HPV types 6, Not reported
2000102 part of foreskin 11, 16, 18, 31, 33, 35, reverse hybridisation, and DNA sequencing
Lazcano-Ponce Coronal sulcus, urethral Accellon Multi biosampler swab (Medscand) GP5+/GP6+ primer, combined probe for HPV types 16, 18, 31, 33, 35, 39, 45, 51, 5%
et al, 200190 meatus 52, 56, 58, 59, 66, 68, combined probe for HPV types 6, 11, 40, 42, 43, 44, and
individual probes for HPV types 6, 11, 16, 18, 31, 33
Franceschi et al, Glans, coronal sulcus, Saline-wetted cotton-tipped swab MY09/MY11 consensus primers, GP5/GP6 and GP5+/GP6+ generic primers, 26%
2002103 distal urethra probes for HPV types 6/11, 16, 18, 31, 33
Svare et al, Glans, coronal sulcus, shaft, Saline-wetted cotton-tipped swab GP5/GP6 generic primers, type-specific probes for HPV types 6, 11, 16, 18, 31, 33 0%
2002104 scrotum, perianal region
Baldwin et al, Glans, coronal sulcus, Saline-wetted sterile Dacron swab PGMY09/PGMY11 consensus primers, Roche strip probes for HPV types 6, 11, 16, 10%
2003105 urethral meatus 18, 26, 31, 33, 35, 39, 40, 42, 45, 51–59, 66, 68, 73, 82–84
Weaver et al, Glans, coronal sulcus, inner Emery paper (600A-grit Wet-or-dry Tri-M-ite; PGMY09/PGMY11 consensus primers, Roche strip probes for HPV types 6, 11, 16, 3%
200489 part of foreskin, shaft, 3M) followed by saline-wetted sterile Dacron 18, 26, 31, 33, 35, 39, 40, 42, 45, 51–59, 66, 68, 73, 82–84
scrotum, urine swab
Shin et al, Glans, coronal sulcus, shaft, Cytobrush, pre-wetted Dacron swab (for SPF primers, line-probe assay (LiPa) for HPV types 6, 11, 16, 18, 31, 33-35, 39, 40, 16%
2004106 scrotum, urethral meatus urethral meatus only) 42–45, 51–54, 56, 58, 59, 66, 68/73, 70, 74
Kjaer et al, Glans, coronal sulcus Pre-wetted cotton-tipped swab GP5+/GP6+ primer, combined probe for HPV types 16, 18, 31, 33, 35, 39, 45, 51, 10%
2005107 52, 56, 58, 59, 66, 68 and combined probe for HPV types 6, 11, 26, 34, 40, 42, 43,
44, 53–55, 57, 61, 70–73, 81–84, 89, followed by individual typing with type-
specific probes
Lajous et al, Coronal sulcus, shaft, Cytobrush for coronal sulcus, shaft, scrotum, BGH20 and BPC04 consensus primers, type-specific probes for HPV types 6, 11, 21%
2005108 scrotum, urethral meatus, cotton swab for urethral meatus, Accellon 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51–59, 66, 68, 73, 82–84
urethra Multi biosampler swab (Medscand) for urethra

Manufacturer details: Medscand, Malmö, Sweden; 3M, St Paul, MN, USA.

Table 1: Sites tested, sampling technique, PCR method, and betaglobin insufficiency by study

24 http://infection.thelancet.com Vol 6 January 2006

 Review

Sample population* (n) Age† (years) Prevalence

DNA Warts‡ High-risk HPV types
Kataoka et al, 1991 100
Swedish Army conscripts (105) Median ~20·5 17·1% (urethra) 1·8% 7·6% (urethra)
43·6% (biopsy) 20·5% (biopsy)
Hippelainen et al, 1993 85
Finnish Army conscripts (285) 19·8 16·5% 5·6% ..
Bosch et al, 1996101 General population Spain (171)§ 45·4 3·5% 2·1%|| 2·3%
Wikstrom et al, 2000102 Swedish STD clinic attenders (235) 27·1 13·2% Excluded 8·1%
Lazcano-Ponce et al, 200190 Mexican college students and industry workers (114) 29·3 36·0% Excluded 16·7%
Franceschi et al, 2002103 General population Spain, Colombia, Brazil, Thailand Median 45·0 13·1% .. 12·2%
and the Philippines (533)§
Svare et al, 2002104 Danish STD clinic attendees (198) Median ~30 44·9% 25%|| ..
Baldwin et al, 2003105 American STD clinic attenders (393) 30·9 28·2% 9·6% 12·0%
Weaver et al, 200489 American university students (317) 20·5 32·8% 5·0% 14·5%
Shin et al, 2004106 Korean university students (381) Median 22·0 8·7% .. 4·2%
Kjaer et al, 2005107 Danish Army conscripts (337) 20·3 33·8% .. ..
Lajous et al, 2005108 Mexican soldiers (1030) Median 23·0 44·6% 5·8% 34·8%

*Based on the number of individuals with samples sufficient for PCR analysis. †Mean age, unless otherwise indicated. ‡Warts prevalence not necessarily from the same sample population
with sufficient samples. §Among control partners only. ||Percentage of men who reported a history of ever having genital warts. STD=sexually transmitted disease; ..=not reported.

Table 2: Estimates of the prevalence of HPV infection by study

insufficient samples for PCR analysis. Exfoliated cell
sampling techniques have included the use of saline-
wetted cotton-tipped or Dacron swabs, cytobrushes,
Urobrushes (Medscand Medical AB, Malmö, Sweden),
and the Accellon Multi biosampler swab (Medscand). In
addition, the selection of genital sites for sampling has
included varying combinations of the penile shaft,
preputial cavity, glans, coronal sulcus, urethra, scrotum,
and perianal region.
Several studies have used PCR assays to compare the
sensitivity of HPV DNA detection in urine samples
versus exfoliated cell samples and have reported lower
sensitivities when using urine samples.86–90 More
recently, Golijow and co-workers91 reported that first-
void urine samples were satisfactory for PCR analysis
and yielded a high prevalence (73%) of HPV DNA in
185 high-risk Argentinian men. However, a comparison
with an exfoliated cell sample was not made.91
Some groups have concluded that HPV is transmitted
in the semen,87,92–97 whereas others believe that HPV is
not transmitted by semen.98 Contamination of seminal
fluid with exfoliated cells from the urethra or from
sampling through the urethra could explain the
presence of HPV in prostatic tissues. A small study in
Finland found HPV DNA in samples from the vas
deferens, which may have eliminated the issue of
urethral contamination. The investigators reported that
18·5% (five of 27) of vas deferens samples contained
HPV types 6, 11, or 16.99 The potential transmission of
HPV through seminal fluid raises the question of
whether HPV can be transmitted via sperm donation.
More work is required in this area.
fact that studies have generally included few men, and
that the men who were studied may not have been
representative of the general population.
We reviewed 12 studies, done between 1991 and 2005,
designed to assess the prevalence of HPV infection in
heterosexual men that met the following criteria:
(1) PCR-based methods with consensus or generic
primers for HPV DNA detection; (2) a study population
of at least 100 individuals; and (3) the study population
was predominantly heterosexual (table 1 and
table 2).85,89,90,100–108 Exfoliated cell specimen insufficiency,
determined by the absence of betaglobin DNA, ranged
from 0% to 26% (table 1). HPV prevalence estimates
ranged from 3·5% to 45·0% (table 2). Despite this wide
variation in prevalence estimates, no clear relation
between age, genital sites sampled, proportion of
inadequate samples, or PCR testing method could be
discerned.
The prevalence of high-risk HPV types ranged from
2·3% to 34·8%, with HPV16 reported as the most
prevalent high-risk type detected,89,90,100–103,105 with the
exception of the study by Lajous and co-workers,108 which
found HPV59 to be the most prevalent high-risk type.
The prevalence of low-risk HPV types ranged from 2·3%
to 23·9%.89,90,100–103,105,108 In studies that did not exclude
individuals with genital warts and reported genital wart
prevalence, the prevalence of HPV6 or HPV11 ranged
from 4·3% to 15·0%.89,100,105,108 The prevalence of multiple
types ranged from 3·4% to 22·6%. However, as the
techniques used in the 1990s were less able to detect
multiple types, multiple infections may be more
common than these data suggest.

Prevalence of infection Prevalence in men and women

The prevalence of symptomless genital HPV infection Weaver and colleagues89 reported that the prevalence in
among men is not well established. This is partly due to male university students aged 18–20 years was similar to
a poor understanding of which sites should be tested the prevalence (28%) in women of the same age at the
(and how specimens for testing should be obtained), the same university.89 In a smaller study in an STD clinic

http://infection.thelancet.com Vol 6 January 2006 25

 Review
30 Men
HPV16 seroprevalence (%)
25 Women
20
15
10
5 Incidence of infection
0 By contrast with the wealth of information on the
15–19 20–29 30–39 40–49
Age (years)
Figure 5: HPV16 seroprevalence in US men and women by age group
Data from the US National Health and Nutrition Examination Survey
1991–1994 (adapted from Stone et al116).
population, Van Doornum and co-workers109 reported
that 28% of men and 23% of women had prevalent HPV
infections. Studies that have included heterosexually
active couples have reported that concordant type-
specific HPV infections occur more often than would be
expected by chance.110,111 Bosch and colleagues101 studied
the association between detection of HPV DNA in
genital samples obtained from men and detection of
cervical cancer in their female partners and found an
increased risk of cervical cancer in the partners of men
who were positive for HPV (odds ratio 4·9, 95% CI
1·9–12·6). In four case-control studies in Colombia and
Spain, penile HPV DNA prevalence was higher in
husbands of women with cervical cancer than in those
without cervical cancer.112
Seroprevalence
Iftner and Villa113 have summarised issues surrounding
the sensitivity and specificity of serological assays.
Overall, HPV VLP ELISAs done on serum obtained from
individuals with molecular evidence of infection have
shown sensitivities of 50–60% with high specificities
(>90%). Seroconversion is often delayed or never occurs
in at least one-third of women who test positive for HPV
DNA. Moreover, women with infections of longer
duration are more likely to show seroconversion than
women with more transient infections, indicating that
the presence of detectable antibodies does not prevent
persistent infection.78 It is not clear whether the absence
of detectable antibody in individuals with documented
infections indicates the sensitivity of the serological
assay or the presence of extremely low antibody levels, or
both.77,78,114 In terms of specificity, it has been shown that
genotype-specific serum antibody response in natural
infection is induced by VLPs of each HPV type with the
exceptions of some cross-reactivity between HPV6 and
HPV11, HPV31, and HPV33, and HPV45 and HPV18.113
Seropositivity does not correlate well with HPV DNA
detection,115–117 in part because there is a substantial delay
between the time when HPV DNA is first detected and
the time when serum antibodies are first detected.77,78,114
Men are less likely than women to mount a detectable
humoral response to HPV.17,116,118–120 Compared with men,
26
the peak seroprevalence occurs at a younger age in
women (figure 5).116 The overall lower prevalence of
detectable antibodies might reflect the occurrence of more
transient infections, a lower viral load, or less robust
immunological responses in men compared with women.
50–59 Overall incidence and duration of HPV infections in women,
much less is known about the natural history of
infections in men. Four studies that used PCR methods
for HPV DNA detection have been reported.102,107–109 Rates
of infection were higher for the two studies done in STD
clinics102,109 than in the two studies done among
soldiers.107,108 In the Netherlands, 85 men and 162 women
with multiple sex partners were recruited through an
STD clinic. The incidence of any HPV infection (types
6/11, 16, 18, or 33) in men and in women was 50·5 per
100 person-years and 47·1 per 100 person-years,
respectively, and men were less likely to have persistent
infections.109 In a prospective study that was done at an
STD clinic in Sweden, 15 of 76 (19·7%) men who were
HPV negative at the first visit were HPV positive at the
second visit an average of 3·5 months later.102 Among
250 Danish soldiers who were HPV DNA negative at
enrolment, 13·8% were infected 6–8 months later.107 The
highest type-specific incidence was seen for HPV16,
which also showed slightly higher persistence than other
types. In a study of 336 Mexican soldiers, who underwent
enrolment and follow-up visits 1 year apart, the incidence
of genital HPV infection was 21·5 per 100 person-years,
and HPV52 was reported to have the highest type-specific
incidence.
Risk factors for HPV infection
Although an association between age and increased risk
for prevalent HPV infection has been reported,104 many
other studies have reported no association with
age.90,103,105,106,108,109,121 Number of sex partners was
associated with prevalent HPV infection in three
studies,85,103,104 and not in another three studies.90,106,122
Kjaer and colleagues107 reported an increased risk for
incident HPV infection in men who had at least three
sex partners during follow-up compared with men
reporting one or fewer sex partners.107 This study also
found that always or occasionally using condoms during
follow-up was protective. The one study that assessed the
relation between frequency of intercourse and HPV
infection found a positive association.122 Hippelainen
and colleagues85 reported an association between the
history of STDs and HPV infection, whereas Franceschi
and colleagues103 reported no association. There are
conflicting results for the risk of HPV infection
associated with circumcision status. Three studies
reported that circumcision was protective for prevalent
infection,104,122,123 whereas two studies reported that it was
not.89,106 One study reported an association between
http://infection.thelancet.com Vol 6 January 2006

smoking and HPV infection,85 whereas three other
studies found no association.103,104,106 Two studies found
no association between HPV infection and age at first
intercourse or education level.103,104
Although studies of women usually report a positive
association between lifetime number of sex partners and
detection of genital HPV infection, the data from studies
of men are less consistent. Overall, conflicting reports of
risk factors for HPV infection in men may be because
most studies were of prevalent rather than incident
infection, and there was substantial variation in
specimen collection and testing procedures, and in
population characteristics across studies.
HPV infection in HIV-positive men
HPV infections and infection with multiple HPV types
are more common in men with HIV infection than in
those without. Moreover, HIV is more strongly
associated with increasing the duration of HPV infection
or the re-activation of latent HPV infection than with
acquisition of a new HPV infection.124–129 Anal HPV
infections have been the focus of most studies, and
although the mechanisms are poorly understood, it is
clear that HPV-related anal cancer and precancerous
anal lesions occur more commonly in HIV-positive men
than in HIV-negative men.126,130–134 One study reported
that the incidence of anal cancer in HIV-positive
homosexual men was twice that of HIV-negative men.135
As in the cervix, precancerous lesions of the anus are
classified on cytology as high-grade anal squamous
intraepithelial lesions (ASILs) and on histology as anal
intraepithelial neoplasia grade 2 or 3. Palefsky and
colleagues125 reported a higher prevalence of anal
infection with multiple HPV types in HIV-positive men
versus HIV-negative men. Detection of multiple types
was associated with both prevalent anal intraepithelial
neoplasia and progression to higher grade anal
intraepithelial neoplasia over time.
Current data suggest that immunosuppression is most
strongly associated with the early stages of anal
neoplasia, but cellular genetic changes and not
immunosuppression may be driving persistence of
high-grade lesions and progression to invasive
cancer.136,137 Piketty and co-workers138 reported a high
prevalence of ASILs, including high-grade ASIL, and
anal HPV infection in HIV-infected men who have sex
with men, despite immune restoration under highly
active antiretroviral therapy. De Sanjose and Palefsky134
concluded that the risk for anal cancer will remain high
even in the era of highly active antiretroviral therapy,
underscoring the need to prevent the initial HPV
infection in these individuals.
Prevention
Behavioural intervention
A comprehensive approach to preventing all sexually
transmitted infections including HPV and HIV has been
http://infection.thelancet.com Vol 6 January 2006
Review
the aim of many public health scientists. The campaign
in Uganda known as “ABC” (abstinence, being faithful,
and using condoms) has been a successful approach to
HIV prevention,139 with specific evidence of the success
of partner reduction.140,141 Whether such behavioural
approaches will affect rates of HPV infection in men
remains to be determined. It is encouraging to note that
three studies reported a negative association between
condom use and HPV infection in men.85,122,142 However,
one study of older men found no association,103 perhaps
due in part to recall bias and detection of long-term
persistent infection, rather than newly acquired
infection. Bleeker and colleagues143 did a study to
investigate the effect of condom use on the clinical
course of HPV-related lesions in male partners of
women with cervical intraepithelial neoplasia. Their
results showed a shorter median time to regression of
flat penile lesions in men randomly assigned to the
condom group than in men in the non-condom group
(7·4 months vs 13·9 months). Overall, these data
suggest that condoms do provide men some protection
from HPV infection and associated lesions.
Vaccination
Prophylactic immunisation of women using vaccines
composed of VLPs synthesised from the L1 protein of
HPV types 6, 11, and 16/18 induces neutralising
antibodies, prevents infection and related lesions, and is
generally well-tolerated.9,11,144–149 Less is known about the
immunogenicity and efficacy of HPV immunisation in
men. A double-blind, randomised, phase I safety and
immunogenicity trial of HPV16 L1 virus-like particles
done at The Johns Hopkins University Center for
Immunization Research included a sample of 14 men.145
Vaccination was well tolerated by all men. An HPV16
VLP ELISA was used to assess serum IgG response, and
in individuals seronegative at baseline, none of the
placebo recipients seroconverted, whereas all vaccine
recipients seroconverted within 1 month after the
second vaccination. Moreover, titres were clearly boosted
1 month after the third vaccination. Sera from all vaccine
recipients 1 month after the third vaccination were also
tested by an HPV16 pseudovirion neutralisation assay.
All of these sera had detectable virion neutralising
antibodies. In a second study, safety, tolerance, and
immunogenicity were similar for the men and women
enrolled in a phase I trial of HPV11 VLP vaccine.146 A
third study of the immunogenicity and safety of
prophylactic HPV6/11/16/18 vaccine administered to
10–15-year-olds showed high levels of immunogenicity
to all four viral capsids (99%) in both boys and girls.150
Phase III clinical trials are continuing in men and
adolescent boys, and results will be available within the
next couple of years.
The advantages and disadvantages of male vaccination
have been discussed. Mathematical models show the
benefit of including men in an immunisation
27
 Review
Search strategy and selection criteria
Data for this review were identified by a Medline search and
references from relevant articles. Search terms used were
“human papillomavirus”, “epidemiology”, “male”, “PCR”,
“anal cancer” “anal intraepithelial neoplasia”, “AIN”, “genital
warts”, “condylomata acuminata”, “vaccine”, “prevalence”,
“incidence”, and “risk factors”. Only English language papers
were reviewed. The sections on prevalence, seroprevalence,
incidence, and risk factors included studies published after
1990.
programme to establish herd immunity, thereby
reducing the probability that a susceptible individual will
come into contact with an infected individual.151 These
models also suggest that estimates of population-level
effectiveness are highly dependent on infection
characteristics (eg, attack rates, duration of infection).
Such information is currently available for women but
not for men.
Conclusions
The lack of epidemiological information on genital HPV
infections in men is undoubtedly due in part to the fact
that, as with other sexually transmitted infections,
morbidity and mortality related to genital HPV infection
is much more common in women than in men.
Furthermore, sensitive methods for collecting and
testing specimens for HPV DNA have only recently been
developed for use in men. Available data suggest that, as
with women, most genital HPV infections in men are
symptomless and unapparent, and that HPV16 is one of
the most, if not the most, commonly detected type. In
populations that are of similar age, the prevalence of
specific HPV types generally seems to be lower in men
than in women. Whether these observations relate to
lower incidence or shorter duration of infection in men
versus women has not yet been determined.
Seroprevalence of specific anti-HPV antibodies also
seems to be lower in men than in women of similar age.
Whether this difference is due to lower viral load, lower
incidence or duration of infection, or lower antibody
responses in men compared with women has not been
determined. Differences in sexual behaviours of men
and women may also be important predictors of HPV
risk. Since HPV-related genital carcinomas are rare in
men, some may argue that learning more about the
epidemiology of genital HPV infections in men is of low
priority. However, with the anticipated availability of
prophylactic HPV vaccines in the near future, it becomes
increasingly important to understand the incidence and
duration of HPV infections in men to develop cost-
effective population-based approaches to prevention that
combine immunisation and promotion of risk-reduction
strategies such as delayed onset of sexual activity and
condom use.
28
Conflicts of interest
LAK receives research funding from Merck Research Laboratories. JMP
has no conflicts of interest to declare.
Acknowledgments
We thank Marsha Weese for her assistance with editing and graphics.
Financial support comes from grants from the US National Institutes of
Health, Bethesda, MD, USA.
References
1 Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural
history of cervicovaginal papillomavirus infection in young women.
N Engl J Med 1998; 338: 423–28.
2 Bosch FX, Manos MM, Munoz N, et al. Prevalence of human
papillomavirus in cervical cancer: a worldwide perspective.
International Biological Study on Cervical Cancer (IBSCC) Study
Group. J Natl Cancer Inst 1995; 87: 796–802.
3 Koutsky LA, Holmes KK, Critchlow CW, et al. A cohort study of the
risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to
papillomavirus infection. N Engl J Med 1992; 327: 1272–78.
4 Winer RL, Lee SK, 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.
5 Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human
papillomavirus infection and low-grade squamous intraepithelial
lesion development in young females. JAMA 2001; 285:
2995–3002.
6 Woodman CB, Collins S, Winter H, et al. Natural history of cervical
human papillomavirus infection in young women: a longitudinal
cohort study. Lancet 2001; 357: 1831–36.
7 Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic
classification of human papillomavirus types associated with
cervical cancer. N Engl J Med 2003; 348: 518–27.
8 Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent
human papillomavirus (types 6, 11, 16, and 18) L1 virus-like
particle vaccine in young women: a randomised double-blind
placebo-controlled multicentre phase II efficacy trial. Lancet Oncol
2005; 6: 271–78.
9 Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a
human papillomavirus type 16 vaccine. N Engl J Med 2002; 347:
1645–51.
10 Brown DR, Fife KH, Wheeler CM, et al. Early assessment of the
efficacy of a human papillomavirus type 16 L1 virus-like particle
vaccine. Vaccine 2004; 22: 2936–42.
11 Harper DM, Franco EL, Wheeler C, et al. Efficacy of a bivalent L1
virus-like particle vaccine in prevention of infection with human
papillomavirus types 16 and 18 in young women: a randomised
controlled trial. Lancet 2004; 364: 1757–65.
12 Siegel JF, Mellinger BC. Human papillomavirus in the male
patient. Urol Clin North Am 1992; 19: 83–91.
13 Gillison ML, Shah KV. Chapter 9: Role of mucosal human
papillomavirus in nongenital cancers. J Natl Cancer Inst Monogr
2003; (31): 57–65.
14 Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital
human papillomavirus infection. Epidemiol Rev 1988; 10: 122–63.
15 Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH. Detection
of multiple human papillomavirus types in condylomata acuminata
lesions from otherwise healthy and immunosuppressed patients.
J Clin Microbiol 1999; 37: 3316–22.
16 Coleman N, Birley HD, Renton AM, et al. Immunological events in
regressing genital warts. Am J Clin Pathol 1994; 102: 768–74.
17 Greer CE, Wheeler CM, Ladner MB, et al. Human papillomavirus
(HPV) type distribution and serological response to HPV type 6
virus-like particles in patients with genital warts. J Clin Microbiol
1995; 33: 2058–63.
18 Li HX, Zhu WY, Xia MY. Detection with the polymerase chain
reaction of human papillomavirus DNA in condylomata acuminata
treated with CO2 laser and microwave. Int J Dermatol 1995; 34:
209–11.
19 Cook LS, Koutsky LA, Holmes KK. Clinical presentation of genital
warts among circumcised and uncircumcised heterosexual men
attending an urban STD clinic. Genitourin Med 1993; 69: 262–64.
20 Simms I, Fairley CK. Epidemiology of genital warts in England and
Wales: 1971 to 1994. Genitourin Med 1997; 73: 365–67.
http://infection.thelancet.com Vol 6 January 2006

21 Chuang TY, Perry HO, Kurland LT, Ilstrup DM. Condyloma
acuminatum in Rochester, Minn., 1950–1978. I. Epidemiology and
clinical features. Arch Dermatol 1984; 120: 469–75.
22 Persson G, Andersson K, Krantz I. Symptomatic genital
papillomavirus infection in a community. Incidence and clinical
picture. Acta Obstet Gynecol Scand 1996; 75: 287–90.
23 Majewski S, Jablonska S. Human papillomavirus-associated
tumors of the skin and mucosa. J Am Acad Dermatol 1997; 36:
659–85; quiz 686–88.
24 Wiatrak BJ. Overview of recurrent respiratory papillomatosis.
Curr Opin Otolaryngol Head Neck Surg 2003; 11: 433–41.
25 Silverberg MJ, Thorsen P, Lindeberg H, Grant LA, Shah KV.
Condyloma in pregnancy is strongly predictive of juvenile-onset
recurrent respiratory papillomatosis. Obstet Gynecol 2003; 101:
645–52.
26 Fredericks BD, Balkin A, Daniel HW, Schonrock J, Ward B, Frazer
IH. Transmission of human papillomaviruses from mother to
child. Aust N Z J Obstet Gynaecol 1993; 33: 30–32.
27 Pakarian F, Kaye J, Cason J, et al. Cancer associated human
papillomaviruses: perinatal transmission and persistence.
Br J Obstet Gynaecol 1994; 101: 514–17.
28 Smith EM, Johnson SR, Cripe T, et al. Perinatal transmission and
maternal risks of human papillomavirus infection. Cancer Detect
Prev 1995; 19: 196–205.
29 Puranen M, Yliskoski M, Saarikoski S, Syrjanen K, Syrjanen S.
Vertical transmission of human papillomavirus from infected
mothers to their newborn babies and persistence of the virus in
childhood. Am J Obstet Gynecol 1996; 174: 694–99.
30 Cason J, Kaye JN, Jewers RJ, et al. Perinatal infection and
persistence of human papillomavirus types 16 and 18 in infants.
J Med Virol 1995; 47: 209–18.
31 Watts DH, Koutsky LA, Holmes KK, et al. Low risk of perinatal
transmission of human papillomavirus: results from a prospective
cohort study. Am J Obstet Gynecol 1998; 178: 365–73.
32 Smith EM, Ritchie JM, Yankowitz J, et al. Human papillomavirus
prevalence and types in newborns and parents: concordance and
modes of transmission. Sex Transm Dis 2004; 31: 57–62.
33 Pao CC, Tsai PL, Chang YL, Hsieh TT, Jin JY. Possible non-sexual
transmission of genital human papillomavirus infections in young
women. Eur J Clin Microbiol Infect Dis 1993; 12: 221–22.
34 Tay SK, Ho TH, Lim-Tan SK. Is genital human papillomavirus
infection always sexually transmitted? Aust N Z J Obstet Gynaecol
1990; 30: 240–42.
35 Sonnex C, Strauss S, Gray JJ. Detection of human papillomavirus
DNA on the fingers of patients with genital warts. Sex Transm
Infect 1999; 75: 317–19.
36 Carter JJ, Madeleine MM, Shera K, et al. Human papillomavirus
16 and 18 L1 serology compared across anogenital cancer sites.
Cancer Res 2001; 61: 1934–40.
37 Cupp MR, Malek RS, Goellner JR, Smith TF, Espy MJ. The
detection of human papillomavirus deoxyribonucleic acid in
intraepithelial, in situ, verrucous and invasive carcinoma of the
penis. J Urol 1995; 154: 1024–29.
38 Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of
squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl
2000; (205): 189–93.
39 Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human
papillomavirus DNA in penile carcinoma: evidence for multiple
independent pathways of penile carcinogenesis. Am J Pathol 2001;
159: 1211–18.
40 Daling JR, Madeleine MM, Johnson LG, et al. Penile cancer:
importance of circumcision, human papillomavirus and smoking
in in situ and invasive disease. Int J Cancer 2005; 116: 606–16.
41 Strickler HD, Schiffman MH, Shah KV, et al. A survey of human
papillomavirus 16 antibodies in patients with epithelial cancers.
Eur J Cancer Prev 1998; 7: 305–13.
42 Parkin DM, Whelen SL, Ferlay J, Storm H. Cancer incidence in five
continents, vol. I to VIII, IARC CancerBase 7. Lyon: International
Agency for Research on Cancer, 2005.
43 Gerber GS. Carcinoma in situ of the penis. J Urol 1994; 151:
829–33.
44 Melbye M, Frisch M. The role of human papillomaviruses in
anogenital cancers. Semin Cancer Biol 1998; 8: 307–13.
http://infection.thelancet.com Vol 6 January 2006
Review
45 Frisch M, Glimelius B, van den Brule AJ, et al. Sexually
transmitted infection as a cause of anal cancer. N Engl J Med 1997;
337: 1350–58.
46 Frisch M. On the etiology of anal squamous carcinoma. Dan Med
Bull 2002; 49: 194–209.
47 Williams GR, Lu QL, Love SB, Talbot IC, Northover JM. Properties
of HPV-positive and HPV-negative anal carcinomas. J Pathol 1996;
180: 378–82.
48 Daling JR, Madeleine MM, Johnson LG, et al. Human
papillomavirus, smoking, and sexual practices in the etiology of
anal cancer. Cancer 2004; 101: 270–80.
49 National Cancer Institute. Surveillance, Epidemiology, and End
Results (SEER) Program (http://www.seer.cancer.gov) SEER*Stat
Database: Incidence - SEER 9 Regs Public-Use, Nov 2003 Sub
(1973–2001). National Cancer Institute, DCCPS, Surveillance
Research Program, Cancer Statistics Branch, released April 2004,
based on the November 2003 submission.
50 Clark MA, Hartley A, Geh JI. Cancer of the anal canal. Lancet Oncol
2004; 5: 149–57.
51 Frisch M, Fenger C, van den Brule AJ, et al. Variants of squamous
cell carcinoma of the anal canal and perianal skin and their relation
to human papillomaviruses. Cancer Res 1999; 59: 753–57.
52 Schiffman M, Kjaer SK. Chapter 2: Natural history of anogenital
human papillomavirus infection and neoplasia. J Natl Cancer Inst
Monogr 2003 (31):14–19.
53 Chin-Hong PV, Vittinghoff E, Cranston RD, et al. Age-specific
prevalence of anal human papillomavirus infection in HIV-
negative sexually active men who have sex with men: the EXPLORE
Study. J Infect Dis 2004; 190: 2070–76.
54 Daling JR, Weiss NS, Hislop TG, et al. Sexual practices,
sexually transmitted diseases, and the incidence of anal cancer.
N Engl J Med 1987; 317: 973–77.
55 Saad F, Gu K, Jean-Baptiste J, Gauthier J, MesMasson AM.
Absence of human papillomavirus sequences in early stage
prostate cancer. Can J Urol 1999; 6: 834–38.
56 Griffiths TR, Mellon JK. Human papillomavirus and urological
tumours: II. Role in bladder, prostate, renal and testicular cancer.
BJU Int 2000; 85: 211–17.
57 Noda T, Sasagawa T, Dong Y, Fuse H, Namiki M, Inoue M.
Detection of human papillomavirus (HPV) DNA in archival
specimens of benign prostatic hyperplasia and prostatic cancer
using a highly sensitive nested PCR method. Urol Res 1998; 26:
165–69.
58 Strickler HD, Burk R, Shah K, et al. A multifaceted study of human
papillomavirus and prostate carcinoma. Cancer 1998; 82: 1118–25.
59 Kuczyk M, Serth J, Machtens S, Jonas U. Detection of viral HPV 16
DNA in prostate cancer and benign prostatic hyperplasia by
quantitative PCR-directed analysis. Prostate Cancer Prostatic Dis
2000; 3 (suppl 1): S23.
60 Serth J, Panitz F, Paeslack U, Kuczyk MA, Jonas U. Increased
levels of human papillomavirus type 16 DNA in a subset of prostate
cancers. Cancer Res 1999; 59: 823–25.
61 Steinberg BM, DiLorenzo TP. A possible role for human
papillomaviruses in head and neck cancer. Cancer Metastasis Rev
1996; 15: 91–112.
62 Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal
association between human papillomavirus and a subset of head
and neck cancers. J Natl Cancer Inst 2000; 92: 709–20.
63 van Houten VM, Snijders PJ, van den Brekel MW, et al. Biological
evidence that human papillomaviruses are etiologically involved in
a subgroup of head and neck squamous cell carcinomas.
Int J Cancer 2001; 93: 232–35.
64 Schwartz SM, Daling JR, Doody DR, et al. Oral cancer risk in
relation to sexual history and evidence of human papillomavirus
infection. J Natl Cancer Inst 1998; 90: 1626–36.
65 McKaig RG, Baric RS, Olshan AF. Human papillomavirus and
head and neck cancer: epidemiology and molecular biology.
Head Neck 1998; 20: 250–65.
66 Gillison ML, Lowy DR. A causal role for human papillomavirus in
head and neck cancer. Lancet 2004; 363: 1488–89.
67 Gillison ML, Shah KV. Human papillomavirus-associated head and
neck squamous cell carcinoma: mounting evidence for an etiologic
role for human papillomavirus in a subset of head and neck
cancers. Curr Opin Oncol 2001; 13: 183–88.
29
 Review
68 Klussmann JP, Dinh S, Guntinas-Lichius O, et al. HPV-associated
tonsillar cancer. An update. HNO 2004; 52: 208–18 (in German).
69 Herrero R. Chapter 7: Human papillomavirus and cancer of the
upper aerodigestive tract. J Natl Cancer Inst Monogr 2003; (31):
47–51.
70 Koskinen WJ, Chen RW, Leivo I, et al. Prevalence and physical
status of human papillomavirus in squamous cell carcinomas of
the head and neck. Int J Cancer 2003; 107: 401–06.
71 Smith EM, Ritchie JM, Summersgill KF, et al. Human
papillomavirus in oral exfoliated cells and risk of head and neck
cancer. J Natl Cancer Inst 2004; 96: 449–55.
72 Syrjanen S. Human papillomavirus (HPV) in head and neck
cancer. J Clin Virol 2005; 32 (suppl 1): S59–66.
73 Mao C, Hughes JP, Kiviat N, et al. Clinical findings among young
women with genital human papillomavirus infection. Am J Obstet
Gynecol 2003; 188: 677–84.
74 Prendiville W, Davies P, eds. The health professional’s HPV
handbook. Volume 1: human papillomavirus and cervical cancer.
London: Taylor & Francis, 2004.
75 Strand A, Rylander E, Wilander E, Zehbe I, Kraaz W.
Histopathologic examination of penile epithelial lesions is of
limited diagnostic value in human papillomavirus infection.
Sex Transm Dis 1996; 23: 293–98.
76 Krebs HB, Schneider V. Human papillomavirus-associated lesions
of the penis: colposcopy, cytology, and histology. Obstet Gynecol
1987; 70: 299–304.
77 Dillner J. The serological response to papillomaviruses.
Semin Cancer Biol 1999; 9: 423–30.
78 Carter JJ, Koutsky LA, Hughes JP, et al. Comparison of human
papillomavirus types 16, 18, and 6 capsid antibody responses
following incident infection. J Infect Dis 2000; 181: 1911–19.
79 Molijn A, Kleter B, Quint W, van Doorn LJ. Molecular diagnosis of
human papillomavirus (HPV) infections. J Clin Virol 2005; 32
(suppl 1): S43–51.
80 Peyton CL, Schiffman M, Lorincz AT, et al. Comparison of PCR-
and hybrid capture-based human papillomavirus detection systems
using multiple cervical specimen collection strategies. J Clin
Microbiol 1998; 36: 3248–54.
81 Swan DC, Tucker RA, Tortolero-Luna G, et al. Human
papillomavirus (HPV) DNA copy number is dependent on grade of
cervical disease and HPV type. J Clin Microbiol 1999; 37: 1030–34.
82 Gravitt PE, Peyton CL, Alessi TQ, et al. Improved amplification of
genital human papillomaviruses. J Clin Microbiol 2000; 38: 357–61.
83 Kleter B, van Doorn LJ, Schrauwen L, et al. Development and
clinical evaluation of a highly sensitive PCR-reverse hybridization
line probe assay for detection and identification of anogenital
human papillomavirus. J Clin Microbiol 1999; 37: 2508–17.
84 Gravitt PE, Viscidi MD. Measurement of exposure to human
papillomaviruses. In: Rohan TE, Shah KV, eds. Cervical cancer:
from etiology to prevention. Dordrecht: Kluwer Academic
Publishers, 2004: 119–141.
85 Hippelainen M, Syrjanen S, Koskela H, Pulkkinen J, Saarikoski S,
Syrjanen K. Prevalence and risk factors of genital human
papillomavirus (HPV) infections in healthy males: a study on
Finnish conscripts. Sex Transm Dis 1993; 20: 321–28.
86 Melchers WJ, Schift R, Stolz E, Lindeman J, Quint WG. Human
papillomavirus detection in urine samples from male patients by
the polymerase chain reaction. J Clin Microbiol 1989; 27: 1711–14.
87 Astori G, Pipan C, Muffato G, Botta GA. Detection of HPV-DNA
in semen, urine and urethral samples by dot blot and PCR.
New Microbiol 1995; 18: 143–49.
88 Katelaris PM, Cossart YE, Rose BR, et al. Human papillomavirus:
the untreated male reservoir. J Urol 1988; 140: 300–05.
89 Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites
and sampling techniques for detection of human papillomavirus
DNA in men. J Infect Dis 2004; 189: 677–85.
90 Lazcano-Ponce E, Herrero R, Munoz N, et al. High prevalence of
human papillomavirus infection in Mexican males: comparative
study of penile-urethral swabs and urine samples. Sex Transm Dis
2001; 28: 277–80.
91 Golijow CD, Perez LO, Smith JS, Abba MC. Human
papillomavirus DNA detection and typing in male urine samples
from a high-risk population from Argentina. J Virol Methods 2005;
124: 217–20.
30
92 Ostrow RS, Zachow KR, Niimura M, et al. Detection of
papillomavirus DNA in human semen. Science 1986; 231: 731–33.
93 Olatunbosun O, Deneer H, Pierson R. Human papillomavirus
DNA detection in sperm using polymerase chain reaction. Obstet
Gynecol 2001; 97: 357–60.
94 Lai YM, Yang FP, Pao CC. Human papillomavirus
deoxyribonucleic acid and ribonucleic acid in seminal plasma and
sperm cells. Fertil Steril 1996; 65: 1026–30.
95 Kyo S, Inoue M, Koyama M, Fujita M, Tanizawa O, Hakura A.
Detection of high-risk human papillomavirus in the cervix and
semen of sex partners. J Infect Dis 1994; 170: 682–85.
96 Inoue M, Nakazawa A, Fujita M, Tanizawa O. Human
papillomavirus (HPV) type 16 in semen of partners of women with
HPV infection. Lancet 1992; 339: 1114–15.
97 Green J, Monteiro E, Bolton VN, Sanders P, Gibson PE.
Detection of human papillomavirus DNA by PCR in semen
from patients with and without penile warts. Genitourin Med
1991; 67: 207–10.
98 Nieminen P, Koskimies AI, Paavonen J. Human papillomavirus
DNA is not transmitted by semen. Int J STD AIDS 1991; 2: 207–08.
99 Rintala MA, Pollanen PP, Nikkanen VP, Grenman SE, Syrjanen
SM. Human papillomavirus DNA is found in the vas deferens.
J Infect Dis 2002; 185: 1664–67.
100 Kataoka A, Claesson U, Hansson BG, Eriksson M, Lindh E.
Human papillomavirus infection of the male diagnosed by
Southern-blot hybridization and polymerase chain reaction:
comparison between urethra samples and penile biopsy samples.
J Med Virol 1991; 33: 159–64.
101 Bosch FX, Castellsague X, Munoz N, et al. Male sexual behavior
and human papillomavirus DNA: key risk factors for cervical
cancer in Spain. J Natl Cancer Inst 1996; 88: 1060–67.
102 Wikstrom A, Popescu C, Forslund O. Asymptomatic penile HPV
infection: a prospective study. Int J STD AIDS 2000; 11: 80–84.
103 Franceschi S, Castellsague X, Dal Maso L, et al. Prevalence and
determinants of human papillomavirus genital infection in men.
Br J Cancer 2002; 86: 705–11.
104 Svare EI, Kjaer SK, Worm AM, Osterlind A, Meijer CJ, van den
Brule AJ. Risk factors for genital HPV DNA in men resemble those
found in women: a study of male attendees at a Danish STD clinic.
Sex Transm Infect 2002; 78: 215–18.
105 Baldwin SB, Wallace DR, Papenfuss MR, et al. Human
papillomavirus infection in men attending a sexually transmitted
disease clinic. J Infect Dis 2003; 187: 1064–70.
106 Shin HR, Franceschi S, Vaccarella S, et al. Prevalence and
determinants of genital infection with papillomavirus, in female
and male university students in Busan, South Korea. J Infect Dis
2004; 190: 468–76.
107 Kjaer SK, Munk C, Winther JF, Jorgensen HO, Meijer CJ,
van den Brule AJ. Acquisition and persistence of human
papillomavirus infection in younger men: a prospective follow-up
study among Danish soldiers. Cancer Epidemiol Biomarkers Prev
2005; 14: 1528–33.
108 Lajous M, Mueller N, Cruz-Valdez A, et al. Determinants of
prevalence, acquisition, and persistence of human papillomavirus
in healthy Mexican military men. Cancer Epidemiol Biomarkers Prev
2005; 14: 1710–16.
109 Van Doornum GJ, Prins M, Juffermans LH, et al. Regional
distribution and incidence of human papillomavirus infections
among heterosexual men and women with multiple sexual
partners: a prospective study. Genitourin Med 1994; 70: 240–46.
110 Baken LA, Koutsky LA, Kuypers J, et al. Genital human
papillomavirus infection among male and female sex partners:
prevalence and type-specific concordance. J Infect Dis 1995; 171:
429–32.
111 Bleeker MC, Hogewoning CJ, Berkhof J, et al. Concordance of
specific human papillomavirus types in sex partners is more
prevalent than would be expected by chance and is associated with
increased viral loads. Clin Infect Dis 2005; 41: 612–20.
112 Castellsague X, Ghaffari A, Daniel RW, Bosch FX, Munoz N,
Shah KV. Prevalence of penile human papillomavirus DNA in
husbands of women with and without cervical neoplasia: a study in
Spain and Colombia. J Infect Dis 1997; 176: 353–61.
113 Iftner T, Villa LL. Human papillomavirus technologies. J Natl
Cancer Inst Monogr 2003; (31): 80–88.
http://infection.thelancet.com Vol 6 January 2006

114 Wideroff L, Schiffman MH, Nonnenmacher B, et al. Evaluation of
seroreactivity to human papillomavirus type 16 virus-like particles
in an incident case-control study of cervical neoplasia. J Infect Dis
1995; 172: 1425–30.
115 Nonnenmacher B, Kruger Kjaer S, Svare EI, et al. Seroreactivity to
HPV16 virus-like particles as a marker for cervical cancer risk in
high-risk populations. Int J Cancer 1996; 68: 704–09.
116 Stone KM, Karem KL, Sternberg MR, et al. Seroprevalence of
human papillomavirus type 16 infection in the United States.
J Infect Dis 2002; 186: 1396–402.
117 Castle PE, Shields T, Kirnbauer R, et al. Sexual behavior, human
papillomavirus type 16 (HPV 16) infection, and HPV 16
seropositivity. Sex Transm Dis 2002; 29: 182–87.
118 Svare EI, Kjaer SK, Nonnenmacher B, et al. Seroreactivity to
human papillomavirus type 16 virus-like particles is lower in high-
risk men than in high-risk women. J Infect Dis 1997; 176: 876–83.
119 Slavinsky J 3rd, Kissinger P, Burger L, Boley A, DiCarlo RP,
Hagensee ME. Seroepidemiology of low and high oncogenic risk
types of human papillomavirus in a predominantly male cohort of
STD clinic patients. Int J STD AIDS 2001; 12: 516–23.
120 Thompson DL, Douglas JM Jr, Foster M, et al. Seroepidemiology of
infection with human papillomavirus 16, in men and women
attending sexually transmitted disease clinics in the United States.
J Infect Dis 2004; 190: 1563–74.
121 Grussendorf-Conen EI, Meinhof W, de Villiers EM, Gissmann L.
Occurrence of HPV genomes in penile smears of healthy men.
Arch Dermatol Res 1987; 279 (suppl): S73–75.
122 Baldwin SB, Wallace DR, Papenfuss MR, Abrahamsen M, Vaught
LC, Giuliano AR. Condom use and other factors affecting penile
human papillomavirus detection in men attending a sexually
transmitted disease clinic. Sex Transm Dis 2004; 31: 601–07.
123 Castellsague X, Bosch FX, Munoz N, et al. Male circumcision,
penile human papillomavirus infection, and cervical cancer in
female partners. N Engl J Med 2002; 346: 1105–12.
124 van der Snoek EM, Niesters HG, Mulder PG, van Doornum GJ,
Osterhaus AD, van der Meijden WI. Human papillomavirus
infection in men who have sex with men participating in a Dutch
gay-cohort study. Sex Transm Dis 2003; 30: 639–44.
125 Palefsky JM, Holly EA, Ralston ML, Jay N. Prevalence and risk
factors for human papillomavirus infection of the anal canal in
human immunodeficiency virus (HIV)-positive and HIV-negative
homosexual men. J Infect Dis 1998; 177: 361–67.
126 Palefsky JM, Holly EA. Immunosuppression and co-infection with
HIV. J Natl Cancer Inst Monogr 2003; (31): 41–46.
127 Critchlow CW, Surawicz CM, Holmes KK, et al. Prospective study
of high grade anal squamous intraepithelial neoplasia in a cohort
of homosexual men: influence of HIV infection,
immunosuppression and human papillomavirus infection. AIDS
1995; 9: 1255–62.
128 Breese PL, Judson FN, Penley KA, Douglas JM Jr. Anal human
papillomavirus infection among homosexual and bisexual men:
prevalence of type-specific infection and association with human
immunodeficiency virus. Sex Transm Dis 1995; 22: 7–14.
129 Critchlow CW, Hawes SE, Kuypers JM, et al. Effect of HIV
infection on the natural history of anal human papillomavirus
infection. AIDS 1998; 12: 1177–84.
130 Klencke BJ, Palefsky JM. Anal cancer: an HIV-associated cancer.
Hematol Oncol Clin North Am 2003; 17: 859–72.
131 Goldstone S. Anal dysplasia in men who have sex with men.
AIDS Read 1999; 9: 204–08, 220.
132 Serraino D, Dal Maso L, La Vecchia C, Franceschi S. Invasive
cervical cancer as an AIDS-defining illness in Europe. AIDS 2002;
16: 781–86.
133 Fordyce EJ, Wang Z, Kahn AR, et al. Risk of cancer among women
with AIDS in New York City. AIDS Public Policy J 2000; 15: 95–104.
http://infection.thelancet.com Vol 6 January 2006
Review
134 de Sanjose S, Palefsky J. Cervical and anal HPV infections in HIV
positive women and men. Virus Res 2002; 89: 201–11.
135 Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDS-associated
malignant disorders. Lancet 1998; 351: 1833–39.
136 Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer
with AIDS-related immunosuppression in adults. JAMA 2001; 285:
1736–45.
137 Palefsky JM, Holly EA, Ralston ML, et al. Effect of highly active
antiretroviral therapy on the natural history of anal squamous
intraepithelial lesions and anal human papillomavirus infection.
J Acquir Immune Defic Syndr 2001; 28: 422–28.
138 Piketty C, Darragh TM, Heard I, et al. High prevalence of anal
squamous intraepithelial lesions in HIV-positive men despite
the use of highly active antiretroviral therapy. Sex Transm Dis
2004; 31: 96–99.
139 Blum RW. Uganda AIDS prevention: A,B,C and politics. J Adolesc
Health 2004; 34: 428–32.
140 Stoneburner RL, Low-Beer D. Sexual partner reductions explain
human immunodeficiency virus declines in Uganda: comparative
analyses of HIV and behavioural data in Uganda, Kenya, Malawi,
and Zambia. Int J Epidemiol 2004; 33: 624.
141 Stoneburner RL, Low-Beer D. Population-level HIV declines and
behavioral risk avoidance in Uganda. Science 2004; 304: 714–18.
142 Wen LM, Estcourt CS, Simpson JM, Mindel A. Risk factors for the
acquisition of genital warts: are condoms protective? Sex Transm
Infect 1999; 75: 312–16.
143 Bleeker MC, Hogewoning CJ, Voorhorst FJ, et al. Condom use
promotes regression of human papillomavirus-associated penile
lesions in male sexual partners of women with cervical
intraepithelial neoplasia. Int J Cancer 2003; 107: 804–10.
144 Zhang LF, Zhou J, Chen S, et al. HPV6b virus like particles are
potent immunogens without adjuvant in man. Vaccine 2000; 18:
1051–58.
145 Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity
trial in adult volunteers of a human papillomavirus 16 L1 virus-like
particle vaccine. J Natl Cancer Inst 2001; 93: 284–92.
146 Evans TG, Bonnez W, Rose RC, et al. A Phase 1 study of a
recombinant viruslike particle vaccine against human
papillomavirus type 11 in healthy adult volunteers. J Infect Dis
2001; 183: 1485–93.
147 Brown DR, Bryan JT, Schroeder JM, et al. Neutralization of human
papillomavirus type 11 (HPV-11) by serum from women vaccinated
with yeast-derived HPV-11 L1 virus-like particles: correlation with
competitive radioimmunoassay titer. J Infect Dis 2001; 184:
1183–86.
148 Emeny RT, Wheeler CM, Jansen KU, et al. Priming of human
papillomavirus type 11-specific humoral and cellular immune
responses in college-aged women with a virus-like particle vaccine.
J Virol 2002; 76: 7832–42.
149 Galloway DA. Papillomavirus vaccines in clinical trials. Lancet
Infect Dis 2003; 3: 469–75.
150 Nolan T, Block SL, Reisinger KS, et al. Comparison of the
immunogenicity and tolerability of a prophylactic quadrivalent
human papillomavirus (HPV) (types 6, 11, 16, 18) L1 virus-like
particle (VLP) vaccine in male and female adolescents and young
adult women. 23rd Annual Meeting of the European Society for
Paediatric Infectious Disease; Valencia, Spain; May 18–20, 2005.
Abstract 236. http://www.kenes.com/espid2005/program/
CopyFile.asp?FileName=236.doc (accessed Nov 23, 2005).
151 Hughes JP, Garnett GP, Koutsky L. The theoretical population-level
impact of a prophylactic human papilloma virus vaccine.
Epidemiology 2002; 13: 631–39.
31