Genital, Oral, and Anal Human Papillomavirus Infection in Men Who Have Sex With Men

Abstract

Even though the incidence of anal cancer among men who have sex with men (MSM) is higher than the incidence of cervical cancer among women, few MSM are identified as high-risk patients in primary care or have received vaccination for human papillomavirus (HPV), the most common sexually transmitted infection worldwide, with 6.2 million new infections each year. The authors review the current literature on diagnosis and basic management of genital, oral, and anal HPV infection. Early diagnosis and treatment of patients with HPV infection is important because this infection causes patients substantial distress even in its benign manifestations. It has also been implicated in a host of cancers, including oral, cervical, penile, and anal cancers and is an independent risk factor for the development of human immunodeficiency virus infection. The incidence of HPV infection drops in women older than 30 years but remains high for MSM in all age ranges. For all of these reasons, physicians should routinely assess the sexual practices of all male patients, especially MSM, and educate them on the HPV infection risks, diagnosis, and treatment options. Physicians can have a significant impact in the primary prevention of HPV by routinely offering HPV vaccination to male patients younger than 26 years.

Full text

JAOA •
Supplement 2 • Vol 111 • No 3 • March 2011• S19Dietz and Nyberg • Genital, Oral, and Anal HPV Infection
Amajor milestone in medicine
occurred in 2006 when the Food
and Drug Administration approved the
first vaccine against human papillo-
mavirus (HPV).1In 2009, the Food and
Drug Administration subsequently
licensed the quadrivalent HPV vaccine
for use in boys and young men aged 9
to 26 years.2Although the vaccine was
initially indicated for young women,
HPV infection is highly prevalent in
males and is responsible for substan-
tial disease in men, particularly men
who have sex with men (MSM).3,4 For
example, HPV infection is an indepen-
dent risk factor for acquiring human
immunodeficiency virus (HIV) infec-
tion and some forms of cancer.5,6 In one
study, a majority of the MSM surveyed
admitted to having genital warts but
did not think they had an HPV infec-
tion.7
Men who have sex with men may
be difficult to identify in general prac-
tice because many of them do not self-
identify as gay or bisexual or are still
having sex with women as they develop
their sexual identity.8Studies indicate
that prior estimates of the MSM popula-
tion were too low and that physicians in
general practice can anticipate that 3%
of their male patients have had sexual
contact with another man in the previous
year.9,10 One study11 found that 15% of
men in a random sample reported some
type of sexual contact with another man,
irrespective of how they self-identified
their sexuality.
In this article we will review the
prevalence and basic management of the
most common manifestations of HPV
infection in MSM, including genital,
penile, oral, and anal HPV infection. We
will also discuss the possible benefits of
offering the HPV vaccine to MSM for the
primary prevention of anal carcinoma
Craig A. Dietz, DO, MPH
Chessa R. Nyberg, PharmD
Even though the incidence of anal cancer among men who have
sex with men (MSM) is higher than the incidence of cervical cancer
among women, few MSM are identified as high-risk patients in pri-
mary care or have received vaccination for human papillomavirus
(HPV), the most common sexually transmitted infection worldwide,
with 6.2 million new infections each year. The authors review the cur-
rent literature on diagnosis and basic management of genital, oral,
and anal HPV infection. Early diagnosis and treatment of patients with
HPV infection is important because this infection causes patients
substantial distress even in its benign manifestations. It has also
been implicated in a host of cancers, including oral, cervical, penile,
and anal cancers and is an independent risk factor for the develop-
ment of human immunodeficiency virus infection. The incidence of
HPV infection drops in women older than 30 years but remains high
for MSM in all age ranges. For all of these reasons, physicians should
routinely assess the sexual practices of all male patients, especially
MSM, and educate them on the HPV infection risks, diagnosis, and
treatment options. Physicians can have a significant impact in the pri-
mary prevention of HPV by routinely offering HPV vaccination to male
patients younger than 26 years.
J Am Osteopath Assoc. 2011;111(3 suppl 2):S19-S25
From the Departments of General and HIV
Medicine at the Kansas City Free Health Clinic in
Missouri (Dr Dietz), and the Department of Phar-
macy Practice at the University of Illinois at Chicago
(Dr Nybert).
Financial Disclosures: None reported.
Address correspondence to Craig A. Dietz, DO,
MPH, Clinical Director, General and HIV Medicine,
Kansas City Free Health Clinic, 3515 Broadway St,
Kansas City, MO 64111.
E-mail: craigd@kcfree.org
Genital, Oral, and Anal Human Papillomavirus
Infection in Men Who Have Sex With Men
This supplement is supported by an independent educational grant from Merck & Co, Inc.

and HPV transmission to men or women
and to reduce the risk of HIV infection.
General Population
The Centers for Disease Control and Pre-
vention (CDC) estimates that 20 million
individuals are infected with HPV. This
number grows larger as 6.2 million new
individuals are infected each year,
making HPV infection the most common
sexually transmitted viral infection
worldwide.12,13 The prevalence of the
virus tends to peak after a patient’s first
sexual encounter (ie, “sexual debut”) and
remains high with each new sexual
partner among all age groups.14,15 The
risk of developing anal cancer is 17 times
higher in gay or bisexual men than in
heterosexual men.3,16 A 2008 meta-anal-
ysis of the current literature found that
HPV is associated with 85% of anal squa-
mous cell carcinomas in men, 50% of
penile cancers, and up to 72% of oropha-
ryngeal cancers.6Cancers associated with
HPV infection are mostly due to HPV-16
or HPV-18, with numbers roughly
approximating the number of cervical
cancers in the United States.17 These find-
ings are particularly worrisome for MSM,
because oral sex, anal receptive inter-
course, and noninsertive, “safe sex” con-
tact can all result in HPV transmission.18
Genital and Penile Condylomas
Caused by HPV-6 or HPV-11
Epidemiology
The CDC reports that only 1% of sexu-
ally active men have visible genital warts
at any given time, yet if advanced anti-
body testing methods are used, up to 73%
of healthy men have detectable HPV in
the external genital tract.6,16 Genital warts
(condyloma acuminatum, venereal warts)
are a common symptom of infection with
HPV-6 or HPV-11.20 Even though condy-
loma-associated HPV strains 6 and 11 are
considered low risk because of their
nononcogenic nature, they are still trans-
missible, incur costs of frequent treatment,
and have emotional costs to patients.19
Both HPV-6 and HPV-11 can cause recur-
rent respiratory papillomatosis, an
uncommon condition in which condy-
lomas develop in the throat, potentially
blocking the patient’s airway.6,12
History and Diagnosis
Most genital HPV infection
is transmitted by skin-to-
skin sexual contact usually
involving friction or micro-
trauma to exposed skin.20
Subclinical infections are
common; exophytic or vis-
ible condylomas usually
appear 1 to 3 months after
exposure but can appear
much later.20 There is no
standard method to diag-
nose genital HPV other than visual
inspection and clinician experience. Biop-
sies are usually not necessary, and HPV
DNA sampling is usually not available or
practical.3,20 Generally, genital warts are
painless, flesh-colored or pale-pink
lesions with cauliflower, velvety, or
smooth textures (Figure 1). Single lesions
can be present anywhere on the penile
shaft, urethra, scrotum, or perineum and
can be symmetric on opposing moist sur-
faces. Individual condylomas may coa-
lesce in large masses around the penis
or perineal area, including the anus.20,21
For confusing or subclinical lesions, a 5%
solution of acetic acid (acetowhite test)
can be applied to reveal or whiten incon-
spicuous lesions, but this is a nonspecific
technique and its positive and negative
predictive values are unknown.3,21
Lesions can be confused for other
conditions, such as pearly penile papules,
molluscum contagiosum, or bowenoid
papulosis lesions (Figure 2), and invasive
precancerous lesions.20 Questionable,
atypical, or treatment-resistant lesions
should be examined with biopsy for
definitive diagnosis. Penile carcinoma is
rare but is highly associated with the
presence of HPV-16 and the state of being
uncircumcised.4Patients who are MSM
with newly diagnosed condylomas
should be screened for other sexually
transmitted diseases including HIV infec-
tion, hepatitis C virus infection, chlamy -
dia, and gonorrhea.
Treatment
There are a variety of patient- and physi-
cian-applied treatments for condylomas,
though no treatment is 100% effective.
Dietz and Nyberg • Genital, Oral, and Anal HPV InfectionS20 •JAOA •Supplement 2 • Vol 111 • No 3 • March 2011
Figure 1. Genital condyloma on a scrotum.
Reprinted with permission from John C. Hall,
MD.
First-line treatments, such as podofilox
0.5% solution or imiquimod 5%, applied
directly to the condyloma, are generally
safe and convenient for self-application
to clinically visible lesions20,22 (Figure 3).
Physician-applied treatments, such as
cryotherapy, podophyllin 20% resin, tri-
choloracetic acid, and surgical removal
are more effective but may also need to
be repeated after 1 to 2 weeks4,22 and
require training by the treating physi-
Figure 2. Penile bowenoid papulosis lesions.
Such lesions can be mistaken for genital condy-
loma. Reprinted with permission from John C.
Hall, MD.

cian (Figure 4 and Figure 5). Lesions that
do not respond to basic therapy or are so
extensive that they cause the patient sub-
stantial physical or emotion distress
should be referred to a specialist for
surgery, carbon dioxide laser treatment,
or advanced immune-modulating ther-
apies, such as interferon α2b or 5-fluo-
rouracil.21 The response rates for
cryotherapy range from approximately
60% to 90%, compared with 0% to 50%
for placebo24,25 (Table).
Oral HPV
Epidemiology
Men who have sex with men have a high
risk of developing oral HPV infection. A
2009 study26 found that oral HPV acqui-
sition was more positively associated with
number of recent oral sex and open mouth
kissing partners than with the number of
vaginal sex partners. Additionally, the
prevalence of oral condylomas has
increased dramatically since the intro-
duction of highly active antiretroviral
therapy among HIV-positive patients,
which may be due to immune reconsti-
tution.27 Human papillomavirus not only
causes oral condylomas but is also
strongly associated with oropharyngeal
cancers and other oral diseases.28,29 Oral
squamous cell carcinoma is the eighth
most common cancer in men, and HPV is
linked to at least 25% of the cases.30,31 The
incidence of HPV-associated carcinomas
of the oropharynx subsantially increased
from 1973 to 2004 (annual percentage
change, 80%; P<.001), most likely because
of a shift in sexual behaviors, particularly
oral sex in young males.31,32
Common noncancerous oral lesions
associated with HPV include oral condy-
lomas (Figure 6), oral leukoplakia (Figure
7), and oral lichen planus.29 Condyloma
lesions appear as white or pink sessile,
flat, raised, or cauliflowerlike nodules on
the mucous membranes or tongue.21 The
most commonly found HPV types are
6, 11, 16, and 18.21 Oropharyngeal cancers
due to HPV occur more commonly
among men than among women and
account for a large proportion of HPV-
associated cancers, second to cervical
cancer.33
Treatment
Oral condyloma treatment is similar to
treatment of lesions in other areas of the
body where mucosal surfaces are
involved. Cryotherapy, surgical excision,
laser treatment and topical 5-fluorouracil
are common treatments but should be
used by physicians or dentists experi-
enced with their use in this area.20,27 Abla-
tion of condylomas does reduce trans-
mission,22 but there is no known way to
completely prevent their spread to sexual
partners.
Anal HPV
Epidemiology
Large multicenter studies have shown
that 57% of HIV-negative MSM have
anal HPV infection, with 26% of them
having a high-risk strain.34 This preva-
lence persists for MSM across all age
groups, whereas the incidence of HPV
infection in women tends to peak when
women are aged in their late 20s and
again after age 55 years.34 Even though
most HPV infections are transient, MSM
have more sexual partners, more new
sexual partners, and therefore more new
exposures to HPV infection after age 30
years than most women.15,32 HPV-16, one
of the types associated with anal neo-
plasms, is the most common strain found
in anal HPV infections among MSM.18,35
HPV-Associated Carcinoma
The incidence of anal cancer among
Dietz and Nyberg • Genital, Oral, and Anal HPV Infection JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S21
Treatment Mechanisms of Action
Cryotherapy Destruction by thermal-induced cytolysis
Imiquimod (Aldara) Cell-mediated immune response modifier; induces
interferon production
Interferon Antiviral, antiproliferative, and
immunomodulatory activity
Podofilox (Condylox; Cytotoxic, antimitotic; major biologically active
solution or gel) component of podophyllin resin
Podophyllin resin Cytotoxic, antimitotic (causes tissue necrosis)
Trichloroacetic acid Protein coagulation of condyloma tissue
Figure 3. Mechanisms of selected treatment options for genital warts. Reprinted with permission
from Kodner and Nasraty.23
Treatment Typical Cycle
◾Patient-Applied
◽Imiquimod (Aldara) Apply at bedtime for 3 days, then rest 4 days;
alternatively, may apply every other day for
3 applications; may repeat weekly cycles up to
16 weeks.
◽Podofilox (Condylox; Apply twice daily for 3 days, then rest 4 days; may
solution or gel) repeat for 4 cycles.
◾Physician-Applied
◽Cryotherapy Use liquid nitrogen or cryoprobe; may be repeated
every 1 to 2 weeks, if necessary.
◽Interferon Not recommended for office use.
◽Podophyllin resin Apply to each condyloma and allow to dry; may be
repeated weekly, if necessary.
◽Trichloroacetic acid Apply a small amount to visible condylomas and
allow to dry; may be repeated weekly, if necessary.
Figure 4.
Typical treatment cycles for patients with genital warts. Reprinted with permission
from Kodner and Nasraty.23

MSM is higher than cervical cancer rates
among women.15,34 The latter tend to
fall substantially after age 30years, but
MSM are at risk for HPV-associated anal
squamous cell intraepithelial lesions
throughout their lives in all age groups.15
Human papillomavirus has been defini-
tively associated with more than 85%
of all cancerous or precancerous anal
lesions worldwide.35,36
Diagnosis and Management
Condylomas associated with HPV infec-
tion can be external or internal, making
many lesions difficult to visualize.
Patients often report noticing the condy-
lomas after defecation or during sex, par-
ticularly if the lesions are in the anal
canal, which extends about 3 cm from
the anal verge to the anorectal transition
zone37 (Figure 8). Exophytic condylomas
can be managed similarly to other genital
warts by using patient- and physician-
applied topical treatments, as discussed
elsewhere38 (Figures 3 through Figure 5;
Table). The treatment algorithm becomes
more complicated with evaluation for
the presence of HPV-16 infection, HPV-
18 infection, or anal dysplasia.
Anal Papanicolaou tests are increas-
ingly being used to diagnose neoplastic
lesions with the same sampling tech-
niques used for cervical Papanicolaou
tests.38 Studies are underway to deter-
mine standard guidelines for interpreting
anal cytologic findings, but abnormal
cells can be easily identified with typical
cervical cytology interpretation practices.4
Patients with abnormal anal cytologic
findings should be referred for high-res-
olution anoscopy, performed by a spe-
cialist trained in its use; high-resolution
endoscopy, or anal colposcopy, is an effec-
tive way to identify, sample for biopsy,
and manage early neoplastic lesions or
identify patients who need referral to a
colorectal surgeon for management.38
The HPV-HIV Link
Physicians who care for MSM should be
aware that HPV infection is an indepen-
dent risk factor for the subsequent devel-
opment of HIV infection.5Patients pre-
senting with HPV infection in any of its
forms should be screened for HIV infec-
tion at the office visit, preferably with a
rapid finger stick or rapid oral HIV test.5
Higher HIV infection rates are seen
among patients already infected with
HPV.5This association is believed to
occur through 2 distinct mechanisms.
One mechanism is that sexually trans-
mitted infections such as HPV disrupt
normal mucosal anatomic barriers and
may allow HIV-infected body fluids
direct access to open or bleeding lesions.
Another proposed mechanism is that
CD4+ T cells and macrophages are
recruited in higher numbers to skin sur-
faces infected with HPV, allowing closer
potential contact between HIV-infected
fluids and host CD4+ T cells.5
HPV Vaccine and Men
Men infected with HPV serve as vectors
for the spread of the virus to both men
and women.19 It has been demonstrated
in recent meta-analyses36,39,40 that the cur-
Dietz and Nyberg • Genital, Oral, and Anal HPV InfectionS22 •JAOA •Supplement 2 • Vol 111 • No 3 • March 2011
◾Patient-Applied
◽Podofilox 0.5% solution or gel. Podofilox solution should be applied with a cotton swab,
or podofilox gel with a finger, to visible genital condylomas twice a day for 3 days,
followed by 4 days of no therapy. This cycle can be repeated, as necessary, for up to 4 cycles.
The total condyloma area treated should not exceed 10 cm2, and the total volume of podofilox
should be limited to 0.5 mL/d. If possible, the healthcare provider should apply the initial
treatment to demonstrate the proper application technique and identify which condylomas
should be treated. The safety of podofilox during pregnancy has not been established.
◽Imiquimod 5% cream. Imiquimod cream should be applied once daily at bedtime, 3
times a week for up to 16 weeks. The treatment area should be washed with soap and
water 6-10 hours after the application. The safety of Imiquimod during pregnancy has
not been established.
◽Sinecatechins 15% ointment. This ointment should be applied 3 times daily (0.5 cm
strand of ointment to each condyloma) using a finger to ensure coverage with a thin layer
of ointment until complete clearance of condylomas. This product should not be continued
longer than 16 weeks. The medication should not be washed off after use. Sexual contact
should be avoided while the ointment is one the skin.
◾Provider-Administered
◽Cryotherapy with liquid nitrogen or cryoprobe. Repeat applications every 1-2 weeks.
◽Podophyllin resin 10%-25% should be applied to each condyloma and allowed to air dry
before the treated area comes into contact with clothing; over application or failure to
air dry can result in local irritation caused by spread of the compound to adjacent areas.
The treatment can be repeated weekly, if necessary. To avoid the possibility of complications
associated with systemic absorption and toxicity, the following 2 guidelines should be followed:
(1) application should be limited to <0.5 mL of podophyllin or an area of <10 cm2of
condylomas per session and (2) the area to which treatment is administered should not
contain any open lesions or wounds. The preparation should be thoroughly washed off
1-4 hours after application to reduce local irritation. The safety of podophyllin during pregnancy
has not been established.
◽Trichloroacetic acid (TCA) or Bichloroacetic acid (BCA) 80%-90%. TCA solutions have a low
viscosity comparable with that of water and can spread rapidly if applied excessively; therefore,
they can damage adjacent tissue. A small amount should be applied only to the condylomas
and allowed to dry before the patient sits or stands, at which time a white frosting
develops. If pain is intense, the acid can be neutralized with soap or sodium bicarbonate.
If an excess amount of acid is applied, the treated area should be powdered with talc,
sodium bicarbonate, or liquid soap preparations to remove unreacted acid. This treatment
can be repeated weekly, if necessary.
◽Surgical removal either by tangential scissor excision, tangential shave excision, curettage,
or electrosurgery
◾Alternative Regimens
◽Intra-lesional interferon
◽Laser surgery
Figure 5. Regimens recommended by the Centers for Disease Control and Prevention for the man-
agement of external genital warts.22

rent HPV vaccine is more than 95% effec-
tive against HPV-16 and HPV-18 and
could prevent up to 80% of anal carci-
nomas. The quadrivalent HPV vaccine
has also been announced to have 90%
efficacy against HPV types 6, 11, 16, and
18 in males aged 16 to 26 years.41 When
an HPV vaccine is approved for males,
physicians should be proactive in offering
it to their young male patients and all
patients who are MSM.42 Even patients
who are knowledgeable about HPV and
HIV can and do engage in high-risk
sexual behaviors,43 and MSM may not
ask to be screened for HPV or HIV infec-
tion.
As knowledge of the HPV vaccine in
US communities grows, MSM are
increasingly interested about the possi-
bility of being vaccinated. More than 93%
of one surveyed group said they would
be willing to disclose their sexual history
to receive vaccination.44 Other attitude
assessments have determined that young
Dietz and Nyberg • Genital, Oral, and Anal HPV Infection JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S23
Table.
Comparison of Treatments for Patients With Genital Warts
Cost by Risk of
Condyloma Clearance Recurrence,
Treatment Type11*Adverse Effects and Their Incidence (%)†Rate, %9,12 %9,10,12-14‡
Cryotherapy Simple: $268 Pain or blisters at application site (20) 60-90 20-40
Extensive: $415
Imiquimod Simple: $607 Erythema (70); irritation, ulceration, 30-50 15
(Aldara) Extensive: $649 and pain (<10); burning, erosion, flaking,
edema, induration, and pigmentary changes
at application site; minimal systemic absorption
Interferon Simple: $2744 Burning, itching, and irritation at injection site; 20-60 NA
(intralesional) Extensive: $5803 systemic myalgias, headaches, fever, chills,
leukopenia, elevated transaminase levels (6),
thrombocytopenia (1)
Laser Simple: $197 Similar to surgical excision; risk for spreading 25-50 5-50
Extensive: $535 human papillomavirus via smoke plumes
Podofilox Simple: $200 Burning at application site (75), pain (50), 45-80 5-30
(Condylox) Extensive: $334 inflammation (70); low risk for systemic toxicity
Podophyllin Simple: $385 Local irritation, erythema, burning, and soreness 30-80 20-65
resin Extensive: $1449 at application site (75); possibly mutagenicity,
oncogenicity
Surgical excision Simple: $210 Pain (100), bleeding (40), scarring (10); risk 35-70 20
Extensive: $318 for burning and allergic reaction from local
anesthetic
Trichloroacetic Simple: $513 Local pain and irritation; no systemic side effects 50-80 35
acid Extensive: $966
Placebo None NA 0-55 NA
* Cost is per successful treatment course.
† Rates of adverse effects are not compared with rates for placebo.
‡ Recurrence rates are approximated from ranges identified in the referenced texts. Time until recurrence varies across studies, but recurrence rates
typically are measured at 3 months after treatment.
Abbreviation:
NA, not available.
Source:
Reprinted with permission from Kodner and Nasraty.23
ABC
Figure 6.Oral condyloma (A), oral condyloma on the lower lip (B), and external lip condyloma (C). Reprinted with permission from David Reznik, DDS.

male patients are more willing to be vac-
cinated if their healthcare provider
emphasizes the high prevalence of HPV
infection in their communities and the
vaccines’ threat to their own health more
than the patients’ risk of transmitting
HPV infection to others.45 A review of
the literature shows that acceptance of
the HPV vaccine for males is generally
high among physicians and patients, but
patient acceptance is highly dependent
on physicians’ offering the vaccine
first.19,46
Historically, physicians have been
uncomfortable discussing sexual health
issues with patients who are MSM.8,47
Young gay males may experiment with
their sexuality and maintain sexual rela-
tionships with both male and female
partners, in essence doubling their risk of
exposure to and transmission of HPV
infection. Given that about 25% of all
HPV-associated carcinomas occur in
men,17 widespread vaccination of young
men is being considered by the CDC
Advisory Committee on Immunization
Practices.42
Conclusion
With the availability of a vaccine that not
only could prevent HPV-associated
cancer and other diseases but could also
help reduce transmission of HIV,5physi-
cians have an obligation to incorporate
sexual health history and vaccinations
into the routine care of their male
patients.
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Dietz and Nyberg • Genital, Oral, and Anal HPV Infection JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S25
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