Human Papillomavirus
EILEEN M. BURD1,2 and CHRISTINA L. DEAN1
1
Emory University School of Medicine, Department of Pathology and Laboratory Medicine,
Atlanta, GA 30322; 2Emory University School of Medicine, Department of Medicine,
ABSTRACT Individuals with inherited immunodeficiencies,
autoimmune disorders, organ or bone marrow transplantation,
or infection with human immunodeficiency virus (HIV) are at
increased risk of infection with both low-risk and high-risk
human papillomavirus (HPV) types. Chronic immunosuppression
provides an environment for persistent HPV infection which
carries a higher risk of malignant transformation. Screening
guidelines have been developed or advocated for processes
that have detectable premalignant lesions, such as anal cancer
or cervical cancer. For other anatomic locations, such as
cutaneous, penile, and oropharyngeal, a biopsy of suspicious
lesions is necessary for diagnosis. HPV cannot be cultured
from clinical specimens in the laboratory, and diagnosis relies
on cytologic, histologic, or molecular methods.
INTRODUCTION
Human papillomavirus (HPV), a member of the Papil-
lomaviridae family, is a small (8kb), nonenveloped,
double-stranded DNA virus. HPV has a predilection for
infecting cutaneous and mucosal epithelial cells (1). In-
fection with HPV is associated with a wide range of
pathology. HPV is the etiological factor in benign cu-
taneous warts and juvenile respiratory papillomatosis,
as well as low-grade squamous intraepithelial lesions
(LSIL), high-grade squamous intraepithelial lesions
(HSIL), a precursor to cancer, and invasive carcinoma
(2). Harald zur Hausen, a German virologist, was the
first to describe the association of HPV and cervical
cancer in the 1970s (3, 4). It is now understood that
HPV is necessary in the development of cervical cancer
and is also associated with carcinoma of the vulva, va-
gina, penis, anus, and oropharynx (5, 6).
HPV does not grow well in tissue culture and is clas-
sified based on its DNA sequence. Currently, more than
200 types of HPV have been fully sequenced (1, 7).
Human papillomaviruses are generally grouped into five
genera (alpha, beta, gamma, mu, and nu) based upon
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Division of Infectious Diseases, Atlanta, GA 30322
tissue tropism and subsequent host pathology (2, 7).
HPV types within the alpha group have been the focus
of a considerable amount of research due to their ability
to cause both cutaneous and mucosal pathology (2, 4).
Individual types within this genus are further classified
into high-risk HPV and low-risk HPV, depending on
their oncogenic ability. HPV6 and HPV11 are low-risk
types and are most commonly associated with benign
anogenital warts (condylomata acuminata) (1, 8). Al-
though HPV16 and HPV18 are the most prevalent types
causing HSIL and cervical carcinoma, at least 12 high-
risk types have been identified (9, 10). Of note, not all
individuals infected with high-risk HPV will go on to
develop cancer (2, 4). Elucidation of the life cycle and
pathogenesis of HPV has largely come from studying
HPV16 infections of the cervical epithelium (4).
Within the circular genome of HPV, eight genes are
encoded, including genes expressed in both early and
late stages in the life cycle. The infection produced by
HPV can follow one of two pathways and is either pro-
ductive or nonproductive (abortive or transforming).
Regardless of the pathway, HPV requires access to the
basal lamina, and such contact is likely achieved through
small areas of damage to the epithelium (7). Capsid
proteins, L1 (major coat protein) and L2 (minor coat
protein), facilitate entry into the basal layer keratino-
Received: 2 March 2015, Accepted: 8 February 2016,
Published: 15 July 2016
Editors: Randall T. Hayden, St. Jude Children’s Research Hospital,
Memphis, TN; Donna M. Wolk, Geisinger Clinic, Danville, PA;
Karen C. Carroll, Johns Hopkins University Hospital, Baltimore, MD;
Yi-Wei Tang, Memorial Sloan-Kettering Institute, New York, NY
Citation: Burd EM, Dean CL. 2016. Human papillomavirus. Microbiol
Spectrum 4(4):DMIH2-0001-2015. doi:10.1128/microbiolspec
.DMIH2-0001-2015.
Correspondence: Eileen M. Burd, eburd@emory.edu
© 2016 American Society for Microbiology. All rights reserved.
1
Burd and Dean
cytes (7, 11). L2 is thought to also be involved in allow-
ing the viral genome to enter the host cell nucleus where
replication ensues via proteins E1 and E2 as well as the
host cell’s replication machinery (7, 12). The E1 gene
product is a viral DNA helicase, which is recruited by the
binding of the viral transcription factor encoded by the
E2 gene (2). E2 is also involved in anchoring the viral
episome to the host cell genome (13).
Initial viral replication in the basal cells seems to be
independent of the host cell cycle, and viral genomes are
amplified to densities of approximately 50 to 200 copies
per cell (2, 8). In the productive pathway, viral DNA
copies are maintained at low copy number until the cell
moves through the epithelium in the process of differ-
entiation. Virus replication and assembly occurs in post-
mitotic differentiated squamous epithelial cells as they
move toward the epithelial surface. E6 and E7 are reg-
ulated by E2, and while their precise role is somewhat
uncertain, they are associated with driving cell cycle
progression to allow HPV DNA replication in the mid-
layers of the epithelium. Virus gene expression is tightly
controlled, and viral DNA is amplified as extrachro-
mosomal nuclear plasmids with viral copies increasing
about two to four logs (2, 7, 8, 14). No viremia is pro-
duced and replication takes place entirely within the
cell, thus producing little immune response from the
host (15). At the epithelial surface, keratinocytes are
considered terminally differentiated, and they die and
are removed from the body by natural processes. Large
amounts of virus are released from the epithelial sur-
face for transmission to other individuals. At this point,
HPV DNA may be found intracellularly as well as ex-
tracellularly (1). This has important implications for
diagnostic testing. These steps that lead to productive
virus synthesis in the superficial epithelial layers can be
followed by either low- or high-risk HPV types, al-
though productive infections never lead to cancer be-
cause the cell cycle is halted and infected cells leave the
body. Most HPV infections become undetectable after
several months (16). Current thinking is that productive
infection is supported in the cellular environment at the
ectocervix but is inefficiently supported by the cells at the
endocervix, where nonproductive infection is favored
(7).
In nonproductive infection, HPV gene expression
becomes deregulated and the normal life cycle of the
virus cannot be completed. The HPV types associated
with nonproductive infections are designated as high-
risk because of their association with progression to
cancer. The high-risk carcinogenic types of HPV cur-
rently designated by the International Agency for Re-
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search on Cancer (IARC) are HPV16, HPV18, HPV31,
HPV33, HPV35, HPV39, HPV45, HPV51, HPV52,
HPV56, HPV58, and HPV59 (9). HPV68 is classified as
probably carcinogenic, and HPV26, HPV30, HPV34,
HPV53, HPV66, HPV67, HPV 69, HPV70, HPV73,
HPV82, HPV85, and HPV97 have been associated with
rare cases of cervical cancer and are considered probable
carcinogens (9). The E6 and E7 proteins in high-risk
HPV types are functionally different from low-risk types
and serve to stimulate proliferation of infected basal
and suprabasal cells, allowing enlargement of the lesion.
Long-term persistence of HPV is a necessary foundation
for nonproductive infection. Persistence facilitates inte-
gration of the viral gene into the host cell chromosome.
Although some cancers continue to harbor episomal
HPV DNA, integration of viral DNA into the host cell
genome is a common step associated with further dereg-
ulation and overexpression of the E6 and E7 oncogenes
and carcinogenic progression (12). Integration occurs by
chance, and E6/E7 overexpression typically results when
HPV DNA integration occurs in the E1/E2 region and
causes disruption or deletion of E2 gene sequences. This
leads to loss of feedback control and overexpression of
the E6 and E7 oncogenes as well as disruption or silencing
of the downstream early genes that are required for reg-
ulated viral replication. The E6 protein prevents cellular
apoptosis by degrading p53 and contributes to the ac-
cumulation of genetic mutations that lead to immortali-
zation. The E7 protein stimulates cell proliferation when
it binds with the retinoblastoma (Rb) protein and also
stimulates host genome instability (17). The E5 protein
appears to interfere with apoptosis and enhances the
transforming ability of the E6 and E7 proteins (2, 12, 18).
After the initial replication, viral DNA is stably main-
tained at an almost constant copy number during suc-
cessive divisions of the basal cells (19). This is thought to
occur because the viral genomes replicate once along with
cellular DNA during the S-phase of the host cell cycle and
are divided equally into the two daughter cells (19).
Even in this setting, most nonproductive infections
are eventually cleared (as measured by current molecular
tests), 50% within one year and 90% within two years,
by way of a T-cell-mediated immune response (2, 8).
High-grade lesions and cancers usually occur in individ-
uals who do not resolve their infection and who main-
tain oncogene expression for years or decades.
There is growing evidence supporting the ability of
some HPV types to persist in a long-term latent state
in basal epithelial cells after apparent resolution of in-
fection (20). Latent infection has been shown to be a risk
factor for the development of disease at the same site at a

later point in time. Studies in animal models suggest that
HPV genome replication can continue even though gene
expression is suppressed by the activity of memory T cells
(20). Since this type of latency is immune-mediated, sub-
sequent immunosuppression can lead to reactivation of
infection in these experimental systems. Although the
duration of the latent state in humans is not known, it is
a possible explanation for new HPV detection as a result
of aging immune systems in older women (20). It appears
that similar silent infections can result from low-titer in-
fections or infections in epithelial cells that do not com-
pletely support the HPV life cycle (20). In this situation,
changes in the local environment that occur with me-
chanical irritation, wounding, or exposure to ultraviolet
light can initiate reactivation (20).
EPIDEMIOLOGY AND RISK FACTORS
Immune-Competent Patients
HPV is the most common sexually transmitted infection
(STI) worldwide. The majority of individuals who are
sexually active will be infected with HPV at some point
in their lifetime (6). Close to 80 million people in the
United States are currently infected with HPV, and an-
other 14 million become newly infected every year (21).
Anogenital warts are a common clinical manifestation
of HPV infection, and there are roughly 350,000 new
cases in the United States every year (6, 22). Persis-
tent infection with high-risk HPV is the most significant
risk factor for developing carcinoma (2, 6). Cervical and
oropharyngeal carcinoma comprise the majority of the
newly identified HPV-associated carcinomas, and most
of these cases are due to infection with high-risk HPV
types, HPV16 and HPV18 (6, 23). Immune-competent
persons infected with HPV generally have a slow progres-
sion to high-grade, precancerous lesions and subsequent
carcinoma (24). However, most people with competent
immune systems are able to clear HPV infections with
no sequelae. Individuals who have compromised cell-
mediated immunity, such as those with human immu-
nodeficiency virus (HIV), AIDS, or solid-organ transplant
(SOT) recipients, have shown accelerated progression to
high-grade lesions and, thus, are at an increased risk to
develop HPV-associated carcinomas (24–26).
Immunocompromised Patients
External skin
Cutaneous warts
HPV infection is very common among HIV-positive
individuals, due to the sexually transmitted nature of
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Human Papillomavirus
both viruses (23). Hence, this patient population is at
an increased risk for developing HPV cutaneous and
mucosal disease. Cutaneous disease including common
warts, epidermodysplasia verruciformis-like lesions,
squamous cell carcinoma (SCC), and basal cell carci-
noma is more prevalent in HIV-positive individuals (27,
28). These cutaneous lesions tend to be associated with
HPV types usually found in the genital tract, and they
are more likely to be aggressive and difficult to treat (28).
Although the role of HPV in the oncogenesis of skin
cancer has not been fully elucidated, there have been
many reported cases of high-risk HPV types associated
with SCC of the distal digits and periungual skin in HIV-
positive individuals (28). These carcinomas require ag-
gressive treatment and tend to recur.
Benign anogenital warts, or condylomata acuminata,
are the most common clinical manifestation of HPV
infection in both immune-competent and immunosup-
pressed individuals. Roughly 90% of anogenital warts
are attributed to low-risk types, HPV6 and HPV11 (6).
Similar to nongenital cutaneous lesions, HIV-positive
patients often present with widespread lesions that can
be more aggressive and difficult to treat (28, 29).
HPV-induced cutaneous warts and SCC also pose a
major health risk for SOT recipients who are receiving
immunosuppressive therapy. In fact, it has been reported
that SOT recipients are at a higher risk for developing
skin cancer than those with HIV or AIDS (30). This
phenomenon has not been fully elucidated, but research
suggests that certain immunosuppressive drugs, as well
as an individual’s humoral immune response, may play a
role (30, 31). The 10-year cumulative incidence of skin
cancer in this population reaches 10 to 40% (32). Renal
transplant recipients seem to be at a particularly high
risk for developing HPV-related cutaneous warts and
skin cancers (32, 33). Immunosuppression, ultraviolet
light, and infection with high-risk HPV types are all
important risk factors in patients with a history of SOT
(33, 34).
Hematopoietic stem cell transplant (HSCT) recipients,
especially those with chronic graft-versus-host disease
(cGVHD), are at an overall increased risk for developing
a secondary malignancy, with cutaneous SCC being the
most frequent lesion identified (35). However, the asso-
ciation with cutaneous SCC and HPV in this patient
population has not been well studied.
Epidermodysplasia verruciformis
Epidermodysplasia verruciformis (EV) is an autosomal
recessive dermatologic condition characterized by per-
sistent HPV infections of the skin that can transform into
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Burd and Dean
carcinoma (25, 34). In fact, nearly 50% of patients with
EV will develop skin cancer by the time they reach their
fifth decade of life (34). There are specific HPV types
associated with EV (EV-HPV), but HPV5, HPV8, and
HPV14 are most commonly associated with malignancy
in these patients (34). Whether EV-HPV is a causal fac-
tor in the development of cutaneous malignancy is still
debated, and the oncogenesis is poorly understood (36).
Recently, an acquired EV, or EV-like, syndrome has been
described in immunosuppressed patients infected with
EV-HPV, specifically those with HIV and SOT recipients
(37). Case reports for this entity are rare and progression
to malignancy has not yet been documented.
Oropharyngeal cancer
Individuals with HIV are at an increased risk of devel-
oping HPV-related cancers, including head and neck
cancer (HNC). Over 400,000 new cases of HNC occur
every year, making it the sixth most common cancer
worldwide (38). HPV is detected in roughly 25% of
cancers arising in the oropharynx, and in the general
population, detection is directly correlated with the num-
ber of recent oral sex partners (39). More than 80%
of HNCs are caused by oncogenic HPV16, and this is
the most frequently detected HPV type in HIV-positive
patients (40, 41). Up to a 3-fold increase in the incidence
of oral HPV infection has been demonstrated in individ-
uals infected with HIV (40). Contrary to HIV-negative
individuals, oral HPV infection in those with HIV is as-
sociated with increased numbers of lifetime oral sex
partners (40). It is still not clear whether CD4 count and/
or AIDS diagnosis has an effect on the prevalence of oral
HPV infection (39). Additionally, the effect of antiretro-
viral therapy (ART) on oral HPV prevalence has not
been fully elucidated, but some studies suggest that there
may be an increase in oral lesions and HPV persistence in
individuals receiving ART (39).
SOT recipients are also at an increased risk for devel-
oping HPV-related cancers. Oropharyngeal carcinoma is
the third most common HPV-related cancer identified
in SOT recipients, after vulvar and anal carcinomas (42).
Factors such as age, race, transplanted organ, and certain
immunosuppressive drugs may affect the incidence of
HPV-related oropharyngeal carcinoma (42).
Oropharyngeal carcinoma is frequently found in
long-term survivors of HSCT. As in cutaneous SCC,
these lesions are strongly associated with cGVHD (35).
Again, the association between HNC and HPV has not
been fully elucidated in HSCT recipients; however, sev-
eral case reports suggest that these lesions may be HPV-
driven (43).
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Anal cancer
Anal cancer is a rare malignancy, with an incidence rate
of around 2 per 100,000 for both men and women (44).
A significant risk factor for anal SCC is coinfection with
high-risk HPV and HIV (45). More than 90% of anal
SCCs are associated with persistent HPV infection, and
the majority of these cases are attributed to HPV16 and
HPV18 (45, 46). The prevalence of anal HPV detected
when screening men and women with HIV surpasses
90%, though not all will have abnormal pathology.
The incidence of anal SCC is increased 30-fold in HIV-
positive individuals and 80-fold in HIV-positive men
who have sex with men, compared to HIV-uninfected
individuals (45, 47). A notable increase in the incidence
of anal SCC was reported with the introduction of ART,
which was attributed to the increased lifespan of HIV-
positive individuals. However, a recent study suggests
that these numbers may be stabilizing (47).
Epidemiological studies have shown that 20 to 50%
of SOT recipients have detectable anal HPV and a
10-fold increase in the relative risk of developing anal
SCC (48, 49). Similar to HIV-positive patients on ART,
the incidence of HPV-associated anal cancer has in-
creased in SOT recipients who remain on immunosup-
pression for long periods of time, likely due to increased
survival (48).
Penile cancer
Penile SCC and penile HSIL are rarely encountered dis-
eases in the general population. In the United States,
penile SCC accounts for less than 0.5% of all cancers in
men (50). HPV is associated with roughly 50% of penile
cancer cases, and oncogenic HPV16 is the most common
type detected (51, 52). Individuals infected with HIV
have a 2- to 3-fold increase in risk of developing penile
SCC (28). Up to 4% of the HIV-infected population
may have precursor lesions (HSIL), but the progression
to cancer only occurs in about 5 to 30% of cases (28).
Other risk factors include tobacco use, poor hygiene,
phimosis, and lack of circumcision (28).
Cervical cancer
With over 500,000 cases every year, cervical carcinoma
is the fourth leading cause of cancer in women world-
wide (53). It is now known that HPV is necessary for
cervical cancer to occur, and its pathogenesis has been
investigated extensively. Risk factors for cervical carci-
noma include tobacco use, young age of sexual debut,
multiple sexual partners, high-risk sexual partners, his-
tory of other STIs, and a history of genital SIL or carci-
noma (54). Women with HIV/AIDS and SOT recipients,

in particular renal transplant, have an increased inci-
dence of persistent HPV infection and, thus, are at an
increased risk for developing cervical carcinoma (25,
55). Of note, some studies suggest that SOT recipients
on immunosuppressive therapy do not have an increased
incidence of cervical cancer (42, 55). HIV-infected
women have up to a 22-fold increased incidence of
cervical cancer, and CD4 count is inversely proportional
to abnormal cervical pathology (24, 25, 56). Because of
the high prevalence, cervical carcinoma was classified as
an AIDS-defining disease in 1993 (25). It is still unclear
whether implementation of ART in HIV-positive women
decreases the incidence of cervical cancer in this risk
group (57).
Cervical carcinoma is the third most common sec-
ondary malignancy in HSCT recipients (35, 58). Women
who receive long-term treatment for cGVHD and those
with an unrelated HLA-matched donor are at greatest
risk for developing SIL after transplantation (58, 59).
Whether this is due to reactivation of HPV or to infec-
tion posttransplant needs to be further investigated.
LABORATORY TESTING
Skin Lesions
Diagnosis
Immunosuppressed patients should be vigilantly fol-
lowed for early diagnosis of skin cancer. Lesions in im-
munosuppressed patients tend to grow more rapidly
and can be more invasive (60, 61). In addition, there
is a strong association for development of additional
squamous cell carcinoma lesions in patients who have
been previously diagnosed (62).
Cutaneous warts can generally be diagnosed by ex-
amining the affected area of skin, which may be exten-
sive in immunocompromised patients. Warts do not
generally need to be biopsied to make the diagnosis or to
determine what treatment may be necessary, unless there
is concern that the changes could be cancerous. There
is some suggestion that persistent low-risk beta-HPV-
induced warts may progress to actinic keratosis and skin
cancer in immunocompromised patients since squamous
cell carcinoma lesions and warts can be found jointly
in this population (61, 63). For this reason, biopsy or
surgical excision specimens for histopathologic assess-
ment should be obtained from all suspicious lesions. The
squamous cell carcinomas that develop in immunocom-
promised individuals have characteristic morphological
features of HPV-induced lesions (63). Some pheno-
typic differences suggestive of a more aggressive process
have been noted in skin cancers of transplant recipients
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Human Papillomavirus
compared to those found in immune-competent patients
(64). These differences include higher levels of immu-
nohistochemical staining for p53 and transforming
growth factor-beta (TGFβ) proteins, along with low
levels of phosphorylated mTOR and P70S6K, and a
higher incidence of a spindle cell component, indicating
epithelial-to-mesenchymal transition (64, 65).
Oropharyngeal Cancer
Screening
Because some parts of the oropharynx are difficult to
visualize, oropharyngeal squamous cell cancers are often
detected in later stages. A number of efforts have been
made toward early detection but they have achieved
only limited success. Current guidelines from the U.S.
Preventive Services Task Force and the American Dental
Association suggest that screening using conventional
visual and tactile examination may facilitate early di-
agnosis of oropharyngeal and other oral cancers, but
there is not sufficient evidence to support the use of
additional screening tests (66, 67).
Diagnosis
The diagnosis of oropharyngeal cancer (OPSCC) is
made by microscopic examination of biopsy tissues or
exfoliated cells. Biopsy is often preferred since exfolia-
tive cytology does not detect all cancers.
The histopathologic terminology used to describe
HPV-related OPSCC has been inconsistent. Rather than
describing specific histologic features, OPSCC tumors
are often described by the presence of HPV and/or
cellular changes due to HPV. The National Compre-
hensive Cancer Network and the College of American
Pathologists have recommended routine testing for HPV
in all OPSCC (68). It is essential for accurate diagnosis
that only specimens obtained from the oropharynx are
tested for HPV, since involvement of HPV with oral
tumors outside of the oropharynx is negligible and may
not be specific to the tumor. Since HPV-positive tumors
tend to have better clinical outcomes, HPV testing can be
helpful as a prognostic indicator (69). While metastatic
disease is not common with OPSCC, and metastases in
HPV-positive tumors are not preceded by bulky or ad-
vanced oropharyngeal disease, HPV testing may help
indicate the site of the primary tumor (70). In the future,
since prognosis is good, HPV testing may also allow for
more directed and less aggressive therapy for OPSCC
than therapy for smoking-related oral tumors. Other
future uses of HPV testing could potentially include the
assessment of response to treatment and monitoring for
recurrence of disease following treatment.
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Burd and Dean

While testing is recommended, the types of test(s) that
should be used to detect HPV-associated OPSCC are not
specified. The FDA-approved nucleic acid amplification
HPV tests for cervical cytology are not approved for
oropharyngeal specimens. Furthermore, tests that assess
transcriptional activity or specifically localize HPV to
the tumor may be more relevant since HPV can occa-
sionally be detected in the absence of disease (71, 72).
Numerous tests, such as RT-PCR for E6/E7 mRNA,
HPV DNA-based in situ hybridization (ISH), and im-
munohistochemistry (IHC) for p16, p53, Ki67, prolif-
erating cell nuclear antigen, and other markers have
been investigated (73–76). HPV DNA ISH and p16
IHC have emerged as the most reliable of the methods.
HPV DNA ISH allows for visualization of the virus in
tumor cells and has been found to be highly specific, but
not as highly sensitive. Modifications that include the
use of nonfluorescent chromogens and changes in sig-
nal amplification steps have resulted in increased sensi-
tivity (76). Because there will be some p16 staining in
nearly all squamous cell carcinomas, the use of tumor-
suppressor protein p16 IHC has been found to be highly
sensitive as a surrogate marker of transcriptionally ac-
tive HPV infection; unfortunately the marker is not en-
tirely specific (76). When a positive p16 IHC stain is
defined as strong nuclear staining plus cytoplasmic
staining, which is present in at least 50% of tumor cells,
then IHC is sufficiently sensitive and specific (76). Re-
gardless of HPV status, p16 IHC staining alone is con-
sidered to be the most useful prognostic indicator for
patients with known OPSCC (76, 77). Outcomes for
p16 IHC-positive tumors are not significantly different
whether they are HPV-positive or negative, but out-
comes are significantly better compared to tumors that
are negative for p16 (77). Along with HPV DNA ISH or
HPV PCR, p16 IHC is recommended to help resolve
focal or weak p16 staining, p16-negative tumors with
typical HPV histologic morphology, and p16-positive
tumors that do not have typical HPV histologic mor-
phology (76) (Fig. 1). In patients with a known primary
OPSCC, p16 IHC may be used instead of HPV testing of
fine-needle aspiration biopsies to determine if the cancer
has spread to the local lymph nodes (76).
Penile Cancer
Diagnosis
Early recognition of penile cancer is based on visual
examination, and changes in penile skin color, thick-
ening, ulcers, bumps, flat growths, or other lesions may
warrant further investigation. Flat penile lesions, in par-
ticular, seem to be associated with HPV (78). A biopsy is
needed to make an accurate diagnosis of cancer. Squa-
mous cell carcinoma is the most common type of penile
cancer, and most squamous cell lesions have distinctive
features that allow their classification as HPV-related
or non-HPV-related. Most penile cancers are not related
to HPV and are usually classified as keratinizing squa-
mous cell carcinomas (78, 79). Others are associated
with high-risk HPV infection and are warty, basaloid,
or mixed (basaloid/usual, warty/basaloid, warty/usual)
histologic types that are HPV ISH-positive and show
strong diffuse p16 IHC staining and the presence of
lymphovascular invasion (78, 79). Although PCR is
often considered to be the gold standard for detection
of HPV, none of the commercially available tests are
FDA-approved for use in men. A recent study showed
good correlation between PCR results and a combina-

FIGURE 1 Algorithm for diagnosis of oropharyngeal squamous cell carcinoma.

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tion of morphology, p16 IHC, and/or HPV DNA ISH
(80). The authors recommend that in order to achieve
the highest diagnostic specificity, morphology, p16 IHC,
and HPV DNA ISH should be considered together and
all should be positive (80).
The importance of determining the HPV status in
penile lesions is often stressed because of the impact on
preventing transmission to sexual partners or to identify
partners who are already infected and at increased risk
for HPV-associated malignancies (80). HPV status may
also be helpful in the differential diagnosis of primary
high-grade urothelial carcinoma versus HPV-related
basaloid or warty/basaloid squamous cell cancer of the
distal penile urethra (80). Both tumors are found with
nearly equal frequency and can look histologically sim-
ilar, especially when biopsies are small (80). The use of
both HPV DNA ISH and p16 IHC is recommended since
although typically associated with HPV, overexpression
of p16 has been found in up to one-half of urothelial
carcinomas (80).
Determining HPV status as a prognostic factor in
penile cancer remains unclear. There are few reported
studies that have examined HPV-positive precursor
lesions and their potential to progress to cancer, and
results have been inconsistent (78). Several studies from
Europe have concluded that HPV status as determined
by PCR and/or p16 IHC positivity in penile squamous
cell carcinoma is favorably associated with cancer-
specific survival (81–83). In a cohort of patients in North
America, HPV status as determined by high-risk HPV
ISH and/or p16 IHC was not predictive of outcome
(recurrence, progression, overall mortality, or disease-
specific survival) (84). A trend toward delayed progres-
sion was associated with high-risk HPV ISH positivity
in this study, although the association did not reach
statistical significance (84). In another North American
study, p16 IHC positivity was not associated with
stage, histologic grade, lymph node status, lymphovas-
cular invasion, lymph node metastases, or overall sur-
vival in patients with penile SCC (85). Lack of p16,
however, was significantly associated with recurrence,
especially in patients who had lymph node involvement
at diagnosis (85). Additional studies are needed to es-
tablish the role of HPV status as a potential prognostic
indicator.
Anal Cancer
Screening
Analogous to cervical cancer, the ability to detect HPV
and identify precursor dysplastic lesions in the transition
zone of the anal canal could allow for the development
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Human Papillomavirus
of screening and prevention programs. Systematic anal
cancer screening is recommended by some groups, while
others suggest that more information is needed before
screening processes other than visual and digital exam-
ination can be recommended.
There are currently no formal recommendations for
routine anal cancer screening in the United States;
however, some programs, such as the New York State
Department of Public Health AIDS Institute, have estab-
lished screening algorithms (86). Screening is proposed
only for high-risk groups, including SOT recipients, men
who have sex with men, women with abnormal cervical
or vulvar histology, all HIV-infected men and women,
and any patient with a history of anogenital condylo-
mas. It has become clear from multiple studies that
testing for HPV is not useful for anal cancer screening
because the prevalence of HPV and frequency of mixed
infections are unusually high in at-risk populations, and
the consequences of infection are not well understood
(87). Cytology, however, may be useful; preliminary re-
commendations for screening men who have sex with
men include obtaining anal cytology at baseline and
annually for those who are HIV-positive and biennially
for those who are HIV-negative (88) (Fig. 2). Either con-
ventional Papanicolaou-stained smears or liquid-based
cytology can be used. Anal cytology smears are evalu-
ated using the same Bethesda nomenclature as for cer-
vical cytology, with abnormalities designated as atypical
squamous cells of undetermined significance (ASC-US);
atypical squamous cells, cannot exclude a high-grade
squamous intraepithelial lesion (ASC-H); and LSIL and
HSIL (Table 1). The koilocytic changes associated with
HPV may not be as pronounced in anal cytology, al-
though binucleation, multinucleation, and cytoplasmic
keratinization may be more prominent than in cervical
lesions (86). There is also a higher incidence and lower
specificity of atypical squamous cells of undetermined
significance in the anal canal (86).
Diagnosis
Similar to cervical cytology, there is substantial inter-
observer variation in interpretation of anal cytology,
and histological confirmation is important. Histologi-
cal grading is also subject to interobserver variability.
Standardized terminology for epithelial lesions in all
anatomic locations of the lower anogenital tract was
developed in 2012 by the Lower Anogenital Squamous
Terminology Standardization (LAST) Project to replace
older nomenclature and eliminate some of the subjec-
tivity in interpretation (89). According to older nomen-
clature, precancerous anal lesions were termed anal
7
Burd and Dean

FIGURE 2 Algorithm for screening and diagnosis of anal cancer in high-risk groups.
There are currently no formal recommendations for routine anal cancer screening in the
United States.

intraepithelial neoplasia (AIN) and were categorized
as grade 1, 2, or 3 (mild, moderate, or severe), based
roughly on the distribution of the abnormalities within
the epithelium. The LAST terminology is LSIL and HSIL
and may include subgrading using the older –IN termi-
nology (Table 1) (89). Clearly identifying a lesion as –IN
2 can be difficult, and p16 IHC is recommended to de-
termine the appropriate classification (Fig. 2). Diffuse,
strong p16 staining in the precancerous lesion supports
classifying the lesion as HSIL (89). Absence of p16 stain-
ing, or presence of minimal patchy staining, supports
reducing the classification to LSIL (89).
Opinions differ as to the optimal management of
precursor lesions, and the success of treatment in the
prevention of development of anal cancer has not been
widely established (90, 91). Studies are needed to better
characterize the natural history of HPV-associated anal
lesions and to provide evidence for effective treatment.

TABLE 1 Cytological and histological classification of anal dysplasia and cervical dysplasiaa

Natural LAST cervical intraepithelial LAST cervical and anal

history Bethesda 2001 cytology neoplasia histology intraepithelial neoplasia histology
Normal NILM Negative Negative
infection ASC-US atypia atypia
ASC-H
LSIL LSIL (formerly CIN 1) LSIL (formerly AIN1)
Precancer HSIL HSIL (formerly CIN 2, CIN 3, CIS) HSIL (formerly AIN2, AIN3, CIS)
Cancer Carcinoma Carcinoma Carcinoma
AGC Correlates with a variety of histologic N/A
• Not otherwise specified (NOS) outcomes including (111):
• Favor neoplasia • Negative or benign
• CIN 1
• CIN 2/3
• Microinvasive squamous cell carcinoma
• Carcinoma in situ
• Cervical adenocarcinoma
• Endometrial adenocarcinoma
• Endometrial hyperplasia
aNILM, negative for intraepithelial lesion and malignancy; ASC-US, atypical squamous cells unspecified significance; ASC-H, atypical squamous cells cannot exclude HSIL;

LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; AGC, atypical glandular cells; CIN, cervical intraepithelial neoplasia; CIS,
carcinoma in situ; AIN, anal intraepithelial neoplasia; AIS, adenocarcinoma in situ.

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 Human Papillomavirus

Cervical Cancer engaged in sexual intercourse should be screened using

Screening
The current most widely recognized cervical cancer
screening guidelines were updated and independently
published in March 2012 by the American Congress of
Obstetricians and Gynecologists (ACOG), the United
States Preventive Services Task Force (USPSTF), and the
American Cancer Society (ACS) in partnership with the
American Society for Colposcopy and Cervical Pathol-
ogy (ASCCP) and the American Society for Clinical
Pathology (ASCP), with an interim update provided
in January 2015 (92–95). These guidelines are focused
on screening algorithms for immune-competent women
with average risk for HPV infection and do not make
recommendations for immunocompromised women.
Data are limited, but most studies seem to indicate
that HPV infection is detected with greater frequency in
immunosuppressed patients and that immune deficiency
increases persistence of HPV and thereby increases the
risk of cervical dysplasia and invasive cervical can-
cer (56, 96–99). There is some evidence to suggest that
high-grade precursor lesions progress more rapidly to
cervical cancer in immune-suppressed women (56). For
HIV-infected women, no apparent reduction in HPV-
associated cervical cancer is afforded by highly active
antiretroviral therapy (100).
The Centers for Disease Control and Prevention
(CDC), National Institutes of Health (NIH), and the In-
fectious Disease Society of America (IDSA) jointly pub-
lished updated cervical cancer screening guidelines for
HIV-infected women in 2009 (101, 102) (Table 2; Fig. 3).
These guidelines recommend that HIV-infected women
cytology (Papanicolaou-stained smear) at 6-month inter-
vals in the first year following diagnosis of HIV infection
and then annually after that as long as the cytology re-
sults remain normal (101, 102). Women with HIV should
not begin screening until age 21 even if their HIV diag-
nosis was before age 21. There are no specific guidelines
regarding screening of transplant recipients for cervical
cancer. However, it is generally agreed that it is prudent
to screen annually beginning at age 21 rather than every
3 to 5 years as is recommended for normal-risk women
(99). Screening plans may be modified for individual
patients, depending on the degree of immune suppression
and other factors (99). Some experts would recommend
continued cytology screening every 6 months in women
with CD4 counts less than 200/mm3 or a history of HPV
infection.
The initial biennial cytology screening is recom-
mended given concerns about the relative insensitivity
of cytology and that an abnormal lesion may be missed
with a single cytology smear. The rate of abnormal cy-
tology is high among HIV-infected women and has been
reported as atypical squamous cell of undetermined
significance or LSIL in 37% and as HSIL in 5%, with
normal cytology in the remaining 58% (56). Prevalence
of HPV is also high among HIV-infected women with
normal cytology and has been reported as 57.4% in
South/Central America, 56.6% in Africa, 32.4% in
Europe, 31.4% in North America, and 31.1% in Asia
(56). In contrast, HPV detection in the absence of ap-
parent disease is found in about 11 to 12% of immune-
competent women. Also of note is that the rate of

TABLE 2 Cervical cancer screening guidelines

Normal-risk women (92–95) Women with HIV (101, 102)

Age at initiation Age 21, regardless of risk Age 21, even if diagnosis of HIV
infection was before age 21a
Frequency
Age 21–29 years Cytology every 3 years –or– primary HPV testing can be considered starting at Cytology at 6-month intervals in the
age 25 every 3 years first year following diagnosis of HIV
infection and then annual cytologyb,c
Age 30–65 years Cytology every 3 years –or– cytology plus HPV every 5 years – or– HPV primary
testing every 3 years starting at age 25 as above
Discontinuation Women age 65 or older who have 3 or more consecutive negative cytology tests or Never?d
of screening two consecutive negative cotests within 10 years, with the most recent test
performed within 5 years
After hysterectomy Women of any age who have had a total hysterectomy and have no history of Same as normal-risk womend
cervical cancer or precancer should not be screened. If there is a history of
CIN 2 or worse, screen for 20 years even if screening extends to beyond age 65
HPV vaccinated No change from above No change from above
aProviders should consider screening within 1 year of onset of sexual activity (101).
bSome experts would recommend continued cytology screening every 6 months in women with CD4 counts less than 200/mm3 or a history of HPV infection.
cAnnual cervical cytology screening is recommended for immunosuppressed women without HIV (90).

dData insufficient in this population.

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Burd and Dean

FIGURE 3 Algorithm for screening and diagnosis of cervical cancer in immunosuppressed

women. For HIV-infected women (90), screen at 6 months, 12 months, then annually;
consider screening within 1 year of onset of sexual activity (92); some experts would
recommend continued cytology screening every 6 months in women with CD4 counts
less than 200/mm3 or a history of HPV infection. For immunosuppressed women without
HIV, annual cervical cytology screening is recommended (90).

infection with multiple HPV types is higher for HIV-
infected women than for the general population (56).
This higher rate of multiple HPV infections is found in
both the presence and absence of abnormal cytology (56).
The utility of detection of high-risk HPV or HPV
genotyping in conjunction with cytology as is endorsed
for the general population has not been determined for
immunosuppressed women. The concern is that HPV
DNA tests may be less specific in immunocompromised
women and might not be as effective for screening be-
cause of the high prevalence and persistence of HPV
among women with HIV (56). Specificity and positive
predictive value may be improved by detecting E6/E7
mRNA, rather than HPV DNA as has been found in the
general population, but this screening strategy has not
been studied in immunosuppressed populations. Studies
that compare detection of high-risk HPV with cytology
and development of precancerous and cancerous lesions
are needed. Results of pilot studies have raised concerns
about normal cytology and unrecognized high-risk HPV
infection, especially in HIV-infected women 21 to 30
years of age (98, 103, 104). Follow-up observations in
one of the studies showed that HIV-infected women
with normal cervical cytology and high-risk HPV were
4-fold more likely than women without high-risk HPV
to have an abnormal finding on colposcopic examina-
tion (103). From these results, it appears that detection
of high-risk HPV and early colposcopic examination
could particularly be of benefit in screening of immuno-
suppressed women.
HPV16 is associated with the majority (48 to 72%) of
high-grade cervical lesions in normal-risk women (105,
106). A large meta-analysis as well as subsequent studies
have found that HPV16 is less prevalent (32 to 51%)
among HIV-infected women with high-grade cervical
lesions, and that other subtypes (11, 18, 33, 51, 52, 53,
58, and 61) and infection with multiple HPV types are
significantly more common (56, 105, 107). These find-
ings suggest that genotype testing may have less of a role
in this population.
Diagnosis
Cytology
Cervical cytology using Papanicolaou-stained smears has
been the standard screening test for detection of prema-
lignant lesions and cervical cancer since 1941. Liquid-
based, thin-layer systems are a more recent technology
for preparation of smears that requires placing cervical
specimens into a vial of liquid preservative. The speci-
mens are processed to remove debris and reduce exces-
sive white and red blood cells. The remaining specimen is
then sedimented if the BD SurePath (BD Diagnostics–
TriPath, Burlington, NC) system is used, or filtered if the
ThinPrep (Hologic Inc., Marlborough, MA) system is
used, to produce a monolayer of cells on a glass micro-
scope slide, which is then stained. The liquid-based pro-

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cess improves disease detection by making diagnostically
relevant cells more clearly visible and results in fewer
unsatisfactory slides when compared to conventionally
prepared smears (108). Stained slides are examined man-
ually using a standard light microscope or by an imaging
system (e.g., ThinPrep Imaging System, Hologic Inc.)
that uses a computer to automatically scan the slide and
mark potentially abnormal cells with larger or darker
nuclei for review by a cytotechnologist and interpreta-
tion by a pathologist for final diagnosis. The consistent
and objective evaluation of cytology smears afforded by
imaging systems is thought to improve diagnostic accu-
racy (109).
The Bethesda System has been the standard termi-
nology used for reporting cervical cytology since 1988.
The system has been modified several times, and the
nomenclature currently in use was developed in 2001
(110) (Table 1). Precancerous cytologic abnormalities in
squamous epithelial cells are stratified in several cate-
gories. Atypical squamous cells (ASC) are the most
common abnormal finding and are divided into ASC-US
and ASC-H. LSIL is mild dysplasia caused by HPV in-
fection and characterized by squamous cells with nu-
clear atypia, perinuclear halo, and dense cytoplasm.
HSIL is a more severe abnormality that includes mod-
erate to severe dysplasia and carcinoma in situ. If LAST
terminology is accepted, squamous histology and cy-
tology descriptions will be consistent (Table 1). The
Bethesda system also allows for description of glandular
cell abnormalities which are caused by HPV but are far
less common and are categorized as atypical glandular
cells (AGC) with identification of whether they are en-
dometrial or endocervical if possible (111). “Adeno-
carcinoma in situ” and “AGC favor neoplastic” are
included as subcategories of AGC and can be difficult to
detect because the ability to completely sample the
endocervical canal for cytologic analysis is somewhat
limited and glandular lesions may be inaccessible.
Cervical cytology has been very effective in cervical
cancer screening programs but carries a false-negative
rate of about 5% to 20% (112). Inadequate sampling of
the transformation zone and small lesion size may ac-
count for much of the reduced sensitivity, but there is
also some interobserver variability as well as screening
errors by cytotechnologists and interpretive errors by
pathologists that contribute. Steps to reduce laboratory
reading errors were mandated under the Clinical Labo-
ratory Improvement Act of 1988 (CLIA), which requires
that a random sample of at least 10% of cytology smears
are rescreened by a pathologist or senior cytotechnol-
ogist for quality control (113). In addition, all slides
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Human Papillomavirus
assessed as positive after a single examination should be
reviewed a second time for verification.
Molecular HPV tests
HPV DNA testing in HIV-infected women or adoles-
cents is not recommended at this time, although it has
now been incorporated into cervical cancer screening for
normal-risk women because of the limitations of cytol-
ogy (114) (Table 3). The most common commercially
available molecular tests are designed to detect HPV
DNA from high-risk types and generate a pooled result
without identification of the specific type present. There
are important differences among the various tests. The
tests include the Digene Hybrid Capture 2 High-Risk
HPV DNA Test (Qiagen, Redwood City, CA) using hy-
brid capture technology, the Cervista HPV HR test
(Hologic Gen-Probe Inc., San Diego, CA) using fluoro-
metric invader technology, and the cobas HPV real-time
PCR test (Roche Molecular Systems Inc., Pleasanton,
CA). The cobas HPV test generates an aggregate result
and indicates the presence of HPV16 and/or HPV18.
Other tests are designed specifically to detect HPV16
and HPV18 (or HPV18/45). Commercially available
genotyping assays include the Cervista HPV16/18 test
and the Aptima HPV16 18/45. Many studies have de-
termined that detection of HPV E6/E7 mRNA is more
specific than DNA-based assays when measured against
clinical disease with a histological diagnosis of moderate
cervical intraepithelial neoplasia (CIN 2) or worse (115,
116). Currently, the only available test that detects HPV
mRNA is the Aptima HPV Assay (Hologic Gen-Probe
Inc.). The HPV molecular tests are approved by the FDA
for cervical cancer screening in combination with a Pap
test among women over age 30 and for follow-up testing
of women with abnormal cytology results. The cobas HPV
test was recently approved as a primary screening test.
It is important to note that HPV tests, as approved by
the FDA, are performed on a fixed volume of sample
TABLE 3 Role for HPV testing in HIV-infected womena
(119)
Normal-risk women HIV-infected women
Triage ASC-US cytology result Triage ASC-US cytology result?a
Cotest with cytology for Follow-up after colposcopy or
women ≥age 30 years treatment (loop electrosurgical
excision procedure/cone biopsy
Postmenopausal women
with LSIL
Follow-up after colposcopy or
treatment (loop electrosurgical
excision procedure/cone biopsy
a Data insufficient in this population.
11
Burd and Dean
randomly obtained from the collection vial used for liq-
uid-based cytology or a cervical brush in preservative
fluid. Because cytology analyzes only cells and HPV tests
analyze cells plus extracellular material, they are not ex-
actly comparable (117). The extracellular material ex-
amined in HPV tests may contain a large amount of
nucleic acids from free virions as are found in produc-
tive transient infections. When HPV tests are performed
using an enriched cellular fraction obtained after centri-
fugation rather than a random whole sample from the
collection vial, the specificity of the HPV test for detection
of corresponding abnormal cytology is improved (117).
Another aspect is that even molecular HPV tests with a
high analytical sensitivity of about 20 to 400 HPV DNA
copies per reaction are not sensitive enough to detect all
cancers (118). The lower limit can easily be reached when
few clonal (abnormal) cells are present in the sample.
Management
There is controversy about management of abnormal
cytology in HIV-infected women. ASCCP guidelines in
2001 presented separate recommendations for the man-
agement of ASC-US in women with HIV infection and
other immunosuppressive conditions. These separate
guidelines were eliminated in 2006 in favor of managing
immunosuppressed women in the same manner as the
general population. ASC-US is managed in the general
population either by repeat cytology (at 1 year is ac-
ceptable) or by high-risk HPV testing, which is preferred
(119). Other guidelines suggest that there are not enough
data to recommend HPV testing alone in the manage-
ment of ASC-US and suggest that either immediate re-
ferral to colposcopy or repeat cytology in 6 to 12 months
should be used (120). Some authorities recommend that
all HIV-infected women with atypical squamous cell of
undetermined significance be referred for only immedi-
ate colposcopy and directed biopsy, with further treat-
ment based on those results (102).
For any lesion greater than ASC-US (i.e., ASC-H,
LSIL, HSIL or AGC), referral for colposcopy is recom-
mended (102, 119). It is also recommended that HIV-
infected women with cervical HSIL should be referred
for anal cytologic screening as they are at increased risk
for anal dysplasia and cancer (102).
Treatment monitoring
Although HPV is more difficult to treat and more likely
to recur with increased immunosuppression, cervical
cancer precursors in HIV-infected and other immunosup-
pressed women should generally be managed accord-
ing to ASCCP guidelines (119). Treatment may include
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ablative (e.g., cryotherapy, laser vaporization, electro-
cautery, diathermy, cold coagulation) or excisional (e.g.,
loop electrosurgical excision procedure, laser coniza-
tion, cold knife conization) to remove or destroy the
abnormal cells. An excisional procedure is indicated in
patients with recurrent or persistent high-grade CIN or
if colposcopy is unsatisfactory (119). For HIV-infected
adolescents, standard treatment guidelines for adoles-
cents and young adults are considered to be safe and
effective (119). Recurrence is more common in these pa-
tients, and close observation as defined in the guidelines
for management of CIN 1 and CIN 2 is important. For
patients with CIN 1 who may not be compliant, fol-
lowing the more stringent management guidelines for
CIN 2 may be preferable (119).
The success of treatment has been monitored using a
wide variety of follow-up approaches including repeat
cytology, HPV testing, cytology and HPV cotesting, or
colposcopy alone or in combination with cytology or
HPV tests. There are no established guidelines for test-
ing, and follow-up intervals vary among reports from
3 to 12 months (119, 121). Although posttreatment
data from randomized trials are not available, HPV
testing is generally considered to be more sensitive than
cytology and may allow for earlier diagnosis of persis-
tent or recurrent disease, while a negative HPV test may
allow for less intense management (119, 121). Further
work to refine follow-up strategies is needed for the gen-
eral population as well as specifically for immunocom-
promised patients.
Prevention
Prophylactic vaccination
The FDA has approved two LI (major capsid protein)
virus-like particle vaccines that also contain adjuvants to
enhance both major histocompatibility complex class I
(to activate cytotoxic [CD8+] T lymphocytes) and class II
(to activate T-helper [CD4+] lymphocytes) presentation
pathways. Gardasil (Merck & Co., Whitehouse Station,
NJ) is a quadrivalent vaccine that protects against disease
caused by HPV types 6, 11, 16, and 18, and Cervarix
(GlaxoSmithKline Biologicals, Rixensart, Belgium) is a
bivalent vaccine that protects against HPV types 16 and
18. The quadrivalent vaccine is approved for both fe-
males and males 9 to 26 years of age while the bivalent
vaccine is approved only for females 9 to 26 years of age.
The vaccine is administered in three doses, with the first
dose of the quadrivalent or bivalent vaccine recom-
mended for girls 11 to 12 years old and the quadrivalent
vaccine for boys 11 or 12 years old, but either vaccine
can be administered as early as age 9 years. The second
ASMscience.org/MicrobiolSpectrum

dose should be administered 1 to 2 months after the first
dose, and the third dose 6 months after the first dose,
with a minimum interval of 12 weeks between the second
and third dose (122). Catch-up vaccination using the
standard dosing intervals is also recommended for
females and males aged 13 through 26 years old if they
were not previously vaccinated or if they have not
completed the three-dose series (122). Vaccination in the
general population induces a cell-mediated immune re-
sponse and a strong humoral immune response with
antibody titers several times higher than typically seen
after natural infections (123, 124). Vaccination is
recommended regardless of the presence of abnormal
cervical cytology, as it may protect against one or more
HPV types to which the individual has not been exposed.
In addition, the vaccine has been shown to be effective in
older individuals, and vaccination up to age 45 has been
recommended by some groups (125).
Several published studies have shown that HPV
vaccines are well tolerated in immunocompromised
individuals and that a specific humoral immune response
was produced with high rates of seroconversion in
HIV-infected individuals after three doses and 100%
seroconversion after four doses in one study (25, 90).
Seroconversion rates, however, have been less than op-
timal in vaccinated organ transplant recipients (126).
Although immunosuppression does not prevent suc-
cessful immunization, most studies have found that
antibody titers are lower in immunocompromised indi-
viduals than in immunocompetent individuals (25, 90,
126). Among HIV-infected individuals, antibody titers
are higher in those who are on treatment with antiretro-
viral agents. While safety has been established, optimal
dosing schedules and the efficacy of vaccination in im-
munocompromised individuals will require additional
study.
The Advisory Committee on Immunization Practices
(ACIP) and IDSA recommend HPV vaccination for im-
munocompromised men and women, including those
with HIV infection, as well as for men who have sex with
men. Vaccination is recommended regardless of the se-
verity of immunosuppression and regardless of history
of abnormal cervical cytology. The dosing schedule for
immunocompromised individuals is the same as for
immunocompetent individuals, with the three-dose se-
ries given at age 11 or 12 years and at age 13 through 26
years if not previously vaccinated (102, 122). Immuno-
compromised individuals should continue to have rou-
tine cervical and anal cancer screening tests and visual
and digital pelvic and anorectal examinations even if
they have been vaccinated.
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Human Papillomavirus
Therapeutic vaccination
There is limited literature regarding therapeutic HPV
vaccination. Clearance of a naturally acquired HPV in-
fection is mediated by a specific cell-mediated immune
response in which dendritic cells stimulate T-helper type
1 lymphocytes, which then elicit the production of
cytotoxic T lymphocytes that attack infected cells. The
ability of an HPV vaccine to stimulate a specific cellular
immune response could potentially have a therapeutic
effect (124). The current FDA-approved L1 VLP vac-
cines were designed to prevent HPV infection primarily
by stimulating a neutralizing antibody response and
were not intended for therapeutic purposes. Several
short-term studies suggest that the current vaccines may
be somewhat effective in patients with existing HPV
infection, while other studies have not found a signifi-
cant effect (125, 127–129).
Vaccines that are designed to boost specific T-cell
responses could potentially be therapeutically effective.
Since the L1 and L2 structural capsid late proteins ap-
pear only in fully differentiated epithelial cells later in
the course of infection, therapeutic vaccines have been
directed toward stimulating T-cell responses to the HPV
E6 and E7 viral oncoproteins, which are continuously
expressed throughout the course of infection (130). Ap-
proaches have included administration of peptide anti-
gens or recombinant proteins, live viral vector vaccines,
whole-cell vaccines, and plasmid DNA vaccines as well
as administration of E7-pulsed dendritic cells (130).
DNA vaccines have been favored since they are stable,
safe for multiple administrations, can provide sustained
release of antigenic proteins, and can be delivered by a
variety of methods (130). Modifications that lead to
enhanced immunogenicity are being investigated (130).
Effective therapeutic vaccination in the face of CD4+
T-cell compromise or depletion is of concern in some
primary immune deficiencies and in HIV-infected indi-
viduals. In a murine immunodeficiency model, a DNA
vaccine against HPV E6 and E7 was shown to be ca-
pable of generating a specific CD8+ T-cell-mediated
immune response in the absence of CD4+ T cells and was
protective when challenged with subcutaneous admin-
istration of E6- and E7-expressing tumor cells, although
no antibody response was detected (131). Further in-
vestigations are needed to determine the long-term effect
of therapeutic vaccination in management strategies
for both immune-competent and immunocompromised
individuals. A chimeric vaccine that contains preventive
and therapeutic components may ultimately be ideal
and could be used for both treatment and prophylaxis
(123).
13
Burd and Dean
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