Seminar

Human papillomavirus and cervical cancer

Emma J Crosbie, Mark H Einstein, Silvia Franceschi, Henry C Kitchener

Cervical cancer is caused by human papillomavirus infection. Most human papillomavirus infection is harmless and Published Online
clears spontaneously but persistent infection with high-risk human papillomavirus (especially type 16) can cause cancer April 23, 2013
[Link]
of the cervix, vulva, vagina, anus, penis, and oropharynx. The virus exclusively infects epithelium and produces new S0140-6736(13)60022-7
viral particles only in fully mature epithelial cells. Human papillomavirus disrupts normal cell-cycle control, promoting
Institute of Cancer Sciences,
uncontrolled cell division and the accumulation of genetic damage. Two effective prophylactic vaccines composed of University of Manchester,
human papillomavirus type 16 and 18, and human papillomavirus type 16, 18, 6, and 11 virus-like particles have been Oxford Road, Manchester, UK
introduced in many developed countries as a primary prevention strategy. Human papillomavirus testing is clinically (E J Crosbie PhD,
Prof H C Kitchener MD);
valuable for secondary prevention in triaging low-grade cytology and as a test of cure after treatment. More sensitive
Albert Einstein College of
than cytology, primary screening by human papillomavirus testing could enable screening intervals to be extended. If Medicine and Albert Einstein
these prevention strategies can be implemented in developing countries, many thousands of lives could be saved. Cancer Center, Montefiore
Medical Centre, Bronx,
New York, NY, USA
Introduction papillomavirus types 16 and 18 account for roughly 70% (M H Einstein MD); and
One of the most important scientific discoveries of the of all cervical cancer. Type 16 has been detected in about International Agency for
past 30 years is the causal link between human papilloma- 24% of women with human papillomavirus infection; Research on Cancer, Lyon,
virus infection of the cervix and cervical cancer. This type 18 has been detected in about 9%.3 France (S Franceschi MD)

finding resulted from the original seminal findings by The International Agency for Research on Cancer HPV Correspondence to:
Prof Henry C Kitchener,
Harald zur Hausen and his group, that human papilloma- Prevalence Surveys4 included roughly 28 000 women
St Mary’s Hospital, Research
virus 16 can be detected in cervical cancer tissue, and was from 26 different regions, mainly in developing countries Floor, Oxford Road,
followed by an enormous worldwide effort involving (figure 1). The Surveys used a standardised protocol for Manchester M13 9WL, UK
epidemiologists, molecular biologists, vaccinologists, and population-based recruitment and detection of human [Link]@manchester.
[Link]
clinicians culminating in the development of effective papillomavirus. The prevalence of human papillomavirus
prophylactic vaccines for human papillomavirus, which was high in countries where the burden of cervical cancer
have the means to prevent 70–80% of cervical cancer. zur is high—ie, in sub-Saharan Africa, Latin America, and
Hausen was awarded the Nobel Prize in Physiology or India,4 but also in countries, such as Mongolia5 and
Medicine in 2008, in recognition of his discovery. China,6 in which the disease burden is uncertain.7 Human
Human papillomavirus belongs to the papillomavirus papillomavirus prevalence in developed countries peaks
family of viruses, which have a diverse range of hosts in young women and decreases after 35 years of age.4 In
in both animals and man. The family has an agreed some regions—eg, some Latin American countries4—a
taxonomy that is based on genome sequence homology, small second peak in human papillomavirus prevalence
biological function, and pathological effect.1 More than occurs in middle-aged women older than 55 years.
100 types of human papillomavirus have been identified, Human papillomavirus prevalence was high and much
including 13 high-risk types, which are responsible for the same across all ages in several low-income and
cervical neoplasias and other anogenital and oropharyn- middle-income countries (India,4 China,6 and some
geal cancers. African countries8,9). The peak in human papillomavirus
We review the worldwide epidemiology and natural prevalence in young women is partly caused by changes
history of cervical human papillomavirus infection, the in sexual behaviour in some countries.10 Long-term
virus’s lifecycle, and the process of viral oncogenesis. follow-up studies of human papillomavirus infection
We then discuss how the unique relationship between should be done to disentangle age-specific and cohort-
human papillomavirus and cervical cancer has been specific effects and more research is needed to assess the
exploited for primary (prophylactic vaccines) and secon-
dary (screening) prevention.
Search strategy and selection criteria
Epidemiology We searched the Cochrane Library and PubMed for relevant
Human papillomavirus infection is the most common randomised trials and other high-quality studies
sexually transmitted infection worldwide and most (eg, systematic reviews, meta-analyses) between Jan 1,
sexually active individuals of both sexes will acquire it at 2000, and July 1, 2012, for the terms ”HPV”, ”human
some point during their life.2 On the basis of a meta- papillomavirus”, ”HPV vaccination”, ”cervical cancer”,
analysis3 of 1 million women with normal cervical ”cervical carcinoma”, “cervical neoplasia”, and “cervical
cytology, around 291 million women worldwide are esti- carcinogenesis”. Widely cited older publications that we
mated to have human papillomavirus infection of the judged to have remained important references were also
cervix at a given point, corresponding to an average included. References from relevant articles identified by our
prevalence of 10·4%, though prevalence is higher in search strategy were also searched.
women younger than 25 years (16·9%). Human

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N
papillomavirus depends on the duration of infection;15,16
Guinea 831 longer persistence reduces the probability of clearance.
Mongolia 969 Human papillomavirus infections detected in women
Vanuatu 987
Nigeria 932 aged older than 30 years persist for longer than those in
Poland 834 younger women because they are more likely to be
Shenzhen, China 1027
Argentina 978
persistent infections of long duration.15,16
India 1891 The only clear risk factors for persistence and pro-
Shenyang, China 685 gression of human papillomavirus are immunodeficiency
Shanxi, China 662
Chile 955 (eg, HIV-positive women and transplant recipients)17 and
Colombia 1834 the human papillomavirus type, although sexual and
Georgia 1309
South Korea 863 reproductive factors, recent oral contraceptive use,18 smok-
Mexico 1340 ing,19 and Chlamydia trachomatis infection20 have also been
Ho Chi Minh City, Vietnam 922
Turin, Italy 1013
implicated.13 Human papillomavirus types have been
Lampang, Thailand 1035 classified as either carcinogenic or probably carcinogenic17
Nepal 932 (ie, high-risk human papillomavirus) and type 16 is by far
Iran 825
Netherlands 3304 the likeliest to persist and cause CIN3 and cervical cancer.21
Algeria 759 In a study by Castle and colleagues,13 women who twice
Songkla, Thailand 706
Spain 911 Type 16 or 18 tested positive for type 16 after a 9–21 month interval had a
Pakistan 899 Other high-risk type 3-year cumulative incidence of CIN2 or worse of 40%. The
Hanoi, Vietnam 994 Low-risk type only
corresponding cumulative incidence was 15% for type 18
0 5 10 15 20 25 30 35 40 45 50 55 and 9% for other high-risk types. Genotyping might
Human papillomavirus prevalence (%)
therefore improve risk stratification of women with
Figure 1: Age-adjusted prevalence of cervical human papillomavirus DNA in sexually active women aged human papillomavirus in cervical screening programmes.
15–69 years A meta-analysis22 has investigated the cross-sectional
Data are from IARC Prevalence Surveys, 1990–2012.4 distribution of high-risk human papillomavirus types
across the full spectrum of cytopathological and histo-
High-grade lesions Cervical cancer pathological cervical diagnoses (table). It included
Type 16 Type 18 Type 16 Type 18 116 000 women with human papillomavirus (including
36 374 cervical cancers) from 432 studies using PCR-based
Europe 54·4 (5·6) 7·7 (1·1) 66·7 (2·0) 16·4 (4·6)
human papillomavirus DNA testing. Worldwide, the most
North America 56·8 (3·1) 9·6 (2·7) 61·2 (3·2) 19·6 (4·3)
common human papillomavirus types in cervical cancer
South and Central America 52·8 (8·1) 9·4 (3·5) 59·5 (2·8) 12·7 (4·5)
were types 16 (57%), 18 (16%), 58 (5%), 33 (5%), 45 (5%),
West and Central Asia 68·4 (16·4) 6·3 (5·0) 73·0 (4·6) 15·1 (3·7)
31 (4%), 52 (3%), and 35 (2%).22,23 Types 16, 18, and 45
East Asia 37·9 (7·1) 7·4 (1·9) 61·7 (5·9) 15·8 (2·6)
accounted for a greater or equal proportion of infections
Oceania 53·9 (3·5) 9·6 (1·7) 62·6 (5·4) 21·2 (4·2)
in cervical cancer compared with normal cytology
Africa 30·3 (5·2) 9·2 (2·8) 53·1 (4·4) 19·8 (4·1)
(panel 1); the ratio between cervical cancer and normal
Data are taken from Guan and colleagues.22 Data are % (±1·96 SE). cytology was 3·1:1 for type 16, 1·9:1 for type 18, and 1·1:1
for type 45. Other high-risk types accounted for substantial
Table: Positivity for human papillomavirus types 16 and 18 as a proportion of human papillomavirus-
positive samples in high-grade lesions and cervical cancer by region
proportions of CIN2 and CIN3, but their contribution to
cervical cancer was low, with ratios ranging from 0·9:1 for
type 33 to 0·2:1 for type 51.
reasons for the large variations in human papillomavirus Human papillomavirus is one of the most powerful
prevalence by age across populations.4 human carcinogens and has been implicated in cancers
Prospective studies have shown that the prevalence of at several sites. Roughly 610 000 new cancers per year
human papillomavirus includes a mix of incident and (5% of all cancers) have been attributed to human
persistent infections that have accumulated over time papillomavirus infection, of which more than 80%
because of lack of clearance.11,12 More than 90% of new occurred in developing countries.24 Such cancers include
human papillomavirus infections at any age regress in effectively all cervical cancer (ie, around 530 000 cases
6–18 months13 and more persistent infection is a per year) and 88% of anal cancer (around 24 000 cases).
prerequisite for progression to cervical intraepithelial Anal cancer is rare in the general population of both
neoplasia (CIN). CIN1 is an insensitive histopathological sexes (<2 cases per 100 000 people) but it is 20-times
sign of human papillomavirus infection,14 CIN2 includes more common in men who have sex with men.25 Anal
a heterogeneous group of lesions that have different cancer is as common in men who have sex with men
potential to progress to cancer, and CIN3 represents the who have HIV, as is cervical cancer in women in
most clinically relevant lesions and is the best surrogate sub-Saharan Africa.25 Other cancers attributed to human
endpoint for cervical cancer in screening and vaccin- papillomavirus infection include those of the vagina
ation trials. The probability of clearance of human (70%), penis (50%), vulva (43%), and oropharynx (26%).24

2 [Link] Published online April 23, 2013 [Link]

 Seminar

Viral replication, malignant transformation,

and immunology Panel 1: Epidemiology of human papillomavirus infection
The viral lifecycle and prophylactic vaccination strategy
Human papillomavirus infects only epithelial cells and The most common human papillomavirus types in cervical
depends on the differentiation pathway of epithelial cells cancer are types 16 (57%) and 18 (16%)23 with small regional
to complete its lifecycle.26 Human papillomavirus infects variations.22 Type 16 makes up the largest proportion in
cells in the basal layer of the epithelium, probably via western-central Asia (73%) and the smallest in Africa (53%).
microabrasions in the epithelial surface. It capitalises on Types 16 (48%) and 18 (10%) are also the most common
the lateral extension of basal cells that accompanies wound types in high-grade precancerous lesions.22 Current vaccines—
healing to gain entry to the cell. Infectious internalisation which target types 16 and 18—should therefore prevent
takes several hours, after which viral DNA is released from roughly 70% of cervical cancers worldwide and half of high-
the capsid and transported into the nucleus as free genetic grade precancerous lesions.22 Thus, human papillomavirus
material or extrachromosomal episomes. Early gene vaccination has the potential to prevent most deaths caused
expression is tightly controlled in the basal epithelial cells by cervical cancer in unscreened populations and to
with substantial amplification of viral DNA. Replication substantially reduce the anxiety and costs associated with
(figure 2) occurs only in suprabasal, differentiating cells27 detection and treatment of cervical intraepithelial neoplasias.
that are destined for maturity and senescence, and as thus
do not naturally express the replicative machinery that the
virus depends on for survival. To circumvent this prob- results in the release and activation of E2F transcription
lem, human papillomavirus encodes two proteins—E6 factors that drive the expression of S-phase genes,
and E7—which together promote cellular proliferation, including those that encode cyclins A and E, which in turn
prolong cell-cycle progression, and prevent apoptosis.28 precipitates cell-cycle entry and promotes DNA synthesis.
The cell becomes permissive for viral replication and High-risk E5 works with E6 and E7 to drive cellular
hundreds or even thousands of human papillomavirus proliferation and might be a weak cofactor in development
genomes are generated within a single cell. The capsid of malignancy.33 Both episomal and integrated copies of
proteins L1 and L2 are expressed in the most superficial the human papillomavirus genome frequently co-occur,
layers of the epithelium, where viral assembly takes place, often within the same cell. In this case, E6 and E7
and finally, new infectious viral particles (virions) are shed expression might not be significantly increased.
from the epithelial surface (figure 2). The papillomavirus
lifecycle takes 2–3 weeks, the time necessary for a cervical Immune evasion
cell to migrate from the basal to most superficial layers of The development of cancer depends not only on efficient
the epithelium, mature, undergo senescence, and die.29 negative regulation of cell-cycle control supporting
the accumulation of genetic damage, but also on
Malignant transformation sophisticated techniques of immune evasion that enable
To complete the infectious lifecycle of the virus, the cell the virus to be undetected for long periods.34 No cell
must undergo terminal differentiation, an essential death, necrosis, or viraemic phase exists that would
prerequisite for virion assembly and release. However, trigger an inflammatory response. Viral antigens are
for some high-risk papillomavirus infections, E6 and E7 detectable only in superficial epithelial cells destined for
are so effective at blocking negative regulators of the cell desquamation and remote from immunological surveil-
cycle that the infected cells never mature. The cells lance.35 High-risk papillomaviruses have evolved several
remain actively involved in cell-cycle progression and mechanisms that minimise their risk of detection by the
cease to apoptose. The resulting genomic instability immune system. High-risk E6 reduces the surface
enables genetic alterations to accumulate, ultimately expression of CDH1 by epithelial cells, reducing their
driving malignant transformation of a cell infected with ability to present human papillomavirus antigens.36 Toll-
human papillomavirus into an invasive cancer cell. like receptors activate antigen-presenting cells as part of
E6 and E7 start oncogenesis through well-characterised the innate immune response to viral infection, but
interactions with products of tumour suppressor genes— transcription of toll-like receptor 9 is inhibited by
TP53 for E6 and retinoblastoma proteins for E7. TP53 has a expression of high-risk E6 and E7.37 E7 reduces expression
crucial role in protecting genomic integrity by forcing of TAP1—a key component of the peptide processing
apoptosis or inducing cell-cycle arrest until errors in DNA and presentation pathway—preventing activation of
replication can be repaired. E6 targets TP53 for degradation specific cytotoxic T lymphocytes.38 High-risk E6 and E7
via the ubiquitin pathway, preventing apoptosis and inhibit interferon synthesis through specific interactions
enabling potentially transformed cells to replicate.30 with IRF-1 and IRF-3.39,40 Changes from proinflammatory
E7 contributes to oncogenesis through its interaction to anti-inflammatory signals—ie, the cytokine milieu—
with the retinoblastoma family members RB1, RBL1, and can affect whether or not an infection is cleared.
RBL2, the so-called pocket proteins. E7 binds these High-risk human papillomavirus downregulates the
proteins and targets them for degradation.31,32 This action expression of proinflammatory cytokines including

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Normal cervix Squamous intraepithelial lesion Invasive cancer

Low grade High grade

Cervical intraepithelial neoplasia

Grade 1 Grade 2 Grade 3

Infectious viral particles

Squamous epithelium

Superficial zone

Midzone

Basal layer
Basement membrane
Dermis

Episome
LCR E6
E7
Integration
Nuclei with episomal Overexpression of
viral DNA E6 and E7 E1 L1 L2 LCR E7 E2
Nuclei with intergrated Expression of early L1
viral DNA and late genes
Normal nuclei Host E6 E1 Host
E2 DNA DNA
L2 E4
E5

Figure 2: Human papillomavirus lifecycle and organisation of its genome

Basal cells in the cervical epithelium rest on the basement membrane, which is supported by the dermis. Human papillomavirus is thought to access the basal cells
through microabrasions in the cervical epithelium. After infection, the early human papillomavirus genes E1, E2, E4, E5, E6, and E7 are expressed and the viral DNA
replicates from episomal DNA. In the upper layers of epithelium (the midzone and superficial zone) the viral genome is replicated further, and the late genes L1 and
L2, and E4 are expressed. L1 and L2 encapsidate the viral genomes to form progeny virions in the nucleus. The shed virus can then initiate a new infection. Low grade
intraepithelial lesions support productive viral replication. An unknown number of high-risk human papillomavirus infections progress to high-grade cervical
intraepithelial neoplasias. The progression of untreated lesions to microinvasive and invasive cancer is associated with the integration of the human papillomavirus
genome into the host chromosomes (red nuclei), with associated loss or disruption of E2, and subsequent upregulation of E6 and E7 oncogene expression.
Reproduced from Woodman and colleagues.27 LCR=long control region.

tumour necrosis factor α, while anti-inflammatory (1) naturally regressing warts are associated with an influx
cytokines that prevent migration of immune cells to the of T lymphocytes;44 (2) cell-mediated immune deficiency
site of infection (eg, IL-10), are upregulated.41 The such as HIV infection can lead to extensive human-
concentrations of antimicrobial peptides—eg, SLPI and papillomavirus-induced lesions; and (3) an increased risk
human β defensins 2 and 3—are low in the cervical– of progressive disease45,46 and human papillomavirus-
vaginal tract of women with CIN.42 specific immune responses have been detected in the
Preinvasive disease that progresses to cancer accumu- lesions and peripheral blood of people with active and
lates genetic alterations that further assist with immune resolving human papillomavirus-associated disease.47–49
evasion. This process is a result of the continuous Antibody responses to the major viral capsid protein,
pressure exerted on the developing tumour by the L1, can be detected from about 6 months after infection50
immune system and is known as cancer immuno- and can still be measured up to 5 years later in individuals
editing.43 The tumour might have MHC class I down- who have cleared human papillomavirus infection.51
regulation and impaired antigen-processing ability, Type-specific L1 antibody responses have also been
insensitivity to and avoidance of T-cell mediated killing, detected in people with persistent disease and cancer,
increased immunosuppressive T regulatory cell infil- although roughly 50% of individuals never seroconvert.52
tration, and produce immunosuppressive cytokines.34 The presence of L1 antibody might therefore represent
previous or persistent infection53 and it is unclear
Natural immune responses whether naturally induced L1-specific antibody responses
Despite this impressive array of immune evasion protect against new infection.
mechanisms, most papillomavirus infections are cleared Several different variables affect the measurement of
within 12 months. Cell-mediated immunity is implicated these immune responses. Each research-based assay
in viral clearance through several lines of evidence: that has been developed to detect anti-L1 human

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papillomavirus responses measures different things.

A B C
Some measure specific immunodominant epitopes (eg,
Luminex immunoassays), whereas others measure total
IgG (eg, standard ELISA).54
Understanding the immunological mechanisms that
underpin natural viral clearance and disease regression
is needed to inform design of a therapeutic vaccine. T-cell
responses specific to human papillomavirus have been D E
detected by measuring proliferation, cytokine release,
or cytotoxicity after extensive in-vitro stimulation with
peptides or viral constructs expressing the human
papillomavirus antigen of interest. T cells are likely to be
important effectors for clearance of established disease,
but the prevalence of T cells specific to human papilloma-
virus in the peripheral blood of women with intra-
epithelial lesions is extremely low55 as a result of the low
antigen load and strict epithelial compartmentalisation
of premalignant disease.
F
A longitudinal, non-intervention study47 of patients with
cytological evidence of low grade CIN reported that CD4+
T-helper 1 responses to E2 coincided with viral clearance.
CD4+ T-helper 1 responses against E2 and E6 have also
been detected in healthy volunteers, possibly as a result of
previous viral clearance.56 Crucially, such responses are
either absent or dysfunctional in patients with low grade
CIN, high grade CIN, or cancer.55,57,58 Regression of disease
is associated with lesion-infiltrating CD8+ cytotoxic T-cell
responses (strongly positive for granzymes),46,47 whereas
regulatory T cell infiltrates, which maintain an immuno-
logically tolerant environment, occur in persistent and
progressive disease.59

Human papillomavirus vaccination

Prophylactic vaccines
Figure 3: Human papillomavirus type 16 virus-like particles
Understanding of the ubiquitous role of human (A) Atomic force microscopy image of a human papillomavirus type 16 virus-like
papillomavirus infection in all CIN and cervical cancer particle after disassembly and reassembly treatment; adapted from Rodriguez and
combined with an understanding of human papilloma- colleagues.16 The scale bar is 50 nm. (B) Cryo-electron microscopy image of a
virus natural history has led to the development of the human papillomavirus type 16 virus-like particle after disassembly and reassembly
treatment. The scale bar is 50 nm. (C) Atomic model of the T=7 structure human
first prophylactic cancer vaccines. These vaccines contain papillomavirus type 16 virus-like particle. The scale bar is 50 nm. (D) A single
human papillomavirus L1 self-assembling virus-like subunit of L1 in the standard orientation. Residues 261–297 are in red and form
particles (figure 3), which induce strong neutralising part of the H16.V5, H16.E70, H263.A2, and H16.J4 epitopes. Residues 339–365
are in pink and form part of the H263.A2, H16.V5, and H16.E70 epitopes. Residues
antibody responses against human papillomavirus
174–185 are in dark green and form the H16.H5 epitope. Residues 111–130 are in
infection.60 These antibodies are thought to block the blue and form the H16.I23 epitope. (E) A pentameric L1 capsomere with the same
human papillomavirus virions before they gain access to colouring as in panel D and with the subunit in the foreground in roughly the
the proliferating basal cell layer of the epithelial surface same orientation. (F) The human papillomavirus type 16 virus-like particle surface
with the capsomere in yellow, in the same orientation as in panel E. Heparin
through microabrasions.61 Two vaccines are available—
oligosaccharides as they bind to L1 capsomeres shown in red. Reproduced from
the quadrivalent vaccine (Merck, Whitehouse Station, NJ Zhao and colleagues.60
USA), which contains virus-like particles to human
papillomavirus types 6, 11, 16, and 18, and the bivalent
vaccine (GlaxoSmithKline, Rixensart, Belgium), which had not previously had human papillomavirus was 98%
contains virus-like particles to human papillomavirus (95% CI 86–100). As expected, efficacy was lower (44%,
types 16 and 18. 95% CI 26–58), for women who had had an active
Both vaccines protect against precancerous lesions human papillomavirus 16 or 18 infection at baseline or
associated with human papillomavirus types 16 and 18, had previous exposure to human papillomavirus based
as shown in global randomised clinical trials.62–64 In the on the presence of human papillomavirus antibodies
pivotal randomised, placebo-controlled trial of the to vaccine-related human papillomavirus types at
quadrivalent vaccine,64 vaccine efficacy in patients who baseline. In the pivotal phase 3 bivalent vaccine clinical

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trial,65 vaccine efficacy was 93% (95% CI 80–98) in and other countries have included a catch-up age range for
human papillomavirus naive patients and less in those vaccination, which overlaps with the typical age of onset of
with active or previous human papillomavirus infec- sexual activity. Because the effectiveness of the vaccine as
tion. Given that the optimum efficacy is in human prophylaxis is higher for a fully vaccinated woman who
papillomavirus-naive women, the focus of vaccine has not had any sexual activity compared with a woman
programmes worldwide has been on female adolescents. vaccinated after the onset of sexual activity, the catch-up
These vaccines seem to confer cross-protection to non- vaccination policy has implications for health economics.
vaccine human papillomavirus types. In a subset The policy also has implications—which might include
analysis62 of the cohort of women who tested negative for extended screening intervals for vaccinated individuals—
human papillomavirus DNA for each of the four types for future cervical cancer screening recommendations.
used in the quadrivalent vaccine, protection against Prophylactic human papillomavirus vaccination has
human papillomavirus 31 was 46% (95% CI 15–66) for been estimated to be cost effective, with the up-front
persistent infection and 57% (29–75) for any CIN or expenditure for vaccination offset by costs averted
adenocarcinoma in situ. An end-of-study analysis66 of the through disease prevention.74 This assumption depends
PATRICIA trial reported that the bivalent vaccine showed on age at vaccination, screening intervals, female only or
cross-protection against CIN2 or worse associated with male and female programmes, and the cost of the vaccine.
human papillomavirus 31 and 33 in lesions with no co- Models suggest that costs of cervical cancer screening
infection with the vaccine types, and to a lesser extent could be substantially reduced by ensuring high coverage
against human papillomavirus 45 and 51. This cross- human papillomavirus vaccination and the consequent
protective efficacy is associated with cross-protective drop in high-grade cytology and colposcopy referrals. The
immune responses in human papillomavirus types that association between human papillomavirus infection
are phylogenetically related to human papillomavirus 16 and several other anogenital diseases—including anal,
and 18, respectively.67 vaginal, and vulval cancers—as well as oropharyngeal
Although the primary focus of human papillomavirus cancers,75 suggests that prophylactic human papilloma-
vaccination programmes has been on women and girls— virus vaccination might protect against some of these
who bear the greatest burden of human-papillomavirus- cancers as well. Despite proven efficacy against human
associated cancers68—recent clinical trial data showing papillomavirus-associated anal disease,69 cost effectiveness
efficacy of vaccination in men69 and the potential for herd models in regions of the world with vaccination for both
immunity, has led to vaccination of adolescent boys to be girls and boys have shown that vaccination of both sexes
recommended in some developed regions. Australia is considerably less cost effective than is vaccination of
provides an example of a successful publicly funded mass- girls only, unless vaccine costs substantially decrease or
vaccination programme. Since its widespread vaccination high coverage in adolescent girls cannot be achieved.76
programme using the quadrivalent vaccine, which began Arguments for male vaccination do not relate solely to
in April, 2007, uptake and completion of the full three- cost, but also to the additional health benefits of moving
dose regimen recommended for human papillomavirus from a sex-specific strategy to a vaccination policy seeking
vaccination in Australia has been one of the highest in the to prevent disease in both sexes, with the potential for
world. Monitoring of vaccination and registries for herd immunity.
tracking incident sexually transmitted infections in Ongoing studies are assessing the next generation
Australian clinics is comprehensive and centralised. L1 virus-like particle human papillomavirus vaccines that
According to these registries, since the introduction of include additional oncogenic human papillomavirus
vaccination, new cases of genital warts have not only fallen types. Prophylactic vaccines against the human
by 73% in vaccine-aged young women, but also by 44% in papillomavirus minor capsid protein L2 are also in clinical
young men, who were not part of the free vaccination development.77,78 Vaccination of rabbits with peptides from
programme. These findings strongly suggest that mass the human papillomavirus minor capsid protein L2
vaccination of girls provides substantial herd immunity.70 induces broadly cross-neutralising antibodies, sufficient
In the UK, the uptake of vaccination in a school-based for broad protection against several phylogenetically
programme for girls aged 12–13 years was 83%,71 where- related papillomavirus types.79,80 Unlike L1 virus-like
as in the catch-up campaign for older teenagers, which particles, the number of types covered could be enhanced
relied largely on general practices, only 41% of eligible by generating a multimer of the protective epitope from
individuals had three doses.72 diverse papillomavirus types.81
These vaccines were not designed as therapeutic vaccines
and have little, if any, prophylactic effectiveness in people Therapeutic vaccines
that have been previously exposed to the virus types Human papillomavirus is an ideal target for a thera-
contained in the vaccine.64,73 Vaccination policy in some peutic vaccine. Therapeutic vaccines targeting human
countries, such as the USA, includes a routine recom- papillomavirus E6 and E782–84 along with broadly targeting
mendation, but vaccination is given on request. To accom- immunotherapies or peptides85 are in clinical develop-
modate a wider range of on-request vaccinations, the USA ment. The rationale of these vaccines is to avoid the

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need for surgical procedures by developing immune

responses specific to human papillomavirus. The Panel 2: Human papillomavirus as a test of cure after treatment of cervical
vaccines in development have several drawbacks. Limit- intraepithelial neoplasia
ations of peptide vaccines include HLA restriction for Human papillomavirus testing—either in combination with cytology or as a single test—
either vaccination or for the ability to measure cell- can be used as a test of cure after treatment of high-grade cervical intraepithelial neoplasia.
mediated immune responses after vaccination. Some of The rationale behind this approach is that human papillomavirus will be a more sensitive
the broad immunotherapies have non-specific toxic detector of residual untreated cervical intraepithelial neoplasia than cytology, and has the
effects that might not be attractive to the generally young advantage of enabling women who test negative to be deemed low risk, and so return to
healthy women who have CIN, for which very effective routine recall rather than need to attend yearly follow-up for up to 10 years. Women who
outpatient surgical treatments exist. Although many test positive for human papillomavirus, even in the presence of normal cytology, would be
vaccines seem to boost immune responses specific to referred for colposcopic examination. This approach has been shown to be a very safe and
human papillomavirus, it is unclear whether such successful way of stratifying treated women. In a UK study of 744 treated women who
systemic responses are appropriate surrogate markers were cytology negative and human papillomavirus negative at 6 months, only five were
for what is happening at the site of the infection.84 To known to have developed high grade cervical intraepithelial neoplasia during 2 years.99
date, no effective therapeutic vaccines have completed Both human papillomavirus triage and test of cure are being implemented at present in
clinical development. Several likely reasons exist for the English NHS Cervical Screening Programme, as well as in several other countries. In the
this lack of success, including the ability of human English programme, women who have been referred for colposcopy and who have a
papillomavirus to evade immune recognition,86 a paucity negative and adequate colposcopic examination are referred back to routine recall. In this
of effective strong immune responses generated by way human papillomavirus testing is being used to enhance the detection of disease and
current vaccine technologies,87 and inadequate time at the same time streamline management, speeding up diagnosis and return to routine
without treatment to see a response within the time recall. By capitalising on the negative predictive value of a human papillomavirus test,
scales of randomised trials in women with CIN. many women will not need to undergo unnecessary colposcopy.

Human papillomavirus testing in cervical

screening useful, since infection with human papillomavirus
Because of its crucial causal role and the need for type 16 or 18 has a relative risk for CIN3 of 7–10
continued expression to maintain the disease phenotype, compared with any high-risk human papillomavirus.95,96
human papillomavirus can be used as a biomarker of Selection of the most appropriate human papillo-
cervical cancer and precancer. Randomised trials88–90 have mavirus tests for cervical cancer screening depends on
shown that human papillomavirus DNA testing provides several considerations: validation in large trials with
greater sensitivity than does cytology for detection of regulatory approval, the need for high-throughput tests
CIN. Human papillomavirus testing is more reproducible or tests that can be cost-effectively done in smaller
with less subjective analytical characteristics,91 and users numbers, the necessary balance of sensitivity and
need less training and expertise. The major drawback of specificity, and whether platforms used for human
human papillomavirus testing is that infection is far papillomavirus testing are already used in a given clinical
more common than is underlying disease—particularly laboratory. Low cost is also a prerequisite, especially for
in women younger than 30 years—and therefore needs medium-resource and low-resource countries.
reflex cytology to achieve the specificity needed to detect
an underlying abnormality. The ARTISTIC trial included The role of human papillomavirus testing
24 000 women aged 20–64 years screened in Manchester, Atypical cytology of unknown significance or borderline
UK. It showed a large fall in high-risk human cytology are associated with underlying CIN2 or worse in
papillomavirus infection with age: from 40% in those roughly 10% of cases. In atypical cytology of unknown
aged 20–24 years to 7% in those aged 50–54 years.92 significance or borderline cytology, about 60% test
However, human papillomavirus is not only capable of positive for high-risk human papillomavirus, which
detecting prevalent disease, but it is also a biomarker of enables human papillomavirus testing to identify those at
increased future risk. very low risk (human papillomavirus negative), who can
The first test to achieve the status of a standard be routinely recalled at standard screening intervals,
commercial kit relied on DNA–RNA hybridisation and whereas a human papillomavirus positive result warrants
chemiluminescence (Hybrid Capture-2; Qiagen, referral to colposcopy. The US ALTS trial97 showed the
Gaithersburg, MD, USA).93 During the past few years effectiveness of human papillomavirus triage and a large
other tests have been developed, including RNA-based implementation study98 confirmed the clinical use of
tests, which have been claimed94 to be more specific, restricting colposcopy referral. In this study, the positive
since RNA transcription is likely to be a clearer indicator predictive value for underlying CIN2 or worse varied
of oncogenesis. Some newly developed tests can provide between referring laboratories, but the mean was 16%
a readout specific for human papillomavirus type 16 (range 9–22). Human papillomavirus triage of equivocal
or 18 as well as non-specific high-risk human cytology enables immediate referral for those at risk and
papillomavirus. These tests might prove to be clinically routine recall for those who test negative. This approach

[Link] Published online April 23, 2013 [Link] 7

 Seminar

avoids the need for repeat testing, which is not only improved disease detection in the initial round. In a
inefficient—risking reduced adherence to recall—but large, four-group, controlled trial in India, screening
also causes distress by prolonging uncertainty and based on human papillomavirus testing was associated
necessitating repeated examination. Human papilloma- with a reduction in the incidence of advanced cervical
virus testing might also be useful as a test of cure after cancer and death compared with cytology or visual
treatment of high grade CIN (panel 2). inspection with acetic acid.101
The additional sensitivity of human papillomavirus A major benefit of human papillomavirus primary
testing and the potential for high-throughput automated screening is the potential for human papillomavirus
testing make it an attractive alternative to cytology for testing to lengthen screening intervals—as shown in a
primary screening. Large randomised trials have been European cohort study102—and follow-up data from
done in Europe and Canada,88–90,100 in which human ARTISTIC96 confirm that human papillomavirus primary
papillomavirus DNA testing combined with cytology was screening provides a longer duration of negative
compared with cytology alone. Apart from ARTISTIC, prediction than does cytology, which could enable
each trial showed significantly greater detection of screening intervals to be safely extended to 6 years.
disease in the first screening round by cotesting com- The main difficulty of human papillomavirus screening
pared with cytology alone. All of the trials showed a is the management of women who are positive for human
reduction in the detection of high grade CIN in the papillomavirus testing and negative for cytology. The risk
second screening round, presumably because of of underlying disease in this group is low, but over 6 years
it is twice that of the screened population as a whole.96
Data from ARTISTIC also showed that both the preva-
Human papillomavirus testing lence and cumulative 6 year rate of disease is three times
higher in women who test positive for human papilloma-
virus type 16 compared with women with all high-risk
human papillomavirus types. Furthermore, in a study
Human papillomavirus Human papillomavirus Reflex
negative positive cytology
Abnormal from the USA,95 women who were positive for human
papillomavirus type 16 but who had negative cytology had
a disease prevalence of 11%, similar to that for atypical
Early rescreen at Normal cytology of unknown significance triaged by Hybrid
12 months
Capture-2. These data also suggest a possible role for
Colposcopy human papillomavirus type 16, or indeed other bio-
markers, in identification of the highest risk group who
Human papillomavirus Human papillomavirus warrant referral for colposcopy and using early recall at
negative positive
less frequent intervals for the remaining women, given
that most will become negative for human papillomavirus,
Reflex with only 30–40% expected to have type-specific persis-
cytology Abnormal tence. Biomarkers such as p16 and Ki67 might offer
alternative means of increasing the specificity of screen-
ing strategies based on human papillomavirus.103
Normal
Primary screening based on human papillomavirus
testing could use cytology triage for women who are
Human papillomavirus type 16 positive for human papillomavirus and colposcopic
or 18 genotyping
referral for those with abnormal cytology (figure 4).
Women who were positive for human papillomavirus
but negative for cytology need not immediately have
Other high- Type 16 colposcopy, but could be offered early recall at
risk type or 18 12–24 months, in the expectation that most would revert
to being negative for human papillomavirus. If they are
Rescreen 12 months later
still human papillomavirus positive, cytology negative,
human papillomavirus genotyping could be used to triage
those who were positive for human papillomavirus
Return to routine recall after Human papillomavirus Human papillomavirus type 16 or 18, and therefore at highest risk, to colposcopy.
an interval of 5–6 years negative positive
The overall benefits of this approach are (1) greater
sensitivity for detection of CIN2 or higher, though
Figure 4: Algorithm for primary human papillomavirus-based cervical screening colposcopic referrals would probably increase, and (2)
Four general principles in the algorithm are: the need for reflex cytology after a positive human papillomavirus
test; the need for early recall of women who are human papillomavirus positive and cytology negative; the use of
extended screening intervals for human papillomavirus-
type 16 or 18 genotyping at early recall to identify those at greatest risk; and the use of extended screening negative women. The reliance on early recall for women
intervals for women who are human papillomavirus negative. who are human papillomavirus positive, cytology negative

8 [Link] Published online April 23, 2013 [Link]

 Seminar

will inevitably lead to some loss to follow-up, which could clinical trials that MHE was the principal investigator for from Merck,
undermine the potential for added sensitivity from GlaxoSmithKline, Roche, Advaxis, Photocure, Inovio, and Hologic. HCK
and SF declare that they have no conflicts of interest.
human papillomavirus testing. For countries without
effective cervical screening, human papillomavirus Acknowledgments
HCK and EJC are funded by the University of Manchester, UK. MHE is
testing could offer a simpler strategy for population funded by the US National Institutes of Health. SF is funded by the
screening than does cervical cytology and if implemented Bill & Melinda Gates Foundation.
could start to save lives within a few years, as shown by References
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human papillomavirus advisory board in November 2010, and was Carcinogenic Risks to Humans. Lyon: International Agency for
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from Merck, GlaxoSmithKline, Roche, Hologic, Advaxis, Inovio, and
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has not received honoraria. His institution has also received grants for

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[Link] Published online April 23, 2013 [Link] 11