REVIEW
Human papillomavirus
Sarah J Bowden
Maria Kyrgiou
Abstract
Human papillomaviruses are ancient small DNA viruses and represent
the most common sexually transmitted infection in the world. In the
majority, HPV infection is cleared by an incompletely understood im-
mune response. HPV is a necessary but not sufficient cause of cervical
cancer, and responsible for a proportion of other anogenital cancers
including vulval, vaginal, anal and oropharyngeal. Oncogenesis is likely
mediated through viral proteins which hijack host-cell machinery in
epithelial keratinocytes and disrupt host tumour-suppressor proteins.
Much work has been undertaken to further characterise the natural
history of HPV infection and cervical disease. Such efforts have
been translated to important public health interventions like the intro-
duction of HPV tests in cervical screening. HPV vaccination pro-
grammes are expected to further reduce the incidence of high-risk
HPV infections and resultantly HPV-related disease.
Keywords cervical cancer; cervical intraepithelial neoplasia; cervical
screening; human papillomavirus
Introduction
Papillomaviruses are ancient and ubiquitous small double-
stranded DNA viruses. They lack the necessary enzymatic ma-
chinery to replicate independently and so have evolved over
millions of years to infect and replicate through a range of animal
hosts including humans. Human papillomavirus (HPV) primarily
infects epithelial cutaneous and mucosal surfaces of oral and
anogenital areas; it is spread through direct, sexual or vertical
transmission. HPV infections are extremely common; rapidly
acquired after sexual debut with a lifetime incidence exceeding
80% in most populations. To date, over 150 HPV have been
identified, sequenced, and classified into five phylogenetic types
(Alpha, Beta, Gamma, Mu and Nu), of which the most common
are Alpha or Beta/Gamma. The majority of HPV infections from
Beta and Gamma types are transient and benign; allowing for
evolutionary fitness through efficient viral transmission in the
population. Where chronic persistent infections occur from these
types, continued virion production, in the absence of visible
disease may continue for months to years. Conversely Alpha
types have developed effective immune evasion strategies, likely
Sarah J Bowden BSc MBBCH, Wellcome Trust Clinical PhD Fellow in
Gynaecological Oncology, Department of Surgery and Cancer,
Imperial College London, Hammersmith Hospital, London, UK.
Conflicts of interest: none.
Maria Kyrgiou MSC PhD MRCOG, Clinical Reader and Consultant in
Gynaecological Oncology, Department of Surgery and Cancer,
Imperial College London, Hammersmith Hospital, London, UK.
Conflict of interest: MK has received institutional research and
educational support from MSD and personal support from MSD for
traveling and speaking at medical symposia.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4
through slow co-evolution with humans, to cause visible and
persistent benign warts (papillomatosis) on anogenital and other
mucocutaneous surfaces.
The major discovery related to HPV and disease came later
when Harald Zur Hausen first confirmed the association between
HPV and cervical cancer. In the 1960’s it was hypothesised that
cervical cancer was a sexually transmitted disease, based on
much earlier observations that celibate women including nuns,
never developed cervical cancer. In 1976e77, several scientific
teams isolated HPV from abnormal squamous epithelial cells.
HPV infection was recognised as the first tumour virus in 1983
and Zur Hausen was later awarded the Nobel prize in medicine.
Extensive study over the last four decades has furthered our
understanding of the causal association of HPV with primarily
cervical, but also other cancers. HPV is now thought to be
responsible for 10% of all malignancies in women and 5% in
men: 99.7% of cervical cancers, a large proportion of other
anogenital cancers (vaginal, vulval, penile, anal), and a subset of
oropharyngeal cancers (w12%).
Human papilloma virus
Genetic structure
HPV is a double-stranded DNA virus with a circular genome of
7900e8000 bp made up of 8 genes (or open reading frames
(ORFs) and a long control region (LCR) of promoters and en-
hancers (Figure 1). Over 40 HPV subtypes have been recognised
to infect the anogenital tract but only 12e13 of these are known
to have the potential to instigate a neoplastic process and are
therefore classified as high-risk HPV (hrHPV): HPV 16, 18, 31,
33, 35, 39, 45, 51, 52, 56, 58, 59 (HPV68 is probably carcino-
genic). These types cause inapparent infection before visible
precancerous lesions become evident. The remaining disease-
causing HPV genotypes are considered low-risk. The most com-
mon of which are HPV 6 and 11 (alpha papillomaviruses) e
responsible for visible genital warts and laryngeal
papillomatosis.
The first early genes, E1 and E2 are transcription factors and
involved in maintaining viral replication. While E4 proteins
contribute to genome amplification and viral synthesis, they may
also facilitate virion release and transmission. E5 is not coded for
in all HPVs; in Alpha types E5 interacts with host factors to
control viral replication and persistence as well as cell prolifer-
ation - such mechanisms include reducing surface major histo-
compatibility (MHC) 1 expression in infected basal cells to aid
immune avoidance. E6 and E7 are known as the oncogenes and
are thought to mediate viral proliferation through cell cycle
control; they induce disruption to normal keratinocyte differen-
tiation through inhibition of tumour suppressor genes (particu-
larly P53 and retinoblastoma protein (pRB)), allowing viral
amplification and influencing cell senescence and apoptosis.
These genes are particularly important in the expansion of lesion
size seen with high-risk types. An important difference between
low-risk and high-risk types is the ability of high-risk E7 to
associate with retinoblastoma protein. Additionally, high-risk E7
expression is thought to cause extensive epigenetic reprogram-
ming and cell cycle stimulation. The late genes, L2 and L1 code
for the minor and major viral capsid proteins
109 Ó 2020 Published by Elsevier Ltd.

HPV viral genome and gene function
Upstream Regulatory Region (URR)/
Long Control Region (LCR):
Promoter and enhancer elements
Viral open reading frame
URR
E6
L1 7906bp
HPV Genome
Late Genes
L2
L1: Major viral
capsid
L2: Minor viral
capsid E5
Figure 1
respectively;necessary for viral packaging and viral release, they
have formed the basis for the first prophylactic vaccines.
Variation in the size of open reading frames varies between
papillomaviruses. E1, E2, L1 and L2 genes tend to be well
conserved between HPV types, the remaining genes (E6, E7, E4
and E5) are more variable by genotype.
Epidemiology
Over 80% of cervical cancers are detected in women in low-
resource settings where screening is not available for the vast
majority. Resultantly in low- and middle-income countries, cer-
vical cancer is the most common female cancer. Introduction of
screening in the UK in 1988 has led to an estimated 24%
reduction in cervical cancer incidence; cervical cancer in now the
14th most common cancer in UK females. Around 8e10% of
women in the UK receive an abnormal smear test in their life-
time, however due to regression and treatment in the majority,
the progression to cancer is much less common (2016: 3200
cases/year).
HPV16 and 18 are thought to cause over 70% of cases of
invasive cervical cancer, with a further five HPV genotypes (31,
33, 45, 52, 58) responsible for the additional 20%. HPV pre-
dominates in squamous cell cancers, whilst HPV 18 may be the
most common type in adenocarcinoma of the cervix (Figure 2).
Completed HPV prevalence studies have been mainly focused
on developed countries where cervical screening is well estab-
lished. However, HPV type-specific prevalence varies globally; in
populations that account for the majority of global cervical
cancer deaths (e.g. South America and Sub-Saharan Africa),
type-specific prevalence of HPV is largely unknown. Rates of
HPV transmission between heterosexual couples also varies
greatly.
Age-specific prevalence of HPV varies, with the peak inci-
dence of HPV infection in adolescents, and incident infections
subsequently decreasing steadily over time (Figure 3). Higher
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4
REVIEW
Early Genes
E1: Transcription and replication
E2: Transcription and replication
E4: Virion release
E5: Cell proliferation
E6: Cell cycle control
E7 (p53 inactivation); oncogene
E1 E7: Cell cycle control
(Rb inactivation); oncogene
E2
E4
rates of HPV in young populations are thought to be related not
only to higher age-specific HPV prevalence, but also a naı̈ve
immune response and possibly an immature cervical epithelium
of the transformation zone in pubescent adolescents.
Natural history of HPV infection and cervical intra-
epithelial neoplasia (CIN)
The natural history of HPV infection and CIN are relatively well
understood due to good accessibility of the cervix, consequently
allowing serial sampling in prospective cohorts. Cervical cancer
has therefore provided the best model for study of all HPV
neoplastic processes.
Direct physical contact, usually as a result of vertical or sexual
intercourse allows HPV transmission. Viral transmission be-
tween sexual partners is thought to be related to both viral load
and duration of exposure. Microtrauma in the epithelial surface
is thought to be required for initial active infection. This is likely
to be influenced greatly by both the host immune response and
the surrounding microenvironment, including the presence of
inflammation secondary to concomitant infection. More recently
it has been found that even in the absence of occult vaginal
infection, an altered vaginal microbiome may predispose to HPV
infection and cervical disease.
The majority of HPV infections (w90%) are thought to be
transient and clear through an incompletely understood immune
response, usually within 12e24 months. It is thought that
clearance of a transient HPV infection occurs through activation
of the local innate immune response, including immunological
cells in cervical mucous.
In 2e5% of women (>30 years), HPV persistence occurs.
Longitudinal natural history studies of HPV incident infections in
cohorts of young women have shown that up to 50% of HPV
infections clear within 6 months, with w90% clearing within a
few years after the initial infection. Longer infections usually
activate the adaptive immune response, which involves antigen-
110 Ó 2020 Published by Elsevier Ltd.
 REVIEW

Global proportion of cervical cancers attributable to HPV type Cumulative

Proportion Number
(%) of cases
HPV16 60.6 320,822
+10.2%
HPV18 70.8 374,970
+5.9%
HPV45 76.7 406,115
+3.8%
HPV33 80.5 426,464 89–90%
+3.7%
HPV31 84.3 446,225
+2.8%
HPV52 87.1 461,148
+2.3%
HPV58 89.4 473,122
+1.9%
HPV35 91.3 483,444
+1.6%
HPV39 92.9 492,056
+1.3%
HPV51 94.2 498,781
+1.1%
HPV59 95.3 504,384
+1.0%
HPV68 96.1 508,808
+0.8%
HPV56 97.1 514,117
+0.5%
HPV73 97.6 516,653
+0.3%
HPV26 97.9 518,482
+0.3%
HPV67 98.2 520,015
+0.3%
HPV53 98.5 521,431
+0.1%
HPV70 98.6 521,962
+0.1%
HPV66 98.7 522,375
+0.1%
HPV82 98.7 522,729
+0.8%
Other 99.5 526,858
+0.5%
HPV X 100.0 529,512
0 10 20 30 40 50 60 70 80 90 100
Cumulative proportion of cancers due to combinations of HPV types (%)

Source: Arbyn, J Pathol 2014

Figure 2

Age-specific prevalence of oncogenic HPV infection and incidence

of cervical cancer in the Netherlands
Oncogenic HPV infection in normal smears (%)
Age-standardised incidence rate for cervical cancer (per 100,000)
20

15

10

0
20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64
Age (years)

Figure 3

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4 111 Ó 2020 Published by Elsevier Ltd.

presenting cells and antibody production, after which a level of
natural immunity occurs. In the presence of HPV persistence,
development of precancerous lesions classified as cervical
intraepithelial neoplasia (CIN) can occur. In cases of CIN with
HPV clearance, disease regresses spontaneously. Regression
rates decrease as CIN grade increases (Figure 4). In HPV persis-
tence, molecular carcinogenic processes continue that can lead to
CIN progression. The time from infection to invasive cervical
cancer is estimated to approximate 10e15 years. In rare cases,
the infection can be more aggressive, with fast progression to
cancer.
Most cervical cancers arise in the transformation zone. The
epithelial transformation zone of the cervix is a boundary of
metaplastic change in cell type from endocervical columnar
epithelium to stratified squamous epithelium (Figure 5). This
process of squamous metaplasia is naturally occurring in a
woman’s lifetime - beginning at puberty where eversion of the
endocervix causes exposure to the acidic vaginal pH and local
irritation. The resultant squamous metaplasia is immature and
particularly vulnerable to HPV infection and lesion formation. A
similar process of squamous metaplasia also occurs in the anal
and tonsillar epithelia.
Once the viral episome has reached the basal keratinocyte
cells (the last layer of the cervical epithelium) viral DNA repli-
cation occurs. The wound healing pathway is thought to drive
the spread of infected cells - mediated by E6/E7 proliferation,
epithelial cell differentiation allows spread of HPV virions from
basal layers through suprabasal, to the epithelial surface. In
established infection, new virions in exfoliated cervical cells
allow spread of infection to other cells and also transmission.
Natural history of CIN
Disease progression
Time Months
Normal HPV infection CIN I
epithelium koilocytosis
Borderline Mild
CIN I 57%
Approximate likelihood of regression
Figure 4
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4
REVIEW
Persistence of infection with or without progression to precan-
cerous lesions, is maintained by HPV infection of basal kerati-
nocytes. Frequency of re-infection after HPV clearance has been
debated, Moscicki et al. demonstrated that in a longitudinal
American cohort where two consecutive negative HPV tests have
been documented, HPV16 reinfection rate is 3e5%.
Although the majority of cervical pre-invasive disease arise in
the squamous epithelium, infection of the endocervix also occurs
and can lead to the development of glandular lesions in 20e30%
of cases e namely cervical glandular intraepithelial neoplasia
(CGIN) and adenocarcinoma. The endocervix consists of a single
layer of columnar cells organised into crypts. Here the epithelial
layer is unable to stratify and therefore the papillomavirus cell
cycle differs. In columnar cells, HPV gene expression deregula-
tion is thought to drive carcinogenesis. As well as being more
difficult to detect in screening, adenocarcinoma is thought to be
able to undergo a faster neoplastic process e not necessarily
requiring a low-grade precursor. It generally has a poorer prog-
nosis, which may reflect in part a delay in diagnosis. Together
HPV 16, 18 and 45 are responsible for almost 90% of cases in
most populations. Adenocarcinomas first detected in the endo-
cervix may occasionally be non-HPV driven and can represent
spread from endometrial cell types.
Disease classification
Cytology reporting of cervical disease is based on a classification
system which evaluates the presence of HPV infection and
severity of dyskaryosis, the most commonly referred to is the
Bethesda system, last updated in 2014 (Table 1). In cervical
histopathology, three pro-carcinogenic stages in the disease
Years
CIN II CIN III Invasive
cervical cancer
Moderate Severe Dyskaryosis
CIN II 43% CIN III 32%
112 Ó 2020 Published by Elsevier Ltd.
 REVIEW
Cervical transformation zone, found between new and old
squamocolumnar junctions
Internal os
Upper limit
of squamous
metaplasia
12 mm
Transformation zone
Figure 5
process of squamous pre-invasive lesions are recognised. The
definition of CIN (which is based on the number of thirds of the
epithelium that are affected by diseased cells) is reliant on a full-
thickness specimen of the transformation zone. CIN1 is defined
as disease affecting the basal third of the epithelium only, CIN2
two thirds, and CIN3 full thickness. Invasive cervical cancer
represents disease which has broken through the basement
membrane of the epithelium, allowing access to lymph and blood
vessels for metastatic spread.
Cervical glandular intraepithelial neoplasia (CGIN) is the pre-
invasive stage of adenocarcinoma of the cervix. These lesions are
more difficult to grade pathologically and usually subclassified
into low- or high-grade CGIN. High-grade CGIN may be morpho-
logically indistinguishable from invasive adenocarcinoma.
Risk factors and cervical pre-invasive disease
Persistent HPV infection is a necessary but not sufficient condi-
tion for the development of cervical preinvasive disease and
cancer. Large epidemiological studies suggest several known risk
co-factors modulate the risk of HPV persistence and cervical
cancer. The most evidence exists for smoking, long-term hor-
monal contraceptive use, immunocompromise (including HIV
infection) and high parity.
Chemicals from cigarette smoke are thought to influence both
acquisition and persistence of HPV infection along with pro-
gression to cancer. Smoking has been shown to mediate innate,
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4
Histologic
squamocolumnar
junction
7 mm
Original
squamocolumnar
junction
New (colposcopic)
squamocolumnar
junction
adaptive and barrier immune responses to HPV infection. Addi-
tionally, carcinogens in cigarette smoke cause genomic instability
through which many cancers are mediated. It has been estimated
that the additional risk of smoking results in 21% of cervical
cancers in the UK.
Use of oral contraceptives has been linked to increased cer-
vical cancer rates, oestrogens in particular are thought to in-
crease the eversion of the endocervical canal, causing more
exposure of vulnerable immature cells to HPV infection. Higher
parity has been associated with a higher incidence of cervical
cancer, which may be related to a higher lifetime hormone
exposure or repeated trauma. Cervical cancer in England is more
common in females living in the most deprived areas, indepen-
dently of other risk factors. In England higher incidence is also
observed in women of Caucasian and Black ethnicity, with a
lower incidence in Asian females.
Sexual behaviour is thought to influence lifetime risk of cer-
vical cancer; an increased incidence is observed in accordance
with earlier sexual debut and increased number of sexual part-
ners. Condom use is only partially effective against HPV infection
as transmission can also occur from direct contact with ano-
genital skin. Additionally, the role of condoms in assisting
clearance of persistent infection is not known. Studies suggest
that co-infection with other sexually transmitted infections, in
particular Chlamydia trachomatis may increase the acquisition of
HPV through promotion of a pro-inflammatory environment.
More recent evidence has shown that alterations to the protective
113 Ó 2020 Published by Elsevier Ltd.
 REVIEW

the cervix: approximately 90% of anal, 70e80% vaginal, 30

Summary of cytology and histology classification e40% penile, 12e20% oropharyngeal and 30e40% of vulval
systems in use by NHSCSP for squamous and glandular cancers are associated with a persistent high-risk HPV infection.
lesions Anal intraepithelial neoplasia appears to have a similar natural
Cytology Histology history and histological appearance to CIN. Anal-cervical and
cervical-anal HPV autoinoculation in women appears to be quite
NHSCSP/BAC 2013 Bethesda 2014 NHSCSP 2012
common. HPV acquisition in women and men who have anal sex is
common, approaching 70e90%. However, few individuals seem to
Borderline changes in ASC-US
develop anal HPV persistence unless immunodeficiency is present.
squamous cells ASC-H
Hence HIV-infected individuals who have anal sex appear to be most
Low-grade dyskaryosis LSIL CIN1
at-risk group of AIN and anal cancer. In women, those with cervical
High-grade dyskaryosis HSIL CIN2
(moderate)
or HPV-associated vulval cancer, seem to be at higher risk of
High-grade dyskaryosis HSIL CIN3
developing anal cancer. In some geographical areas of the UK, anal
(severe)
screening programmes have been initiated for high-risk individuals.
High-grade dyskaryosis/? HSIL SCC
Invasive vaginal cancer is rare (2014e16: w250 cases/
invasive SCC SCC
annum), whilst vulval cancer is uncommon (2014e16: w1300
cases/annum). Two independent pathways are proposed for the
Borderline changes in AGC NOS
development of vulval squamous cell carcinoma. The first is
endocervical cells
related to HPV infection, and the second to a chronic inflam-
? Glandular neoplasia Endocervical L-CGIN
matory (vulval dystrophy) or autoimmune process; often asso-
Endocervical type Endometrial
ciated with lichen sclerosus. The natural history of vaginal
Non-cervical Glandular
cancer is less well understood. Both vaginal and vulval cancers
AGC favours neoplastic H-CGIN
Endocervical
associated with HPV have a precursor lesion namely VAIN and
Glandular
VIN respectively. The malignant progression of such lesions is
Endocervical AIS
probably less than in CIN with 9e10% of VAIN cases progressing
Adenocarcinoma ACC
to cancer, progression of VIN has been estimated at 5%. Both
Endocervical
preinvasive lesions are histologically similar to CIN and
Endometrial
commonly occur in association. In a review of over 2000 women,
HPV DNA was detected in 86.7% of VIN and 28.6% of invasive
Extrauterine
vulval cancer cases; HPV 16 was the most frequent genotype
NOS
(72.5%), followed by HPV 33 (6.5%) and HPV 18 (4.6%).
ACC: adenocarcinoma; AGC NOS: atypical glandular cells, not otherwise speci- Studies of penile intraepithelial neoplasia have shown HPV
fied; AIS: adenocarcinoma in situ ASCUS: atypical squamous cells of undeter-
involvement in 70e100% of lesions. However, in terms of
mined significance; ASC-H: atypical squamous cells cannot exclude HSIL; BAC:
British association for cytopathology; CIN: cervical intra-epithelial neoplasia; L- overall incidence, penile cancers are rare.
CGIN: low grade cervical glandular intraepithelial neoplasia; H-CGIN: high grade There are currently no screening strategies for other HPV-
cervical glandular intraepithelial neoplasia; LSIL: low-grade squamous intra- related malignancies, but high awareness is needed in women
epithelial lesion; HSIL: high-grade squamous intra-epithelial lesion; NHSCP:
National health system cervical screening programme; SCC: squamous cell car-
with previous CIN.
cinoma.
Benign HPV conditions
Table 1 The incidence of anogenital warts has also been on the rise, with
an estimated annual incidence of 756e938,000 new cases in both
type vaginal microbiome also influence HPV persistence and genders. These, although benign, can be difficult to treat and
development of CIN. often recur; more than 85% are caused by the low-risk HPV types
It has been reliably demonstrated that in immunocompro- 6 and 11. Low-risk HPV types are also responsible for causing
mised individuals such as in HIV infection, the risk of cervical respiratory papillomatosis.
cancer is higher. Such individuals are invited to annual screening
in the UK. Recent genetic studies suggest that there may a small Cervical screening programmes
heritable component to cervical cancer risk, possibly through
Organised screening programmes have substantially reduced the
common polymorphisms coding for immune function, however
incidence and mortality from cervical cancer. In the UK, inci-
further study is required.
dence rates have dropped 44% since the early 1970s; while
introduction of the ‘call and recall’ system in 1988 led mortality
Non-cervical cancers
rates to drop from 7.1 to 2.4 per 100,000 in 2007. The largest
HPV primarily infects basal keratinocytes of mucosal epithelium benefits of screening are seen when this is centrally organised,
and therefore also causes a number of other cancers in anogenital population-wide, and has high coverage. Maintaining a well-
and oropharyngeal areas. Over 50,000 new diagnoses of HPV- developed screening organisation is expensive and requires
related cancers were made in Europe each year before the substantial infrastructure. These challenges are obvious when
introduction of HPV vaccination. However, the number of can- reviewing worldwide statistics. Within Europe, the majority of
cers in other areas attributable to HPV is proportionally less than cases (almost 60%) are still diagnosed in countries of Eastern

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4 114 Ó 2020 Published by Elsevier Ltd.
 REVIEW
Europe where screening programmes are not implemented. To
address this the World Health Organisation (WHO) have
announced a call to action including recommendations that all
countries should initially aim for a minimum standard of twice-
lifetime screening, particularly targeting the highest risk age-
group (women aged 30e49) and adopting a screen-and-treat
approach as an acceptable and realistic first step (where
screen-diagnose-treat programmes remain infeasible).
Screening tests
Traditionally, cervical screening has relied on cytology, which
requires only loose cervical cells exfoliated from tissue. Cytology-
based screening however, has inherent limitations including a
low sensitivity - which ranges from 50 to 70% depending on the
quality of the cytopathological laboratory. Meanwhile, intra-
observer agreement has been recorded to be low in many labo-
ratories. Training and maintaining high-quality cytopathologists
and laboratories are expensive and a logistical challenge for
many national screening programmes.
A meta-analysis of four European randomised controlled trials
provided Level A evidence to suggest that HPV-based screening
offers a 60e70% greater protection against invasive cervical
cancer when compared to cytology. This year HPV testing will
replace cytology as the primary screening test in the UK and
many other national screening programmes worldwide
(Figure 6). Improved accuracy may permit the prolongation of
screening intervals from three to five years. However, consider-
ation must be given to the fact that many women testing positive
will have just transient HPV infections. Triage tests are required
to better identify the women who would benefit most from col-
poscopic referrals and minimise overload of colposcopy clinics,
whilst also reducing unneccesary anxiety and over-intervention.
In the UK, reflex cytology will be used for triage largely because
of pre-existing infrastructure and safety follow-up data. Howev-
er, the sensitivity of cytology in detecting CIN3 or cancer is at
best 50e70% with a specificity of 78e86%. New molecular
markers may offer better accuracy for triage of HPV-positive
women and are currently under investigation. These include
HPV genotyping, HPV and human methylation, HPV E6/E7
mRNA and viral protein detection (e.g. E4, E6, and E7 and P16/
Ki-67 immunostaining). Self-sampling with HPV tests have been
shown to offer high accuracy and are increasingly considered for
use in screening programmes for non-responders.
Treatment of HPV-related disease
The majority of HPV associated disease is treated by local sur-
gical excision. High-grade intraepithelial neoplasia is treated
most commonly by Large Loop Excision of the Transformation
Zone (LLETZ) which is frequently carried out under local
anaesthetic in colposcopy clinics. Risk of high-grade disease
recurrence is estimated at 5e10%, with risk of invasive cancer
two to four times above population incidence rates. After treat-
ment a test of cure HPV test is performed at 6 months e a
negative HPV result greatly reduces risk of recurrence and allows
discharge to routine screening. VIN, VAIN and AIN are
commonly treated by wide local excision (WLE) under general
anaesthetic. Topical treatments including Imiquimod (licenced
for anogenital warts) and the antiviral agent Cidofovir and are
under clinical trial for treatment of VIN.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4
Vaccines
Prophylactic vaccination
HPV vaccines represent a major public health breakthrough and
immunisation programmes of prepubescent girls (and some
boys) have been implemented across many developed countries.
Methods of delivery, uptake, gender-policy and monitoring sys-
tems vary greatly, as does the choice of vaccines and dosing
schedule.
Natural infection with HPV induces a response from epithelial
antigen-presenting cells (APCs) and antigen-producing B-cells.
Interaction with cytotoxic T-cells aims to restrict the infection to
the epithelium, while T-helper cells enhance the antigen
response. The cell-mediated immune response becomes detect-
able within weeks of infection, whereas seroconversion takes 8
e9 months. Resultant antibody concentrations after natural HPV
infection are low and only roughly 50e70% of women with
incident HPV infection seroconvert. Even in the presence of
seroconversion following natural infection, there is minimal
against new HPV infection by the same type.
Currently available vaccines are comprised of virus-like par-
ticles (VLPs), which are based upon the L1 viral capsid protein
which self-assemble into VLPs. VLPs do not contain the viral
genome and therefore are not infectious but are highly immu-
nogenic and can generate high levels of anti-HPV L1 IgG anti-
bodies against included subtypes. The adjuvant used in the
vaccines is known to further enhance antibody production and
generation of B memory cells. There is emerging evidence that
vaccines offer considerable cross-protection against phylogenet-
ically similar HPV types.
The high prevalence and oncogenicity of HPV 16 and 18 led to
their selection for the first prophylactic vaccines, with addition of
types 6 and 11 to protect against genital warts (Table 2). In the
UK, the quadrivalent GardasilÒ vaccine is now freely offered to
girls and boys aged 12e13, men who have sex with men (aged
under 45), sex workers and HIV positive individuals. Gardasil9Ò
is also licensed and available in many countries.
Bi- and quadrivalent vaccines are proven to be very safe, with
an effective long-term immune protection, and some cross-
protection for non-vaccine types. Long term follow-up studies
of HPV vaccines show efficacy above 95% and protection 12
years after vaccination. Side-effects are similar to other vaccines
and include predominantly local reactions, and mild to moderate
systemic effects - resultantly the WHO has classified these vac-
cines as ‘extremely safe’. However, consistent public health
promotion will be necessary to maintain coverage in existing
countries where vaccination is offered, and also to increase ac-
cess in the majority of the world’s population where the HPV
vaccine is not routinely available.
Current recommendations are for three vaccine doses as rand-
omised trials have consistently demonstrated that antibody levels
after the 3rd vaccine dose are substantially greater (up to 100 times)
than after natural infection. However emerging evidence suggests
that in boys and girls younger than 15 years, only two doses may
be required. Current recommendations promote a prepubescent
vaccination programme at age 13, however the stronger immune
response during childhood and potential for increased coverage
through established childhood vaccination regimes, justifies
further investigation of vaccinating younger children.
115 Ó 2020 Published by Elsevier Ltd.
 REVIEW

UKNHSCSP cervical screening algorithm with HPV primary screening and cytology triage to be
introduced 2019/20

HPV Primary Screening Pilot Protocol Algorithm

All women aged 25–64 on routine call/recall and early recall

HR-HPV Test

HR-HPV -ve HR-HPV +ve

Routine recall 3 y (25–49) 5 y (≥50) Cytology triage

Cytology abnormal –
Cytology normal#
borderline or worse

Rescreen in 12 m Colposcopy referral

HR-HPV -ve HR-HPV +ve

Routine recall Cytology abnormal –

Cytology normal#
3 y (25–49) 5 y (≥50) borderline or worse

Rescreen in 12 m Colposcopy referral

HR-HPV +ve
HR-HPV -ve Cytology normal#
/abnormal

Routine recall Colposcopy referral

3 y (25–49) 5 y (≥50)

Notes
1) Inadequate tests at any screening episode in the pathway will be repeated in 3 months. Three inadequate tests in a row will
lead to a colposcopy referral.
2) Women entering the pilot under follow up for treatment for CIN will be given a 3 year recall if HR-HPV-ve and will be referred
to colposcopy if HR-HPV+ve/any grade of cytology.
3) Women entering the pilot under follow up for CGIN or SMILE (complete excision margins) will follow the protocol for CGIN at
their next two tests as detailed in the HPV Primary Screening Pilot Colposcopy Mangagement Recommendations Algorithm.
4) Women in follow up for cervical cancer (who still have a cervix) and CGIN/SMILE (without complete excision margins) at a pilot
site will be given annual HPV testing (instead of cytology) for 10 years.
#

12 month follow up test can be referred to colposcopy without further repeat tests.

Version 3.0 January 2016

Source: Public Health England 2016

Figure 6
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4 116 Ó 2020 Published by Elsevier Ltd.
 REVIEW

Types of currently licensed HPV vaccines

Bivalent Quadrivalent Nonavalent

Manufacturer, GlaxoSmithKline, CervarixÒ Merck, GardasilÒ Merck, Gardasil9Ò

Trade Name
Vaccine type HPV L1 VLP HPV L1 VLP HPV L1 VLP
HPV types 16, 18 6, 11, 16, 18 6, 11, 16, 18, 31, 33, 45, 52, 58
Age range FDA: 9-25y (females) FDA: 9-26y (females-males) FDA: 9-45y (females-males)
EMA: from 9y without upper limit EMA: from 9y without upper limit EMA: from 9y without upper limit
(females-males); recommended up (females-males); recommended up (females-males); recommended up
to 25y to 45y to 26y
Administrationa 15y: 0, 1, 6 14y: 0, 2, 6 15y: 0, 2, 6
<15y: 0, 5-13 <14y: 0, 6-12 <15y: 0, 6-12
Contraindications Severe allergic reaction to previous Hypersensitivity to yeast; severe Hypersensitivity to yeast; severe
dose allergic reaction to previous dose allergic reaction to previous dose

EMA: European medicines agency; FDA: food and drug administration; VLP: virus-like particle.
a
The 2-dose schedule for girls or boys <15y is FDA-approved only for Gardasil9.

Table 2

In most countries, a programme of vaccinating only girls have
been adopted. However, cost-effectiveness measurements and
moral arguments are leading to the introduction of gender-
neutral vaccination in several countries including Austria, the
US, Australia, Germany and the UK. It is hoped universal
vaccination will increase protection for men (from anogenital
cancers), further protect women where coverage is suboptimal
(<70%) and reduce stigma associated with a gender-based vac-
cine. Additionally, some mathematical modellers suggest that to
achieve complete herd immunity and eventual eradication of
cervical cancer, vaccination of boys is imperative.
Vaccination may be partially effective in sexually active in-
dividuals with previous but cleared natural infections, as the im-
munity level induced by vaccination may offer greater protection
against reinfection (although cost-effectiveness is unclear). A
randomised-control trial NOVEL will start recruiting in 2019 to
examine the value of HPV vaccination after CIN local treatment.
Therapeutic vaccination
Prophylactic HPV vaccines are highly efficacious but do not have
any therapeutic effect against existing HPV infections. Numerous
research groups are working on the development of therapeutic
vaccines with several being assessed in clinical trials.
Conclusions
Persistent infection by oncogenic HPV subtypes has been asso-
ciated with the development of a number of anogenital and
oropharyngeal cancers and >99.7% of cervical cancers. National
screening programmes have substantially reduced the incidence
and mortality from cervical cancer where implemented, however
the global burden of cervical cancer continues to increase. In
countries that screen, the introduction of HPV-based screening
will likely lead to further reduction in cervical cancers, whilst the
development of tests that will best identify the HPV positive
women that should be referred to colposcopy is required. Pro-
phylactic vaccines are expected to result in a dramatic reduction
of all HPV-related malignancies in countries with high coverage.
Increasing access to prophylactic vaccination and cervical
screening should be a global priority. Further research should
explore molecular markers that could determine the progressive
and regressive potential of precancerous lesions. A
Practice points
C Human papillomavirus is a common sexually transmitted infection
responsible for several anogenital cancers and benign
papillomas.
C Persistent infection by oncogenic high-risk subtypes is a neces-
sary condition for the development of cervical cancer.
C Cervical cancer is largely preventable through local treatment of
screen-detected cervical pre-invasive lesions.
C Cervical screening programmes based on cytology have led to
significant reductions in mortality from cervical cancer.
C HPV testing is expected to further reduce the incidence of cervical
cancer due to higher accuracy, whilst more specific triage tests are
required to select women that should be referred to colposcopy
C HPV-based testing and vaccination hold great promise for
reducing the burden of HPV-related disease but concerted inter-
national efforts are needed to expand coverage globally.
FURTHER READING
Cuschieri K, Ronco G, Lorincz A, et al. Eurogin roadmap 2017: triage
strategies for the management of HPV-positive women in cervical
screening programs. Int J Canc 2018 Aug 15; 143: 735e45.
Doorbar J, Griffin H. Refining our understanding of cervical neoplasia
and its cellular origins. Papillomavirus Res 2019; 7: 176e9.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4 117 Ó 2020 Published by Elsevier Ltd.
 REVIEW
Joura EA, Kyrgiou M, Bosch FX, et al. Human papillomavirus vacci-
nation: the ESGO-EFC position paper of the European society of
Gynaecologic Oncology and the European Federation for colpos-
copy. Eur J Canc 2019 Jul; 116: 21e2.
€ m KM, et al. International HPV screening
Ronco G, Dillner J, Elfstro
working group. Efficacy of HPV-based screening for prevention of
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4 118
invasive cervical cancer: follow-up of four European randomised
controlled trials. Lancet 2014 Feb 8; 383: 524e32.
Tidy J, Luesley D. Colposcopy and programme management: guide-
lines for the NHS cervical screening programme. Third edition.
London: NHSCSP publication no. 20, March 2016.
Ó 2020 Published by Elsevier Ltd.