REVIEW

Human papillomavirus through slow co-evolution with humans, to cause visible and
persistent benign warts (papillomatosis) on anogenital and other
mucocutaneous surfaces.
Sarah J Bowden The major discovery related to HPV and disease came later
Maria Kyrgiou 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,
Abstract
never developed cervical cancer. In 1976e77, several scientific
Human papillomaviruses are ancient small DNA viruses and represent
teams isolated HPV from abnormal squamous epithelial cells.
the most common sexually transmitted infection in the world. In the
HPV infection was recognised as the first tumour virus in 1983
majority, HPV infection is cleared by an incompletely understood im-
mune response. HPV is a necessary but not sufficient cause of cervical
and Zur Hausen was later awarded the Nobel prize in medicine.
Extensive study over the last four decades has furthered our
cancer, and responsible for a proportion of other anogenital cancers
understanding of the causal association of HPV with primarily
including vulval, vaginal, anal and oropharyngeal. Oncogenesis is likely
cervical, but also other cancers. HPV is now thought to be
mediated through viral proteins which hijack host-cell machinery in
responsible for 10% of all malignancies in women and 5% in
epithelial keratinocytes and disrupt host tumour-suppressor proteins.
men: 99.7% of cervical cancers, a large proportion of other
Much work has been undertaken to further characterise the natural
anogenital cancers (vaginal, vulval, penile, anal), and a subset of
history of HPV infection and cervical disease. Such efforts have
oropharyngeal cancers (w12%).
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. Human papilloma virus
Keywords cervical cancer; cervical intraepithelial neoplasia; cervical
Genetic structure
screening; human papillomavirus
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-
Introduction
hancers (Figure 1). Over 40 HPV subtypes have been recognised
Papillomaviruses are ancient and ubiquitous small double- to infect the anogenital tract but only 12e13 of these are known
stranded DNA viruses. They lack the necessary enzymatic ma- to have the potential to instigate a neoplastic process and are
chinery to replicate independently and so have evolved over therefore classified as high-risk HPV (hrHPV): HPV 16, 18, 31,
millions of years to infect and replicate through a range of animal 33, 35, 39, 45, 51, 52, 56, 58, 59 (HPV68 is probably carcino-
hosts including humans. Human papillomavirus (HPV) primarily genic). These types cause inapparent infection before visible
infects epithelial cutaneous and mucosal surfaces of oral and precancerous lesions become evident. The remaining disease-
anogenital areas; it is spread through direct, sexual or vertical causing HPV genotypes are considered low-risk. The most com-
transmission. HPV infections are extremely common; rapidly mon of which are HPV 6 and 11 (alpha papillomaviruses) e
acquired after sexual debut with a lifetime incidence exceeding responsible for visible genital warts and laryngeal
80% in most populations. To date, over 150 HPV have been papillomatosis.
identified, sequenced, and classified into five phylogenetic types The first early genes, E1 and E2 are transcription factors and
(Alpha, Beta, Gamma, Mu and Nu), of which the most common involved in maintaining viral replication. While E4 proteins
are Alpha or Beta/Gamma. The majority of HPV infections from contribute to genome amplification and viral synthesis, they may
Beta and Gamma types are transient and benign; allowing for also facilitate virion release and transmission. E5 is not coded for
evolutionary fitness through efficient viral transmission in the in all HPVs; in Alpha types E5 interacts with host factors to
population. Where chronic persistent infections occur from these control viral replication and persistence as well as cell prolifer-
types, continued virion production, in the absence of visible ation - such mechanisms include reducing surface major histo-
disease may continue for months to years. Conversely Alpha compatibility (MHC) 1 expression in infected basal cells to aid
types have developed effective immune evasion strategies, likely 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-
Sarah J Bowden BSc MBBCH, Wellcome Trust Clinical PhD Fellow in larly P53 and retinoblastoma protein (pRB)), allowing viral
Gynaecological Oncology, Department of Surgery and Cancer,
amplification and influencing cell senescence and apoptosis.
Imperial College London, Hammersmith Hospital, London, UK.
Conflicts of interest: none. These genes are particularly important in the expansion of lesion
size seen with high-risk types. An important difference between
Maria Kyrgiou MSC PhD MRCOG, Clinical Reader and Consultant in
low-risk and high-risk types is the ability of high-risk E7 to
Gynaecological Oncology, Department of Surgery and Cancer,
associate with retinoblastoma protein. Additionally, high-risk E7
Imperial College London, Hammersmith Hospital, London, UK.
Conflict of interest: MK has received institutional research and expression is thought to cause extensive epigenetic reprogram-
educational support from MSD and personal support from MSD for ming and cell cycle stimulation. The late genes, L2 and L1 code
traveling and speaking at medical symposia. for the minor and major viral capsid proteins

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4 109 Ó 2020 Published by Elsevier Ltd.
 REVIEW

HPV viral genome and gene function

Early Genes
Upstream Regulatory Region (URR)/
Long Control Region (LCR): E1: Transcription and replication
E2: Transcription and replication
Promoter and enhancer elements E4: Virion release
Viral open reading frame E5: Cell proliferation
URR
E6
E6: Cell cycle control
L1 7906bp
E7 (p53 inactivation); oncogene
E1 E7: Cell cycle control
(Rb inactivation); oncogene

HPV Genome
Late Genes
L2

L1: Major viral

capsid

E2
L2: Minor viral
E4
capsid E5

Figure 1

respectively;necessary for viral packaging and viral release, they rates of HPV in young populations are thought to be related not
have formed the basis for the first prophylactic vaccines. only to higher age-specific HPV prevalence, but also a naı̈ve
Variation in the size of open reading frames varies between immune response and possibly an immature cervical epithelium
papillomaviruses. E1, E2, L1 and L2 genes tend to be well of the transformation zone in pubescent adolescents.
conserved between HPV types, the remaining genes (E6, E7, E4
and E5) are more variable by genotype. Natural history of HPV infection and cervical intra-
epithelial neoplasia (CIN)
Epidemiology The natural history of HPV infection and CIN are relatively well
Over 80% of cervical cancers are detected in women in low- understood due to good accessibility of the cervix, consequently
resource settings where screening is not available for the vast allowing serial sampling in prospective cohorts. Cervical cancer
majority. Resultantly in low- and middle-income countries, cer- has therefore provided the best model for study of all HPV
vical cancer is the most common female cancer. Introduction of neoplastic processes.
screening in the UK in 1988 has led to an estimated 24% Direct physical contact, usually as a result of vertical or sexual
reduction in cervical cancer incidence; cervical cancer in now the intercourse allows HPV transmission. Viral transmission be-
14th most common cancer in UK females. Around 8e10% of tween sexual partners is thought to be related to both viral load
women in the UK receive an abnormal smear test in their life- and duration of exposure. Microtrauma in the epithelial surface
time, however due to regression and treatment in the majority, is thought to be required for initial active infection. This is likely
the progression to cancer is much less common (2016: 3200 to be influenced greatly by both the host immune response and
cases/year). the surrounding microenvironment, including the presence of
HPV16 and 18 are thought to cause over 70% of cases of inflammation secondary to concomitant infection. More recently
invasive cervical cancer, with a further five HPV genotypes (31, it has been found that even in the absence of occult vaginal
33, 45, 52, 58) responsible for the additional 20%. HPV pre- infection, an altered vaginal microbiome may predispose to HPV
dominates in squamous cell cancers, whilst HPV 18 may be the infection and cervical disease.
most common type in adenocarcinoma of the cervix (Figure 2). The majority of HPV infections (w90%) are thought to be
Completed HPV prevalence studies have been mainly focused transient and clear through an incompletely understood immune
on developed countries where cervical screening is well estab- response, usually within 12e24 months. It is thought that
lished. However, HPV type-specific prevalence varies globally; in clearance of a transient HPV infection occurs through activation
populations that account for the majority of global cervical of the local innate immune response, including immunological
cancer deaths (e.g. South America and Sub-Saharan Africa), cells in cervical mucous.
type-specific prevalence of HPV is largely unknown. Rates of In 2e5% of women (>30 years), HPV persistence occurs.
HPV transmission between heterosexual couples also varies Longitudinal natural history studies of HPV incident infections in
greatly. cohorts of young women have shown that up to 50% of HPV
Age-specific prevalence of HPV varies, with the peak inci- infections clear within 6 months, with w90% clearing within a
dence of HPV infection in adolescents, and incident infections few years after the initial infection. Longer infections usually
subsequently decreasing steadily over time (Figure 3). Higher activate the adaptive immune response, which involves antigen-

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4 110 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

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 REVIEW

presenting cells and antibody production, after which a level of Persistence of infection with or without progression to precan-
natural immunity occurs. In the presence of HPV persistence, cerous lesions, is maintained by HPV infection of basal kerati-
development of precancerous lesions classified as cervical nocytes. Frequency of re-infection after HPV clearance has been
intraepithelial neoplasia (CIN) can occur. In cases of CIN with debated, Moscicki et al. demonstrated that in a longitudinal
HPV clearance, disease regresses spontaneously. Regression American cohort where two consecutive negative HPV tests have
rates decrease as CIN grade increases (Figure 4). In HPV persis- been documented, HPV16 reinfection rate is 3e5%.
tence, molecular carcinogenic processes continue that can lead to Although the majority of cervical pre-invasive disease arise in
CIN progression. The time from infection to invasive cervical the squamous epithelium, infection of the endocervix also occurs
cancer is estimated to approximate 10e15 years. In rare cases, and can lead to the development of glandular lesions in 20e30%
the infection can be more aggressive, with fast progression to of cases e namely cervical glandular intraepithelial neoplasia
cancer. (CGIN) and adenocarcinoma. The endocervix consists of a single
Most cervical cancers arise in the transformation zone. The layer of columnar cells organised into crypts. Here the epithelial
epithelial transformation zone of the cervix is a boundary of layer is unable to stratify and therefore the papillomavirus cell
metaplastic change in cell type from endocervical columnar cycle differs. In columnar cells, HPV gene expression deregula-
epithelium to stratified squamous epithelium (Figure 5). This tion is thought to drive carcinogenesis. As well as being more
process of squamous metaplasia is naturally occurring in a difficult to detect in screening, adenocarcinoma is thought to be
woman’s lifetime - beginning at puberty where eversion of the able to undergo a faster neoplastic process e not necessarily
endocervix causes exposure to the acidic vaginal pH and local requiring a low-grade precursor. It generally has a poorer prog-
irritation. The resultant squamous metaplasia is immature and nosis, which may reflect in part a delay in diagnosis. Together
particularly vulnerable to HPV infection and lesion formation. A HPV 16, 18 and 45 are responsible for almost 90% of cases in
similar process of squamous metaplasia also occurs in the anal most populations. Adenocarcinomas first detected in the endo-
and tonsillar epithelia. cervix may occasionally be non-HPV driven and can represent
Once the viral episome has reached the basal keratinocyte spread from endometrial cell types.
cells (the last layer of the cervical epithelium) viral DNA repli-
cation occurs. The wound healing pathway is thought to drive Disease classification
the spread of infected cells - mediated by E6/E7 proliferation, Cytology reporting of cervical disease is based on a classification
epithelial cell differentiation allows spread of HPV virions from system which evaluates the presence of HPV infection and
basal layers through suprabasal, to the epithelial surface. In severity of dyskaryosis, the most commonly referred to is the
established infection, new virions in exfoliated cervical cells Bethesda system, last updated in 2014 (Table 1). In cervical
allow spread of infection to other cells and also transmission. histopathology, three pro-carcinogenic stages in the disease

Natural history of CIN

Disease progression
Time Months Years

Normal HPV infection CIN I CIN II CIN III Invasive

epithelium koilocytosis cervical cancer

Borderline Mild Moderate Severe Dyskaryosis

CIN I 57% CIN II 43% CIN III 32%

Approximate likelihood of regression

Figure 4

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 REVIEW

Cervical transformation zone, found between new and old

squamocolumnar junctions

Internal os

Upper limit
of squamous Histologic
metaplasia squamocolumnar
junction
12 mm

7 mm

Original
squamocolumnar
junction

New (colposcopic)
Transformation zone squamocolumnar
junction

Figure 5

process of squamous pre-invasive lesions are recognised. The adaptive and barrier immune responses to HPV infection. Addi-
definition of CIN (which is based on the number of thirds of the tionally, carcinogens in cigarette smoke cause genomic instability
epithelium that are affected by diseased cells) is reliant on a full- through which many cancers are mediated. It has been estimated
thickness specimen of the transformation zone. CIN1 is defined that the additional risk of smoking results in 21% of cervical
as disease affecting the basal third of the epithelium only, CIN2 cancers in the UK.
two thirds, and CIN3 full thickness. Invasive cervical cancer Use of oral contraceptives has been linked to increased cer-
represents disease which has broken through the basement vical cancer rates, oestrogens in particular are thought to in-
membrane of the epithelium, allowing access to lymph and blood crease the eversion of the endocervical canal, causing more
vessels for metastatic spread. exposure of vulnerable immature cells to HPV infection. Higher
Cervical glandular intraepithelial neoplasia (CGIN) is the pre- parity has been associated with a higher incidence of cervical
invasive stage of adenocarcinoma of the cervix. These lesions are cancer, which may be related to a higher lifetime hormone
more difficult to grade pathologically and usually subclassified exposure or repeated trauma. Cervical cancer in England is more
into low- or high-grade CGIN. High-grade CGIN may be morpho- common in females living in the most deprived areas, indepen-
logically indistinguishable from invasive adenocarcinoma. 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.
Risk factors and cervical pre-invasive disease
Sexual behaviour is thought to influence lifetime risk of cer-
Persistent HPV infection is a necessary but not sufficient condi- vical cancer; an increased incidence is observed in accordance
tion for the development of cervical preinvasive disease and with earlier sexual debut and increased number of sexual part-
cancer. Large epidemiological studies suggest several known risk ners. Condom use is only partially effective against HPV infection
co-factors modulate the risk of HPV persistence and cervical as transmission can also occur from direct contact with ano-
cancer. The most evidence exists for smoking, long-term hor- genital skin. Additionally, the role of condoms in assisting
monal contraceptive use, immunocompromise (including HIV clearance of persistent infection is not known. Studies suggest
infection) and high parity. that co-infection with other sexually transmitted infections, in
Chemicals from cigarette smoke are thought to influence both particular Chlamydia trachomatis may increase the acquisition of
acquisition and persistence of HPV infection along with pro- HPV through promotion of a pro-inflammatory environment.
gression to cancer. Smoking has been shown to mediate innate, More recent evidence has shown that alterations to the protective

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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

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Europe where screening programmes are not implemented. To Vaccines

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

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

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

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:4 118 Ó 2020 Published by Elsevier Ltd.