1 Introduction
Neoplasias associated with anogenital human papilloma viruses (HPV) are characterised
by high patient
morbidity and mortality and by appreciable limitations in the patientʼs quality of
life. Each year
530,000 women worldwide and 4800 women in Germany develop cervical cancer [1], [2]. Biomolecular and epidemiological studies carried out in
the past 25 years have demonstrated causal link between persisting infections with
HPV 16 and HPV 18 and
at least 11 other so-called high-risk HPVs (HR-HPVs) and the development of cervical
cancer and its
precursor lesions (so-called dysplasias or, respectively, cervical intraepithelial
neoplasias – CIN).
HPV 16, HPV 18 and other HR-HPVs are also the causes of other cancers and their precursors,
for example,
vulvar, vaginal, penile and anal cancers as well as tonsillar and throat cancers and
certain forms of
skin cancer. So-called low-risk HPVs (LR-HPVs) such as HPV 6 and HPV 11 are responsible
for over 90 % of
anogenital condylomata acuminata (anogenital warts). Condylomata acuminata are the
most common viral
sexually transmitted disease (STD) worldwide [3]. It is estimated that around
1 % of European and German populations (aged 15–49 years) have these benign but often
very unpleasant
tumours. The development of a prophylactic quadrivalent vaccine (HPV 6, 11, 16, 18)
and a bivalent
vaccine (HPV 16, 18) has made it possible to prevent infections of the cervical epithelium
and other
squamous epithelia and the development of precancerous lesions. In the case of the
quadrivalent vaccine
(HPV 6, 11, 16, 18), the development of condylomata acuminata can also be prevented.
The Standing
Committee on Immunisation of the Robert Koch Institute (STIKO) has published a recommendation
on HPV
vaccination. Based on data from studies on the efficacy of HPV vaccines for the prevention
of
precancerous lesions of the cervix, vagina, and vulva, the STIKO recommends immunisation
for girls aged
between 12 and 17 years. The current guidelines do not contradict this recommendation
but rather provide
a more comprehensive supplement. The S3 guidelines focus on prophylactic vaccination
against HPV-16 and
HPV-18 or, respectively, HPV-6 and HPV-11 infections and thus on the prevention of
cervical, vulvar,
vaginal, anal and penile cancer and their precursors as well as on the primary prevention
of condylomata
acuminata and laryngeal papillomas. This S3 guideline thus clearly differs from other
guidelines such as
the S1 guideline “Condylomata acuminata and other HPV-associated clinical entities
of the genitals, anus
and urethra” (Guideline of the German STI Society in cooperation with the German Dermatological
Society
and the Paul-Ehrlich Society) and the S2 guideline of the German Society for Gynaecology
and Obstetrics
“Prevention, diagnostics and therapy for HPV infections and HPV-associated pre-invasive
lesions in
gynaecology and obstetrics”. After the debate on HPV immunisation has been concluded,
the S3 guideline
for the prevention of cervical cancer issued by the German Society for Gynaecology
and Obstetrics will
follow the recommendations in the current guideline, which will be updated. The development
process and
most important contents of the guideline are briefly described below. The long version
of the guideline
gives a more detailed account (www.awmf.org).
Abbreviations
AIN:
Anal intraepithelial neoplasia
CIN:
Cervical intraepithelial neoplasia
HC2-Test:
Hybrid capture 2-test
HPV:
Human papilloma viruses
HR:
High-risk (high-risk HPV)
ICC:
Invasive cervical carcinoma
MSM:
Men who have sex with men
PCR:
Polymerase chain reaction
PIN:
Penile intraepithelial neoplasia
STIKO:
Standing committee on immunisation at the Robert Koch Institute
TVC:
Total vaccinated cohort
VAIN:
Vaginal intraepithelial neoplasia
VIN:
Vulvar intraepithelial neoplasia
VLP:
Virus-like Particles
2 Methods
The present guidelines are an update of the first version of the S3 guideline on vaccination
against
neoplasias published in 2009 (short version) [4]. The core guideline group
(HPV management forum) that initiated the update of this S3 guideline is a working
group of the
Paul-Ehrlich Society for Chemotherapy. It consists of a multidisciplinary group of
experts whose members
are appointed by various professional societies. In addition, an expanded, multidisciplinary
panel of
experts drawn from several relevant specialist medical societies also participated
in the update. The
composition of the guideline group is presented in [Table 1].
Table 1 Composition of the group.
|
Members of the HPV management forum
|
|
Deutsche Dermatologische Gesellschaft e.V
|
Prof. Dr. med. Gerd Gross
|
|
Deutsche STI-Gesellschaft e. V.
|
Prof. Dr. rer. nat. Lutz Gissmann
Prof. Dr. med. Gerd Gross
PD Dr. med.
Hans Ikenberg
Prof. Dr. med. K. Ulrich Petry
|
|
Paul-Ehrlich Gesellschaft für Chemotherapie e. V.
|
Prof. Dr. med. Gerd Gross
PD Dr. rer. nat. Andreas Kaufmann
|
|
Deutsche Krebsgesellschaft, AGO
|
Prof. Dr. med. Peter Hillemanns
|
|
Deutsches Krebsforschungszentrum, Heidelberg
|
Prof. Dr. med. Magnus von Knebel Doeberitz
|
|
Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V.
|
Prof. Dr. med. K. Ulrich Petry
Prof. Dr. med. Achim Schneider
|
|
Gesellschaft für Virologie
|
Prof. Dr. rer. nat. Dr. h. c. Herbert Pfister
Prof. Dr. med. Sigrun Smola
|
|
Deutsche Gesellschaft für Urologie
|
Prof. Dr. med. Peter Schneede
|
|
Members of the expanded expert group
|
|
Deutsche Gesellschaft für Epidemiologie
|
Prof. Dr. med. Nikolaus Becker
Prof. Dr. rer. nat. et med. habil. Stefanie
Klug
|
|
Deutsche Dermatologische Gesellschaft e. V.
|
Prof. Dr. med. N. H. Brockmeyer
|
|
Deutsche STI-Gesellschaft e. V.
|
Prof. Dr. med. N. H. Brockmeyer
|
|
Deutsche Gesellschaft für Koloproktologie
|
PD Dr. med. Daniel Dindo
|
|
Deutsche AIDS Gesellschaft e. V.
|
Dr. med. Stefan Esser
Dr. med. Heiko Jessen
|
|
Berufsverband der Frauenärzte
|
Dipl med. Ulrich Freitag
|
|
Frauenselbsthilfe nach Krebs-BV e. V.
|
Marion Gebhardt
|
|
Berufsverband für Kinder- und Jugendärzte
|
Dr. med. Herbert Grundhewer
|
|
Deutsche Gesellschaft für Pathologie
|
Prof. Dr. med. Lars-Christian Horn
|
|
Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie
e. V.
|
Prof. Dr. rer. nat. et med. habil. Stefanie Klug
|
|
Deutsche Gesellschaft für Hals-Nasen-Ohrenheilkunde, Kopf und Hals-Chirurgie
e. V.
|
Prof. Dr. med. Jens P. Klußmann
|
|
Deutsche Krebsgesellschaft, PRIO, PSO
|
Prof. Dr. Karsten Münstedt
Prof. Dr. Susanne Singer
|
|
VulvaKarzinom-Selbsthilfegruppe e. V.
|
Ulf Röllinghof
Enzia Selka
|
|
Berufsverband Frauenärzte
|
Dr. med. Michael Wojcinski
|
|
Deutsche Vereinigung zur Bekämpfung der Viruskrankheiten
|
Prof. Dr. med. Peter Wutzler
|
As part of the update, the HPV management forum formulated six key questions which
were answered based on
currently available evidence. All six key questions are clearly marked in the guideline
and listed in
the Methods report. A more recent systematic literature search using the databases
Medline, Medline in
Process, Embase and Cochrane Library was done with a closing date of 27. 03. 2012
to answer the six key
questions. The closing date for the literature search of the initial guideline was
31. 07. 2007. A total
of 665 publications were identified. After documentation and elimination of duplicates,
the relevance of
the articles for the guideline was evaluated on the basis of their abstracts. The
full texts of 59
studies were acquired and evaluated using the inclusion criteria of this guideline
to answer the key
questions. After completion of this evaluation a total of 28 studies were included
in the guideline and
their methodological quality was assessed. These 28 studies served to answer the key
questions and as a
basis for part of the chapter “ADR/Safety”. For each study included to answer the
key questions, an
evidence level was defined as follows as an indication of its quality:
A1 Meta-analyses that contained at least one randomised study at the A2 level where
the results of
the various studies were consistent.
A2 Randomised, double-blind clinical comparative studies of good quality (e.g., calculation
of
sample size, flow charts, ITT analysis, sufficient scope).
B Randomised, clinical studies of a less good quality or other comparative studies
(not
randomised: cohort or case-control studies).
C Non-comparative studies.
In addition, a standard of evidence was defined, which summarised the state of the
evidence for each key
question and which took account of the evidence levels of the individual studies:
1 Studies at evidence level A1 or studies with predominantly consistent results at
evidence level
A2;
2 Studies at evidence level A2 or studies with predominantly consistent results at
evidence level
B;
3 Studies at evidence level B or studies with predominantly consistent results at evidence
level
C;
4 Little or no systematic empirical evidence.
Based on the data on the key questions, evidence-based and non-evidence-based recommendations
were
discussed and agreed upon in formal consensus procedures in a nominal group process.
Statements or
recommendations for which no experimental scientific studies were available but which
are generally
followed and for which good agreement could be achieved within the consensus group
are referred to as
clinical consensus points (CCP, syn.: good clinical practice, GCP). The other aspects
of the guideline
were assessed based on the available literature without a systematic evaluation but
taking account of
the expertʼs many years of personal experience.
3 Background
3.1 Virology and pathogenesis
Following the initial determination of the DNA sequences of HPV in genital warts and
in cervical
cancer at the beginning of the 1980s, numerous biomolecular and epidemiological studies
confirmed
the relationship between HPV infection and the development of cervical dysplasias
and cervical
cancer. Moreover, a causative role of HPV is assumed for the majority of anal cancers
and subgroups
of vulvar, vaginal, penile and head and neck cancers [5]. Analogous
conclusions with regard to the pathogenesis of these tumours are probably justified
but require
further substantiation. Today, at least 15 different so-called low-risk HPV types
have been
described as causes of genital warts or low-grade dysplasias. The role of 12 high-risk
HPV types in
the development of high-grade dysplasias or cervical cancer is considered to be certain;
for 13
further types an involvement is assumed on the basis of limited epidemiological evidence
or
phylogenetic relationships with recognised or presumed high-risk HPV types [6]. HPV is transmitted by direct contact. Sexual contact is considered the main infection
route for genital HPV types. Most HPV infections are recognised early and eliminated
by the immune
system, without progression to clinically relevant lesions [7]. In about
40 % of cases the infection can persist for more than 6 months and eventually progress
to a
high-grade intraepithelial neoplasia [8]. Since high-risk HPV infection is
one cause of cervical cancer [4], it can be assumed that prevention of the
primary HPV infection will lead to a reduction in the incidence of cervical cancer
and probably also
that of other HPV-induced cancers.
3.2 Vaccines/vaccine manufacturers and approval of vaccines
Europe-wide, two HPV vaccines for the prevention of infections by certain HPV types
have been
approved by the European Medicines Agency. The approval covers the vaccination of
girls and boys
(quadrivalent vaccine) or, respectively, of girls (bivalent vaccine) from the age
of 9 years upwards
without an upper age limit. The STIKO has recommended use of this vaccination in Germany.
This
recommendation currently applies to the vaccination of girls and young women aged
from 12 to 17
years [9].
3.3 Mechanism of action
Vaccination with the prophylactic HPV-VLP vaccine generates serum antibodies with
a titre that is
more than 100 times higher than that occurring with a natural infection [10], [11]. The antibodies are virus-neutralising, i.e., they
prevent infection of epithelial cells through binding to the virus capsid. It is not
yet known to
what extent the cellular immune system with CD4 helper cells and CD8 cytotoxic T-cells
plays a role
in immunological memory and the prevention of persisting infection. In the currently
available
studies with > 25,000 subjects high antibody titres were detected in > 99.9 % of vaccinated
subjects after the first immunisation.
3.4 Dosage and timing of vaccination/duration of protection
The clinical trials carried out and published to date on the efficacy of the vaccine
involved women
aged between 15 and 25 years. In addition, studies of healthy 9- to 15-year-old adolescents,
boys
and men as well as women up to the age of 55 have shown that the vaccination is generally
well
tolerated, highly immunogenic and, insofar as this can be measured, effective. At
present the
vaccination is recommended by the STIKO for girls/young women aged between 12 and
17 years. If
possible, vaccination should be completed (i.e., with three doses) prior to the first
sexual
intercourse. The vaccine has been approved for boys and girls aged 9 years and above
without an
upper age limit. An expansion of the recommendation to younger girls and boys could
improve
vaccination coverage and achieve a better herd immunity, probably however at the cost
of its
cost-efficiency. Factors which would support an early start to immunisation are:
-
Lower risk of prior exposure to HPV (first sexual intercourse),
-
Higher immunogenicity in younger subjects and no evidence for poorer tolerance,
-
Accessibility of the target group (compatible with vaccination scheme).
After the initial immunisation, it is recommended that the vaccination programme is
completed after
one (bivalent vaccine) or two (quadrivalent vaccine) months and again after six months.
However, new
data confirm that similarly high immune responses can be achieved in cases which deviated
from the
recommended scheme and when vaccinations are carried out at 0, 6 and 12 months [12], [13], [14]. Those women who
were not vaccinated in the period recommended by STIKO can still benefit from vaccination.
Their
physicians should assess the risks and benefits of vaccination and inform the patients
accordingly
taking their cue from the vaccine approval data [9]. In this context, data
from investigations into the recurrence of dysplasias after conisation are of interest.
In a
retrospective comparison of patients from the phase III trials FUTURE I + II (quadrivalent
vaccine)
and PATRICIA (bivalent vaccine), a significant reduction of recurrent disease was
found in the
vaccinated group compared to the placebo group. After only 1.4 yearsʼ follow-up, an
analysis of the
FUTURE data reported a reduction in the incidence of recurrent disease of 65 % [15]. Analysis of the PATRICIA data revealed a reduction of CIN2 or higher-grade lesions
of 88.2 % over the course of the study [16]. These data can be
interpreted together with a higher reinfection rate for those patients who, apparently,
develop
effective immunity prior to conisation, who were rapidly re-infected thereafter and
thus should be
considered a special high-risk group. Data on the duration of vaccination protection
cannot be
expected from studies performed by manufacturers. Nevertheless, in a subgroup of women
from a phase
II b trial followed up for more than 9.4 years, no breakthrough infection was seen
whereas 4 cases
of persisting infections occurred in the placebo group (difference not statistically
significant)
[17]. This correlates with a constant average antibody titre over
time in vaccinated women that is much higher than that of a naturally acquired immune
response [18]. Information on the duration of vaccine protection will only be
available after many years from population-based studies – if, in fact, an appreciable
number of
recurrent infections do occur after vaccination.
3.5 Major contraindications/limitations for use
No specific contraindications for the use of HPV vaccination are listed in the approval
for the
quadrivalent and bivalent vaccine [19], [20].
Vaccination during pregnancy is not recommended because there is insufficient data
to confirm that
the vaccine is harmless. The HPV vaccine may be administered to breast-feeding women
[9].
4 Primary Prevention of CIN, Vulvar Dysplasias and Genital Warts
4 Primary Prevention of CIN, Vulvar Dysplasias and Genital Warts
An almost 100 % vaccine protection against CIN caused by HPV 16 or HPV 18 has been
demonstrated in women
who were negative for HPV vaccine genotypes at the time of complete immunisation,
i.e., after three
doses of the vaccine (no evidence of disease found with PCR assay and patients were
also seronegative)
[21]. A partial vaccination protection of 44 % has been observed after
administration of at least one vaccine dose to women irrespective of their HPV status.
Protection from
vaccine-type associated VIN/VAIN was also around 100 % after prophylactic administration.
Irrespective
of the HPV status at the start of the trial, this protection decreased to 71 % with
regard to prevention
of vaccine type-associated VIN/VAIN grade 2/3. Irrespective of HPV type, VIN/VAIN-1
lesions can be
prevented in 18 % and VIN/VAIN 2/3 lesions in 26 %. Naturally induced antibodies against
one HPV type do
not react or react only very weakly against the capsids of other HPV types [22]. However, after vaccination antibody titres are appreciably higher than after natural
infection. It has also been shown that induced antibodies can have a partially cross-neutralising
and
cross-protective effect [23]. Cross-binding or cross-reactions have been
demonstrated in the sera of women vaccinated with the quadrivalent vaccine. These
sera contained
antibodies that, although less effective, bound to the capsids of HPV types 31, 45,
52 and 58, which are
closely related to HPV 16 and 18. In a pseudovirion neutralisation assay, it was shown
in vitro that
this cross-reaction also reduces infectivity [24]. Thus, vaccines provide
greater protection than merely protection against the respective vaccine types. A
partial
cross-protection over and beyond the vaccine genotypes HPV 16 and 18 has been demonstrated
for the
closely related genotypes 31 and 45 in a phase II study with the bivalent vaccine
[23]. Effectiveness was 50 and 90 %, respectively. These data were also supported by
serological investigations into the cross-neutralising action of specifically induced
antibodies. In a
phase III study by Paavonen et al. [25], effectiveness with regard to
prevention of six-month persistence of HPV types 45, 31, 33, 52 was 59.9 %, 36.1 %,
36.5 % and 31.6 %,
respectively. New analyses of the end-of-study data from the PATRICIA trial showed
a consistent
effectiveness against persisting infections and CIN2 or higher grade lesions in sub-cohorts
for HPV 31,
33, 45 and 51. Vaccine effectiveness against 12 HPV types not contained in the vaccine
(HPV 31, 33, 35,
39, 45, 51, 52, 56, 58, 59, 66, and 68) amounted to 46.8 % for the according-to-protocol
(ATP)
population, 56.2 % in the TVC-naive population (all vaccinated subjects who were HPV-negative
in month
7) and 34.2 % for all subjects who had been vaccinated at least once. The effectiveness
in the
prevention of CIN 3 or higher grade lesions in the same groups amounted to 73.8 %,
91.4 % and 47.5 %,
respectively.
5 Primary Prevention of PIN and AIN
5 Primary Prevention of PIN and AIN
AIN and anal cancer are a particular clinical problem in HPV-infected men with homosexual
contacts; the
corresponding AIN2/3 prevalence is more than 30 % and the incidence of anal cancer
is now about 100-fold
higher than in the heterosexual population. In more than 50 % of all AIN2/3 lesions
the DNA of the HPV
16 contained in the vaccine can be detected [26]. Similar numbers are seen
for organ-transplanted subjects: an AIN was found in 20 % (27/133) of investigated
patients, and
high-risk HPV type 16 was demonstrated in 47 % of the patients [27]. The
possible efficiency of the vaccine in HIV-infected MSM (men who have sex with men)
is difficult to
assess due to immunosuppression and multiple infections with high-risk HPV types.
Multiple HPV
infections have been identified in more than 60 % of AIN2/3 lesions of HIV patients
and HPV 16 is
underrepresented relative to others [26], [28].
The predominance of HPV 16 in anal cancer (73 % positive) supports the notion that,
in spite of the
presence of other HR-HPV infections, HPV 16 is mainly responsible for tumour progression.
In recipients
of organ transplants there are no appreciable differences in the extent of virus burden
and the number
of HPV types in comparison with healthy control subjects [29]. In a
multinational study, Giuliano et al. [30] examined the quadrivalent vaccine
in 4065 men aged 16–26 years. After an average follow-up period of 2.9 years, the
per-protocol analysis
revealed an effectiveness with regard to prevention of external genital lesions associated
with HPV 6,
11, 16 and 18 (condylomas, PIN, perianal and perineal intraepithelial neoplasias)
of 90.4 % (95 % CI:
69.2–98.1). Giuliano et al. [30] also investigated the effectiveness of the
vaccine against PIN. An effectiveness of 100 % was observed (95 % CI: − 3788.2–100.0)
in the
per-protocol analysis with regard to the prevention of PIN 2 or 3. In a sub-analysis
of MSM in the same
total population, Palewski et al. [31] calculated an effectiveness with
regard to the prevention of HPV 6, 11, 16 und 18-associated AIN of 77.5 % (95 % CI:
39.6–93.3) in the
per-protocol analysis.
6 HPV Tests Prior to Vaccination
6 HPV Tests Prior to Vaccination
There is a clear recommendation for vaccination prior to first intercourse if possible.
However, in
practice the question of later vaccination is often posed and the question of HPV
testing prior to
vaccination also arises regularly. Although detection of HPV proteins or HPV-specific
antibodies
(serology) [32] or of the cytopathological effects caused by HPV are still
not suitable or have not been sufficiently validated for routine diagnostics, the
detection of HPV-RNA
is considered sufficiently validated for this purpose [33]. One such
procedure has already been recognised by the FDA [34]. Standardised methods
for HPV-DNA detection are polymerase chain reaction (PCR) and hybridisation procedures
with signal
amplification. One prototype is the Hybrid-Capture-2 (HC2) test. It is used to detect
HPV types of
high-risk (13 types) and low-risk groups (5 types). Recently, the separate detection
of types 16, 18 and
45, which are all associated with the highest risk of progression, has become possible.
In the meantime
a second procedure based on signal amplification has been approved by the FDA [35]. In PCR assay, hybridisation with specific oligonucleotides, the primers, is done;
the
hybridisation product is subsequently amplified in reaction cycles. The sensitivity
of PCR is very high;
in theory a single molecule can be detected using this method. The very high analytical
sensitivity of
all PCR procedures for HPV, however, has not resulted in a higher sensitivity compared
with HC2 for the
detection of precancerous lesions and cancers in cancer screening. Because of the
increased registration
of clinically irrelevant HPV infections, early studies showed a marked reduction in
the specificity of
PCR in comparison to HC2 [36], [37]. Detailed HPV
typing in clinical routine currently seems to offer more disadvantages than advantages
[38]. Results of trials into prophylactic HPV vaccines show that vaccination
has no impact on already existing HPV infections [21]. Based on this
assumption, it could be concluded that HPV testing should precede vaccination. This
is currently not the
case for the following reasons:
-
Persisting HPV infections are almost always single infections, so that in most cases
protection
against further types remains intact. Simultaneous infection with 4 HPV types is present
in only
1 of 10,000 cases. Complete inefficacy of the vaccination due to persisting infections
is even
less probable as the existing infection can offer cross-protection against other HPV
types.
-
Comprehensive HPV screening in the age group 18 years and older would identify numerous
transient
infections that have no any clinical relevance; their identification would lead to
considerable
uncertainties for patients and their physicians. Not without reason do all experts
only
recommend the use of HPV tests in primary screening from the age of 30 year or more.
Even then,
this should be done using a test validated according to the guideline on account of
the
relatively high cut-off (and correspondingly high specificity).
-
If an HPV test result is available prior to vaccination it would appear to be reasonable
in cases
of HPV-HR positivity to perform a test for HPV 16 and 18. If this is negative, vaccination
can
be carried out. In cases of HPV 18 and, in particular, HPV 16 positivity, it is useful
to repeat
the test after 6–12 months and to vaccinate only those patients who are HPV 16 negative.
-
At present there are no tests for the serological detection of type-specific immune
response to
HPV vaccine types. The respective investigations in the vaccination trials were done
using
detection procedures that were developed by the manufacturers themselves which are
not
commercially available.
NB: In the presence of cytologically suspicious findings after vaccination, HPV tests
are reasonable
according to the recommendations of S2K Guideline [39]. Non-16 or 18 HPV
types are detected in most cases. This provides a good argument to exclude an assumed
vaccination
failure.
In contrast, an HPV test to supplement cytology in cancer screening is reasonable
from the age of 30
years onwards. In the presence of suspicious cytological or colposcopic findings or
a suspicious case
history, this is also valid for younger women. HPV testing is also indicated after
therapy for CIN (see
also the S2 guideline of the German Society for Gynaecology and Obstetrics (Deutsche
Gesellschaft für
Gynäkologie und Geburtshilfe)] [39].
7 Recommendations of the Guideline
7 Recommendations of the Guideline
|
Recommendation 1
|
|
Clinical consensus point (CCP)
|
HPV tests to assist decision-making prior to vaccination are not recommended at
present as these tests currently have no practical consequences.
|
Strong consensus
|
7.1 Recommendations for girls/young women
|
Recommendation 2
|
|
Evidence-based recommendation (presentation of evidence, see long version)
|
All girls should be vaccinated as soon as possible after reaching 9 years of
age.
|
Consensus
|
|
Statement 1
|
|
Evidence-based recommendation (presentation of evidence, see long version)
|
After starting sexual activities the expected benefits of vaccination will be
reduced.
|
Majority agreement
|
|
Recommendation 3
|
|
Clinical consensus point (CCP)
|
Decisions should be made on a case-by-case basis for these people.
|
Consensus
|
|
Recommendation 4
|
|
Clinical consensus point (CCP)
|
Treating a pre-existing CIN or ICC by vaccinating is not recommended since the
efficacy of this approach has not been demonstrated.
|
Strong consensus
|
|
* This statement is not supported by the following professional societies:
Deutsche Gesellschaft für Epidemiologie, Deutsche Gesellschaft für Medizinische
Informatik, Biometrie und Epidemiologie e. V.
|
|
Statement 2
|
|
Clinical consensus point (CCP)
|
There is some evidence that disease recurrence after surgical treatment can be
prevented in patients who have received HPV vaccination.
|
Strong consensus*
|
|
* This recommendation is not supported by the following professional societies:
Deutsche Gesellschaft für Epidemiologie, Deutsche Gesellschaft für Medizinische
Informatik, Biometrie und Epidemiologie e. V.
|
|
Recommendation 5
|
|
Clinical consensus point (CCP)
|
HPV vaccination can be considered as an option prior to surgical treatment to
reduce the risk of disease recurrence.
|
Majority agreement*
|
7.2 Recommendations for men/male adolescents
|
Recommendation 6
|
|
Evidenced-based recommendation (for presentation of evidence, see Section
5.3)
|
All boys aged 9 years or more should be vaccinated as early as possible.
|
Consensus
|
|
* This statement is not supported by the following professional societies:
Deutsche Gesellschaft für Epidemiologie, Deutsche Gesellschaft für Medizinische
Informatik, Biometrie und Epidemiologie e. V., Gesellschaft für Virologie
|
|
Statement 3
|
|
Clinical consensus point (CCP)
|
There is some evidence that disease recurrence after surgical treatment can be
prevented in subjects who have received HPV vaccination.
|
Consensus*
|
|
* This recommendation is not supported by the following professional societies:
Deutsche Gesellschaft für Epidemiologie, Deutsche Gesellschaft für Medizinische
Informatik, Biometrie und Epidemiologie e. V., Gesellschaft für Virologie
|
|
Recommendation 7
|
|
Clinical consensus point (CCP)
|
HPV vaccination can be considered as an option prior to surgical treatment to
reduce the risk of disease recurrence.
|
Consensus*
|
7.3 Recommendations for cancer screening
|
Recommendation 8
|
|
Clinical consensus point (CCP)
|
At present vaccinated women should continue to participate in cancer screening
programmes because the currently available vaccines cannot prevent all oncogenic
HPV infections.
|
Consensus
|
8 ADR/Safety
It is the general opinion of the agencies approving and recommending HPV vaccination
that the vaccine has
an excellent safety profile and exhibits only few side effects. It has been demonstrated
that the
methodology and evaluation of the safety analyses are appropriate and in accordance
with established
procedure [17], [40]. Very few participants
(0.2 %) dropped out of the trials carried out to date due to side effects. These drop-outs
occurred in
both study arms and the numbers were comparable for the drug and placebo groups. No
severe side effects
that were definitively triggered by the vaccine were observed. Vaccination-typical
acute local and
systemic reactions did occur but were designated as mild to moderate and were of only
transient duration
(< 3 days). Local side effects at the injection site such as pain, reddening and swelling
were
common, i.e., occurred in over 10 % of participants and were seen more often and were
of a more severe
nature in subjects receiving the vaccine compared to those receiving placebo. This
was explained as a
specific reaction against the antigen. Systemic side effects were fever, headache
and nausea. Body
temperatures of over 37.8 °C were observed in about 10 % of participants and temperatures
of more than
38.9 °C in about 1 %. The rates of side effects did not differ significantly between
drug and placebo
groups. Isolated cases (< 0.1/1000) of severe side effects possibly related to the
vaccine were
recorded and included bronchospasm, gastroenteritis, headache with high blood pressure
and vaginal
bleeding. Because of the low case numbers no conclusions about an increase after vaccination
can be
drawn. Only larger phase IV application studies will be able to confirm or exclude
an association
between such incidents and the vaccination. There were no deaths during the trials
that could be
connected to the vaccination. Between 2006 and 2009 Gee et al. [41]
prospectively recorded the occurrence of severe diseases (Guillain-Barré syndrome
[GBS], stroke, venous
thromboembolism, appendicitis, seizure, syncope, allergic reactions and anaphylaxis)
after vaccination
with the quadrivalent vaccine. After more than 600,000 doses of vaccine their study
found no
statistically increased risk for any of the above-mentioned diseases. To date the
maximum observation
time after vaccination is 9.4 years. In this period, no increases in the frequency
of newly occurring
autoimmune diseases were observed in the study arms of various phase II and III trials.
No statistically
significant differences were seen between study arms. The somewhat higher numerical
occurrence of
possible autoimmune diseases such as arthritis in the vaccine group remains within
the range of
variation for naturally occurring cases. Between June 2006 and October 2007 about
3500 potential side
effects after the quadrivalent vaccine were reported to the internet-based US reporting
system VAERS
(Vaccine Adverse Event Reporting System), of which 347 were classified as serious.
There were 3 deaths
that occurred chronologically after vaccination. However, a causal relationship to
the vaccination could
not be detected, and other causes were found. On evaluation of the data on unwanted
events after
quadrivalent HPV vaccinations in the USA reported between 2006 and 2008 (VAERS data),
a slightly higher
notification rate was seen for venous thrombosis and syncope compared to other vaccinations
[42]. The analyses carried out so far by the Center for Disease Control (CDC)
and the US Food and Drug Administration FDA) have not revealed any increases in specific
illnesses or
complications, so that the HPV vaccine can still be classified as very safe and well
tolerated. In a
systematic review, Pomfret et al. [43] came to similar conclusions. They
systematically evaluated the literature from 1966 to 2008. Both vaccines were considered
to be safe, and
most of the adverse effects were mild and transient. The reported serious effects
were considered by the
authors and the FDA to have occurred chronologically after vaccination but there was
no causal
relationship to the vaccination [43]. Lu et al. [44] performed a systematic meta-analysis of trials up until the middle of 2009 to assess
the
efficacy and safety of HPV vaccines. The cited studies showed a good tolerance, and
severe adverse
events were only rarely reported; there were isolated cases of complications during
pregnancy. Since the
introduction of HPV vaccination in Europe, two deaths have been reported that occurred
subsequent to the
quadrivalent vaccine vaccination in Germany and Austria. The case in Germany involved
an 18-year-old
woman who was found dead on the day after the second dose of the quadrivalent vaccine.
The autopsy did
not reveal any clear cause of death. In the second case of a 19-year-old woman in
Austria, the first
dose of the vaccine had been administered three weeks previously. Again, the autopsy
did not reveal any
remarkable findings, except for bronchitis. The German authorities (Paul-Ehrlich Institute),
the
vaccination committee of the Austrian Society for Paediatric and Adolescent Medicine
(Gesellschaft für
Kinder- und Jugendheilkunde) and the European approval agency (European Medicines
Agency) did not find a
causal relationship between the administration of HPV vaccines and the deaths of the
two young
women.
In discussions on vaccination, concerns about autoimmune diseases such as multiple
sclerosis (MS) and
Guillain-Barré syndrome have been voiced time and again. There have also been media
reports about
chronological connections between HPV vaccination and isolated cases of polyneuropathy
and non-specific
complications of strabismus.
The phase III trials of both vaccines showed no increased incidences in comparison
with placebo. Chao et
al. [45] investigated whether any of 16 different autoimmune diseases
occurred in ca. 190,000 girls and women in the period of 180 days after quadrivalent
HPV vaccination.
There was no evidence of an increased occurrence of autoimmune diseases following
vaccination. Isolated
cases have been reported in the literature; these include a case of autoimmune hepatitis
subsequent to
vaccination [46], lipoatrophy at the injection site [47] and erythema multiforme [48], [49].
Souayah et al. [50] analysed the US data from the Vaccine Adverse Event
Reporting System (VAERS) between 2006 and 2009 by investigating how often Guillain-Barré
syndrome was
reported subsequent to vaccination of the quadrivalent vaccine. They found a rate
of 6.6 cases per 10
million in the 6 weeks after vaccination. This rate was slightly increased in comparison
with other
vaccinations and that of the age-matched average population [50]. There are
several isolated case reports of demyelinising CNS diseases that occurred subsequent
to HPV vaccination
[51], [52], [53], [54], [55]. To what extent they
represent coincidental findings or whether there is, in fact, a causal relationship
cannot be deduced
from these individual observations. Certainly, more attention should be paid to these
rare incidents. In
the last report of the Paul-Ehrlich institute on pharmacovigilance in 2010, multiple
sclerosis was
reported in three patients after HPV vaccinations in the years 2007, 2008 and in one
case with an
unknown vaccination date. Causal relationships could not be assessed. A quantitative
evaluation of the
relative reporting frequency of multiple sclerosis in relation to HPV vaccination
between 2006 and the
end of 2010 was undertaken. No indications of a possible relationship to the vaccine
were found [56].
In Great Britain seven cases of anaphylaxis after vaccination were reported between
2008 and 2009. Three
of these cases occurred after bivalent HPV vaccination, which corresponds to a rate
of 1.4 cases per one
million doses of the vaccine. Almost all of these seven cases occurred in children
who had previously
already exhibited anaphylactic reactions, e.g., to foodstuffs [57]. In
Australia, eight cases of anaphylaxis after vaccination with the quadrivalent vaccine
were identified in
2007; this corresponds to a rate of 2.6 cases per 100,000 vaccine doses [58].
This rate and the reported British rate is slightly elevated in comparison with other
vaccines. Overall,
however, anaphylaxis after vaccination and especially after HPV vaccination is extremely
rare.
HPV vaccination is mostly administered to young women who have an increased chance
of becoming pregnant.
No evidence that use of the vaccine in pregnant women could be unsafe has been found.
The rate of
pregnancies with a congenital anomaly amounted to 3–4 %; this was low and within the
range of
frequencies reported by surveillance registers. The numbers of spontaneous abortions,
premature births
and Caesarean sections were comparable in both trial arms. However, the existing studies
were not
designed to investigate vaccination in pregnant women. Thus, until evidence for the
clinical safety of
the vaccination becomes available in phase IV studies, use of the vaccine in pregnant
women in Germany
cannot be recommended. Vaccination during the breast-feeding period has not led to
any severe
vaccine-induced side effects in mother or baby.
Monitoring and recording potential side effects is important. However, in complete
accordance with the
European Medicines Agency, the Paul-Ehrlich Institute and the American Center for
Disease Control, the
HPV management forum recommends the unrestricted use of HPV vaccinations. Given the
vaccination rates
already achieved, statistically we must expect a number of unclear deaths as well
as cases of autoimmune
diseases subsequent to, but not caused by, the vaccination.
