Author’s Accepted Manuscript
Human papillomavirus prevalence and type
distribution in urine samples from Norwegian
women aged 17 and 21 years: A nationwide cross-
sectional study of three non-vaccinated birth cohorts
Tor Molden, Berit Feiring, Ole Herman Ambur,
Irene K. Christiansen, Mona Hansen, Ida Laake,
Roger Meisal, Ellen Myrvang, Christine
Monceyron Jonassen, Lill Trogstad
To appear in: Papillomavirus Research
Received date: 19 February 2016
Revised date: 6 May 2016
Accepted date: 7 May 2016
Cite this article as: Tor Molden, Berit Feiring, Ole Herman Ambur, Irene K.
Christiansen, Mona Hansen, Ida Laake, Roger Meisal, Ellen Myrvang, Christine
Monceyron Jonassen and Lill Trogstad, Human papillomavirus prevalence and
type distribution in urine samples from Norwegian women aged 17 and 21 years:
A nationwide cross-sectional study of three non-vaccinated birth cohorts,
Papillomavirus Research, http://dx.doi.org/10.1016/j.pvr.2016.05.002
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Human papillomavirus prevalence and type distribution in urine samples
from Norwegian women aged 17 and 21 years: A nationwide cross-sectional
study of three non-vaccinated birth cohorts
Tor Moldena±, Berit Feiringa, Ole Herman Amburb, Irene K. Christiansenb, Mona Hansenb, Ida
Laakea, Roger Meisalb, Ellen Myrvangb, Christine Monceyron Jonassenb,c*, Lill Trogstada*.
aNorwegian Institute of Public Health, PO Box,4404 Nydalen, 0403 Oslo, Norway.
bAkershus University Hospital, PO Box 1000, 1478 Lørenskog, Norway.
cØstfold Hospital Trust, PO Box 300, 1714 Grålum, Norway (present address).
±Corresponding author. Tor Molden, Norwegian Institute of Public Health, PO Box 4404
Nydalen, 0403 Oslo, Norway. Tel: +4721077000. E-mail address: email@example.com
E-mail addresses co-authors:
Berit Feiring: firstname.lastname@example.org
Ole Herman Ambur: email@example.com
Irene Kraus Christiansen: firstname.lastname@example.org
Mona Hansen: email@example.com
Ida Laake: firstname.lastname@example.org
Roger Meisal: email@example.com
Ellen Myrvang: firstname.lastname@example.org
Christine Monceyron Jonassen: email@example.com
Lill Trogstad: firstname.lastname@example.org
The aim of the current study was to assess the HPV prevalence in unscreened and
unvaccinated young women living in Norway to provide important baseline data for early
estimation of the impact of the HPV vaccination program.
A total of 13,129 self-sampled urine samples from two complete birth-cohorts of 17-year old
women born in 1994 and 1996 and one third of a birth-cohort of 21-year old women born in
1990 living all across Norway were analysed for the presence of 37 HPV types using PCR
and a DNA hybridisation technique.
In the two birth cohorts of 17-year old women, HPV was detected in 19.9% (95% CI 18.8-
20.9) and 15.4% (95% CI 14.5-16.3), respectively. High-risk HPV types were detected in
11.2% (95% CI 10.3-12.0) and 7.6% (95% CI 6.9-8.2), respectively, while vaccine types were
detected in 7.4% (95% CI 6.7-8.1) and 6.0% (95% CI 5.4-6.6), respectively. Among the 21-
year old women HPV was detected in 45.4% (95% CI 42.9-47.8), whereas high-risk types
were detected in 29.8% (95% CI 27.5-32.0). Vaccine types (HPV 6, 11, 16, 18) were detected
in 16.2% (95% CI 14.4-18.1).
This large population based study confirms that HPV testing in urine samples is easy and
highly feasible for epidemiological studies and vaccine surveillance in young women. HPV
was very common and a broad spectrum of HPV types was identified. Differences in HPV
prevalence was seen both between age groups and between the two birth cohorts of 17-year
Keywords human papillomavirus, immunisation, urine, vaccine, HPV prevalence, HPV
Infection with an oncogenic type of human papillomavirus (HPV) is a pre-requisite for
developing cervical pre-cancerous lesions and carcinomas. More than 40 HPV types are
known to infect the human anogenital tract. At least 12 types are considered carcinogenic and
are commonly referred to as high-risk types [1-3].
Vaccination against HPV infection was introduced in the Norwegian childhood immunization
program in the school year 2009/2010. All girls born in 1997 and later have been offered the
vaccine in the 7th grade at age 11-12 years. No publically funded catch-up vaccination for the
older age groups has been introduced. The 4-valent vaccine, Gardasil® (Sanofi Pasteur Merck
Sharp & Dome Ltd.) is used in the program. The vaccine offers protection against HPV 16
and 18, which cause about 70% of invasive cervical carcinomas , as well as the low-risk
types 6, 11, the main etiologic agent for external genital warts [5, 6].
Knowledge of the baseline HPV prevalence and type distribution in unscreened and
unvaccinated birth cohorts is essential for estimating the impact of HPV vaccination.
However, few population-based studies have been conducted to assess the prevalence of HPV
and type distribution in pre-teens or young adults. Smaller studies of unvaccinated women
from Scotland and the Netherlands show an HPV prevalence in urine of 4.4% to 32.2% in the
age groups of 14-16 and 20-21 years, respectively [7, 8]. A few studies have assessed the
prevalence of circulating HPV types in Norway, generally focusing on HPV types present in
cervical precancerous or cancerous lesions or in women visiting gynaecology clinics [9-15].
Less is known about the HPV prevalence and genotype distribution in women in their late
teens or early twenties, who have not yet been invited to participate in the national screening
program against cervical cancer. The aim of the current study was to describe the HPV type
prevalence in young women in Norway who have not been offered the vaccine against HPV
as part of the national childhood immunization program. We were also interested in
comparing the HPV prevalence between 17-year olds and 21-year olds and between two birth
cohorts of 17-year olds to document natural fluctuations of HPV prevalence.
Material and methods
Enrolment, sample collection, and study sample
Women eligible for the study were identified through the Norwegian Population Register.
In 2011, an invitation letter was sent to all women born in 1994 residing in Norway as of
January 1st 2011, except some born at the end of 1994, in total 83.0% of the birth cohort (Fig.
1). In 2013, a total of 99.5% of the women born in 1996 were invited to participate in the
study. The invitation was sent the same month the women became 17 years (in 2011 and
2013, respectively). Women born between August and December in 1990 were invited in the
period January to May 2012. The HPV prevalence in this age-group was expected to be at
least twice the HPV prevalence in the 17-year olds. Therefore, only women born between
August and December were invited, in total 30.8% of the birth cohort. From the initial birth
cohort list obtained at the beginning of the year of sample collection, some were not invited
due to missing address, invalid social security number, death, or emigration.
The invitation was sent by mail and included information about the study, an informed
consent form, and a pre-franked envelope for returning the signed informed consent. Women
who consented to participate received a sample kit and instructions for obtaining a first void
urine sample together with a pre-franked return envelope. The sample device contained a
preservative (boric acid), to prevent bacterial growth. The urine samples were shipped by mail
to the Norwegian Institute of Public Health (NIPH) where the samples were marked,
processed and stored at -80°C until further analysis. An aliquot was sent to the Norwegian
HPV Reference Laboratory (Akershus University Hospital) for isolation of nucleic acids and
HPV genotyping. HPV results were not routinely communicated to the participants, but were
provided upon request. Participants could withdraw from the study at any time. All
participants were rewarded with two cinema tickets for their contribution.
A total of 13,129 women contributed with a urine sample. The participation rates were similar
for the northern, middle, western, southern and eastern region of Norway, and ranged from
14.2 to 17.8% for the 21-year olds and 16.9-22.3% for the 17-year olds.
Linkage to the immunisation register for individual vaccination status was not performed
since the current study population is largely unvaccinated. These young women were not
offered vaccine against HPV as part of the national immunisation program. According to
distribution numbers, very few vaccine doses have been distributed for sale to this group.
The study was approved by the Regional Committee for Medical and Health Research Ethics
and the Norwegian Data Protection Authority.
Isolation of nucleic acids
Nucleic acids were isolated using Boom’s isolation method  and the automatic
NucliSENS easyMAG extraction device (bioMérieux Corporate, Marcy l’Etoile, France).
Total nucleic acids were kept cold and analysed within four hours or stored at -80°C until
Validation of sample adequacy and HPV genotyping
Human β-globin quantitative real-time PCR for validation of sample adequacy and HPV
genotyping using PCR and DNA hybridization and Luminex based technology was performed
as previously described [17, 18]. The HPV genotyping method detects 37 HPV types; 12
high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59), six probable high-risk
types (26, 53, 66, 68, 73, 82), and 19 undetermined or low-risk types (6, 11, 30, 40, 42, 43,
54, 61, 67, 69, 70, 74, 81, 83, 86, 87, 89, 90, 91)[1, 2].
In order not to compete with the HPV PCR, the β-globin PCR was run in a separate reaction.
The PCR products were kept frozen at -20°C until further analysis.
Upon Luminex detection of values in the range from the cut-off value up to two times the cut-
off value for any HPV-type, a re-analysis was performed in duplicate. Individual cut-off
values for each HPV-type were calculated for each run based on the level of background
noise. Cut-off modification values and factors for cross-hybridization correction used to
calculate the cut-off were adapted from the WHO HPV reference laboratory in Sweden. A
total of 202 samples (1.5%) did not give a valid result for β-globin or for HPV, and were
excluded from the analyses.
The prevalence of HPV types was defined as the number of positive specimens divided by the
total number of specimens with valid PCR result (β-globin and Luminex). We calculated the
corresponding 95% Wald confidence intervals (CIs).
Chi squared tests were used to test for differences between proportions. All tests were two-
sided, and p<0.05 was considered statistically significant. The data were analysed with
STATA/SE version 13.0 (StataCorp, College Station, Texas, USA).
HPV prevalence by birth cohort is shown in Table 1. The overall HPV prevalence in urine
specimens from 21-year old women was 45.4% (95% CI 42.9, 47.8). High-risk types were
detected in 29.8% (95% CI 27.5, 32.0), corresponding to 65.5% of all HPV positive samples.
The vaccine types 6, 11, 16, and 18, were detected in 16.2% (95% CI 14.4, 18.1),
corresponding to 35.7% of all HPV positive samples. Multiple infections were observed in
26.1% (95% CI 23.9, 28.2).
For 17-year old women born in 1994, the overall HPV prevalence was 19.9% (95% CI 18.8,
20.9). High-risk types were detected in 11.2% (95% CI 10.3, 12.0). Vaccine types 6, 11, 16,
and 18, were detected in 7.4% (95% CI 6.7, 8.1). Multiple infections were observed in 9.2%
(95% CI 8.5, 10.0). Among all positive HPV samples, 56.2% were high-risk types and 37.1%
were positive for any vaccine type.
For 17-year old women born in 1996, the overall HPV prevalence was 15.4% (95% CI 14.5,
16.3). High-risk types were detected in 7.6% (95% CI 6.9, 8.2). Vaccine types 6, 11, 16, and
18, were detected in 4.8% (95% CI 4.3, 5.3). Multiple infections were observed in 6.0% (95%
CI 5.4, 6.6). Among all HPV positive samples, 49.1% were positive for high-risk types, and
31.2% were positive for any vaccine types.
The HPV prevalence was significantly higher (p<0.001) in 21-year old women as compared
to the 17-year old women combined for HPV overall (45.4% vs. 17.5%), high-risk HPV types
(29.8% vs. 9.3%), probable high-risk HPV types (8.2% vs. 3.1%), low-risk HPV types (29.1%
vs. 10.0%), vaccine HPV types (16.2% vs. 6.0%), and multiple infections (26.1% vs. 7.5%).
Moreover, the prevalence was significantly higher (p<0.001) among 17-year olds born in
1994 than 17-year olds born in 1996 for HPV total, high-risk HPV types, low-risk HPV types,
vaccine HPV types, and multiple infections, whereas the prevalence of probable high-risk
types was not significantly different (p=0.45).
The prevalence of HPV types defined as high-risk or probable high-risk are presented in Fig.
2. HPV 16 was the most common HPV genotype detected in 21-year old women, with a
prevalence of 11.4%. Following HPV 16, the four most common high-risk or probable high-
risk HPV types were in decreasing order; HPV 51, 56, 18, and 31.
Among 17-year old women born in 1994, HPV 16, the most common HPV type, was detected
in 3.5% of the samples. After HPV 16, the four most common high-risk or probable high-risk
HPV types were in decreasing order; HPV 51, 18, 59, and 66.
Among 17-year old girls born in 1996, HPV 16, the most common HPV type, was detected in
2.4% of the samples. After HPV 16, the four most common high-risk or probable high-risk
HPV types were in decreasing order; HPV 66, 51, 31 and 59.
The prevalence of HPV types defined as undetermined or low-risk is presented in Fig. 3. For
21-year old women, HPV 90 was the most common low-risk HPV genotype with a
prevalence of 6.4%. Other common low-risk HPV types were in decreasing order; HPV 42,
87, and 89. The vaccine types HPV 6 and 11 were detected in 3.3% and 0.04% of the 21-year
old women, respectively.
Among 17-year old girls born in 1994, the most common low-risk HPV type was HPV 6
(2.7%), followed by HPV 90, 42, and 87. The vaccine type HPV 11 was detected in 0.3%.
Among 17-year old girls born in 1996, the most common low-risk HPV type was HPV 6
(1.8%), followed by HPV90, 89, and 87. The vaccine type HPV 11 was detected in 0.3%.
This study is the first of a series of nationwide, population-based, cross-sectional studies with
the aim to estimate the early impact of the HPV vaccination program in Norway. We assessed
HPV prevalence in self-sampled urine specimens in 17- and 21-year old women who have not
been offered the vaccine against HPV as part of the national childhood immunization
All the 37 HPV types included in the HPV Luminex assay were detected in our study sample.
Knowledge of the prevalence of high-risk HPV types 16 and 18 as well as the low-risk HPV
types 6 and 11 in the population prior to vaccination is of primary interest for future studies of
the impact of the 4-valent vaccine. The vaccine types HPV16 and 18 were detected in nearly
half of the HPV high-risk positive samples across all age groups, which correspond well with
previous results from unvaccinated 20-21 year old women in Scotland . Of the other
vaccine types, HPV 6 was common, whereas HPV 11 was quite rare. These results are in
accordance with a Swedish study . In contrast, the prevalence of HPV 6 was similar to the
prevalence of HPV 11 in a Dutch study .
HPV high-risk types were detected in a large proportion of the samples and were similar to
what has been reported in other European studies, both regarding types detected and
prevalence [7, 8, 20]. The prevalence increased with age and was found to be two- to three
times higher in 21-year old women compared to 17-year olds. Increasing prevalence with age
is in line with several studies [20-23]. All together, these observations confirm that infection
with HPV vaccine types or other high-risk types is common in young Norwegian women.
The HPV prevalence differed between the two birth cohorts of 17-year olds. The prevalence
was significantly higher among girls in the 1994 birth cohort as compared to the 1996 birth
cohort. The regional participation pattern was similar in the two birth cohorts (results not
shown), thus regional differences in HPV prevalence do not explain the difference between
these two birth cohorts. The finding may be a result of natural fluctuations in the prevalence
of HPV. Also, a few of the participants in the study may have received the HPV-vaccine
outside the national childhood immunization program. According to data from the Norwegian
immunization register, approximately 3% of all girls born in 1996 and 2% of all girls born in
1994 have been vaccinated with three doses of the 4-valent vaccine (unpublished data). We do
not suspect the small proportion of individuals in the cohorts already vaccinated to
differentially affect the HPV results. The assumption that the difference in HPV prevalence
between the two cohorts of 17-year olds is not due to vaccination is supported by the
prevalence of non-vaccine HPV types which is also generally lower in the 1996 birth cohort
compared to the 1994 birth cohort.
A major strength of the current study is the population-based design and large sample.
However, the low participation rate may cause selection bias if willingness to participate is
systematically associated with certain sexual behaviours increasing the risk of HPV, or
vaccination status which would reduce the risk of HPV. Nevertheless, the aim of the HPV
surveillance program is to monitor changes in prevalence and type distribution over time and
we believe this potential bias to be comparable from year to year, so the comparison of HPV
prevalence’s across birth cohorts is still expected to be valid.
Considering the young age of the study subjects, taking a less intrusive urine sample is for
ethical reasons preferred over a cervical sample.
Testing for HPV in urine samples may not be comparable to testing cervical smears, as
detection of HPV in urine may not be representative for HPV infections in the cervix. This
has been shown in several studies where in general the HPV prevalence is lower when HPV
DNA is isolated from urine compared to when HPV DNA is isolated from the cervical smears
[8, 24]. Accordingly, the HPV prevalence observed in our study is most likely an
underestimate of the true prevalence in cervical specimens. Nevertheless, our large study
confirms that HPV testing in urine samples is easy to implement and highly feasible for
epidemiological studies and vaccine surveillance in young women, as also stated in other
Further surveillance of the early impact of the HPV vaccination program in Norway will
include urine samples from both vaccinated and not vaccinated birth cohorts. Changes in the
HPV prevalence over time will be documented. Additionally, the surveillance program is
planned to include routine HPV-testing of cervical histological samples with cancerous and
pre-cancerous lesions. So far, only girls in the 7th grade in Norway has been offered the HPV
vaccine. Thus, it will take several more years before the vaccine effectiveness including these
endpoints can be estimated.
In conclusion, this large population based study confirms that HPV testing in urine samples is
easy and highly feasible for epidemiological studies and vaccine surveillance in young
women. We have assessed the prevalence and genotype distribution of HPV in urine
specimens from young women from a largely unvaccinated population, providing important
baseline data for early estimation of the impact of the HPV vaccination program in Norway.
HPV was frequently detected. A broad spectrum of HPV types was identified and multiple
infections were prevalent. HPV was detected two to three fold more frequently in 21-year old
women compared to 17-year old women, and there were also differences between the two 17-
year old birth cohorts. The vaccine specific HPV types 6, 16 and 18 were quite common in
young Norwegian women, whereas the vaccine type HPV 11 was quite rare.
Conflict of interests
Sources of support
This research received funding from the Norwegian Ministry of Health and Care Services.
TM contributed with preparation of data files, analysis and interpretation of the data, and
drafting the article. OHA and IKC contributed with laboratory analysis, analysis and
interpretation of the data and revising the article for important intellectual content. MH and
EM contributed to conception and design of the study, laboratory analysis, interpretation of
the data, and revising the article for important intellectual content. IL contributed with
analysis and interpretation of the data and revising the article for important intellectual
content. RM contributed with laboratory analyses and revising the article for important
intellectual content. BF, CMJ and LT contributed to conception and design of the study,
interpretation of the data, and revising the article for important intellectual content. All
authors have given final approval of the version to be published.
We thank the HPVnorvaks study group for their contribution in making this study
manageable. Special thanks to Alexander Eieland and Nermin Zecic at the HPV reference
laboratory for technical support, Jeanette Stålkrantz, Nina Hovland, Patricia Schreuder, at
Norwegian Institute of Public Health (NIPH) for their work with invitations letter and
informed consent forms, Ole-Martin Kvinge at NIPH for data management, Nina Kristin
Stensrud and Kari Harbak at the NIPH biobank for management of sampling kit and urine
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Figure 1: Flow-chart study population
¹ ² ³ Total female birth cohort alive the 1st of January the year of sample collection .
Figure 2: Prevalence of high-risk and probably high-risk HPV types in urine samples from
unvaccinated Norwegian women by birth cohort.
Figure 3: Prevalence of undetermined or low-risk HPV types in urine samples from
unvaccinated Norwegian women by birth cohort.
Table 1: HPV prevalence in urine samples from Norwegian women by birth cohort
21 yrs 1990 (N=1565)
17 yrs 1994 (N=5468)
17 yrs 1996 (N=5894)
% (95% CI)
% (95% CI)
% (95% CI)
Wald’s method was used to calculate 95 % CIs
¹HPV total includes those who are positive for at least one of the 37 HPV types tested for and those
who are HPV type negative, but positive for HPV using generic primers.
²HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
3HPV types 26, 53, 66, 68, 73, 82
4HPV types 6, 11, 30, 40, 42, 43, 54, 61, 67, 69, 70, 74, 81, 83, 86, 87, 89, 90, 91
5HPV types 6, 11, 16, 18
6Infection positive for two or more HPV types
1. Self-sampled urine proved suitable for large scale HPV testing
2. HPV 16 and 18 was very common among young girls
3. A wide variety of HPV types circulates in the population
4. HPV was detected in nearly half of the 21-year old women
5. HPV was detected in 15-20% of the 17-year old women
Birth cohort 19901
Invitation letter sent girls aged
21 in 2012 (n=9977 (100%))
Informed consent received at
NIPH (n=1952 (19.6%))
Urine samples received at the
Birth cohort 19942
Invitation letter sent girls aged
17 in 2011 (n=25 811 (100%))
Informed consent received at
NIPH (n=6778 (26.3%))
Urine samples received at the
NIPH (n=5528 21.4%))
PCR Luminex (n=5468 (21.2%))
Birth cohort 19963
Invitation letter sent girls aged
17 in 2013 (n=31 749 (100%))
Informed consent received at
NIPH (n=7485 23.6%))
Urine samples received at the
0 2 4 6 8 10 12