Adding a quadrivalent human papillomavirus vaccine to the UK cervical cancer screening programme: A cost-effectiveness analysis.

Abstract

We assessed the cost-effectiveness of adding a quadrivalent (6/11/16/18) human papillomavirus (HPV) vaccine to the current screening programme in the UK compared to screening alone.
A Markov model of the natural history of HPV infection incorporating screening and vaccination was developed. A vaccine that prevents 98% of HPV 6, 11, 16 and 18-associated disease, with a lifetime duration and 85% coverage, in conjunction with current screening was considered.
Vaccination with screening, compared to screening alone, was associated with an incremental cost-effectiveness ratio of pound21,059 per quality adjusted life year (QALY) and pound34,687 per life year saved (LYS). More than 400 cases of cervical cancer, 6700 cases of cervical intraepithelial neoplasia and 4750 cases of genital warts could be avoided per 100,000 vaccinated girls. Results were sensitive to assumptions about the need for a booster, the duration of vaccine efficacy and discount rate.
These analyses suggest that adding a quadrivalent HPV vaccine to current screening in the UK could be a cost-effective method for further reducing the burden of cervical cancer.

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BioMed Central
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Cost Effectiveness and Resource
Open Access
Research
Adding a quadrivalent human papillomavirus vaccine to the UK
cervical cancer screening programme: A cost-effectiveness analysis
Shalini L Kulasingam*1, Steve Benard2, Ruanne V Barnabas3,4,
Nathalie Largeron2 and Evan R Myers1
Address: 1Dept. of Obstetrics and Gynecology, Duke University, Durham, NC 27705, USA, 2sanofi pasteur MSD, Lyon, 69007, France, 3Cancer
Epidemiology Unit, University of Oxford, Oxford, OX3 7LF, UK and 4HIV Vaccines Trials Network, Fred Hutchinson Research Center, Seattle, WA,
USA
Email: Shalini L Kulasingam* - kulas002@mc.duke.edu; Steve Benard - sbenard@steve-consultants.com;
Ruanne V Barnabas - rbarnaba@fhcrc.org; Nathalie Largeron - NLargeron@spmsd.com; Evan R Myers - Myers008@mc.duke.edu
* Corresponding author
Abstract
Background: We assessed the cost-effectiveness of adding a quadrivalent (6/11/16/18) human
papillomavirus (HPV) vaccine to the current screening programme in the UK compared to
screening alone.
Methods: A Markov model of the natural history of HPV infection incorporating screening and
vaccination was developed. A vaccine that prevents 98% of HPV 6, 11, 16 and 18-associated disease,
with a lifetime duration and 85% coverage, in conjunction with current screening was considered.
Results: Vaccination with screening, compared to screening alone, was associated with an
incremental cost-effectiveness ratio of £21,059 per quality adjusted life year (QALY) and £34,687
per life year saved (LYS). More than 400 cases of cervical cancer, 6700 cases of cervical
intraepithelial neoplasia and 4750 cases of genital warts could be avoided per 100,000 vaccinated
girls. Results were sensitive to assumptions about the need for a booster, the duration of vaccine
efficacy and discount rate.
Conclusion: These analyses suggest that adding a quadrivalent HPV vaccine to current screening
in the UK could be a cost-effective method for further reducing the burden of cervical cancer.
Background
Despite a well-organised screening programme in the UK,
and a marked decrease in cervical cancer incidence since
1988, there were 3,181 new cervical cancer cases and
1,529 deaths reported in 2002. In 2003, the National
Health Service Cervical Screening Programme modified
its recommendations by increasing the age to begin
screening from 20 years to 25 years combined with a more
frequent screening interval (every 3 years in women aged
25 to 49 years and 5 years for women between 50 and 64).
Invasive carcinoma of the cervix is preceded by premalig-
nant lesions. These precancerous lesions are defined as
cervical intraepithelial neoplasia (CIN), and classified as
low grade (CIN 1) or high grade (CIN 2 or CIN 3) accord-
ing to severity. Prevention of cervical cancer has been
based on early detection of these precancerous lesions
Published: 15 February 2008
Cost Effectiveness and Resource Allocation 2008, 6:4doi:10.1186/1478-7547-6-4
Received: 10 July 2007
Accepted: 15 February 2008
This article is available from: http://www.resource-allocation.com/content/6/1/4
© 2008 Kulasingam et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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using conventional Pap smear tests or, more recently, liq-
uid-based cytology (LBC) tests. However, with the knowl-
edge that infection with
papillomavirus (HPV) is necessary for the development of
cervical cancer [1], alternative methods, beside the Pap
smear are being researched to improve cervical cancer pre-
vention. In 2006, the first prophylactic quadrivalent HPV
recombinant vaccine (HPV types 6,11,16,18) (Gardasil®,
Merck, Sharpe and Dohme (MSD), Whitehouse Station,
New Jersey, USA) has been granted a marketing authorisa-
tion in the European Union [2]. This vaccine is indicated
for the prevention of high grade cervical dysplasia (CIN 2/
3), cervical carcinoma, high grade vulvar dysplastic
lesions (VIN 2/3) and external genital warts causally
related to HPV types 6, 11, 16 and 18. More recently, the
European Commission has granted a marketing authori-
sation for a second cervical cancer vaccine (Cervarix, Glax-
oSmithKline Biologicals s.a., Rixensart, Belgium) that is
indicated for the prevention of precancerous cervical
lesions (high-grade cervical intraepithelial neoplasia
[CIN] grades 2 and 3) and cervical cancer causally related
to human papillomavirus (HPV) types 16 and 18 [3].
Although the UK Health Minister has recommended the
use of the HPV vaccine for girls aged 12–13 and catch-up
for girls aged up to 19 years, a decision has not yet been
made regarding which vaccine to use in the National
Immunization program [4].
oncogenic human
The quadrivalent vaccine showed >90% efficacy in pre-
venting pre-cancerous high grade lesions due to these two
HPV types [5,6]. This vaccine presents an opportunity to
further reduce cancer incidence and mortality.
Genital warts are the most common sexually transmitted
infection in the UK. In 2004, 79,678 first attack cases of
genital warts were reported in Genitourinary Medicine
(GUM) clinics [7]. Of these, 47% were diagnosed in
women and 53% in men. Current methods for treating
warts include therapies such as cryotherapy, electrocau-
tery, podophyllotoxin and imiquimod. However, up to
40% of patients experience a recurrence of genital warts
post-treatment [8]. The psychological impact of warts can
be high; both men and women report feelings of embar-
rassment and depression [9]. Over 90% of genital warts
are attributable to infection with HPV types 6 and 11 [10].
Results from a Phase III trial of a quadrivalent vaccine that
includes HPV types 6 and 11, in addition to the oncogenic
HPV types 16 and 18, showed that vaccination prevented
>90% of warts [11].
We examined the potential effectiveness and cost-effec-
tiveness of a quadrivalent vaccine targeted at HPV types 6,
11, 16 and 18, administered to a cohort of girls aged 12
through a school-based vaccination programme in con-
junction with the current screening programme in the UK
over a lifetime period.
Methods
We adapted a previously published and validated state-
transition Markov model of HPV infection and cervical
cancer [12,13] to estimate total lifetime costs, life expect-
ancy and incremental cost-effectiveness ratios (ICERs)
associated with different screening strategies either alone
or in combination with vaccination to prevent HPV types
6, 11, 16 and 18 in the UK. Estimates and ranges used in
the model for the natural history are presented in Table 1.
Briefly, the model simulates a cohort of women at age 12
and follows them until age 85 years. Movement through
the health states of the model (i.e. HPV infection, CIN 1,
CIN 2, CIN 3, Cancer [Stages I–IV]) over time is based on
yearly transition probabilities derived from the literature.
Women who are infected with HPV can have their infec-
tion clear, progress, or persist. For those women whose
infections persist, the majority is assumed to develop CIN
1 but a minority is assumed to develop CIN 2 directly;
these rates are age-dependant. Women who develop CIN
1, CIN 2, or CIN 3 can have their disease progress, regress,
or persist. Women with cancer (stages I, II, III, IV) can
have their cancer detected during screening or if they
present to a health care provider based on symptoms.
Women who do not have their disease detected can
progress to the next stage, remain in the same stage, or die
of cervical cancer. Each year, women also face an age-spe-
cific risk of dying from other causes.
The model was calibrated to produce prevalence curves
for HPV infection [14,15], cervical cancer lifetime risks
and cervical cancer incidence in the UK [16]. The model
was revised to separate high-grade CIN into CIN 2 and
CIN 3 using data from Canfell et al. [17]. Non-cervical
cancer deaths were estimated using data from UK statistics
[18]. Benign hysterectomy rates were estimated using age-
specific estimates from Redburn et al. [19]. Cancer pro-
gression rates between FIGO (International Federation of
Gynecology and Obstetrics) stages (FIGO I through IV)
were based on the original model [12]. Cancer stage-spe-
cific symptoms were based on calibrating the model to
produce a stage-specific distribution of cancer, in the
absence of screening consistent with Bjorge et al. [20].
Five-year stage-specific survival was based on data from
the West Midlands [21]. Finally, we assumed that only
women who were normal (i.e. did not have CIN or cervi-
cal cancer) were at risk for developing warts due to a lack
of published data on women who have CIN or cancer and
warts. We used data from the Health Protection Agency
[7] to determine the "incidence" of symptomatic warts,
since these data are based on women presenting to clinics
with symptoms. We conservatively assumed that all

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Table 1: Annual transition probabilities for the natural history model
ParametersAgeTransition
probability
Time
period
References
Normal
Uninfected to Cervical HPV infection (HPV
incidence)
10–120.000012 monthsCalibrated from Canfell et al17
13
14
15
16
17
18
19
0.0100
0.0300
0.0400
0.0460
0.0700
0.0700
0.1700
0.2000
0.1200
0.1100
0.0850
0.0320
0.0170
0.0095
12 months
12 months
12 months
12 months
12 months
12 months
12 months
12 months
12 months
12 months
12 months
12 months
12 months
12 months
20–21
22
23
24–29
30–33
34–49
50+
HPV infected state
Progression from HPV infection to SIL – all risk HPV
Percentage CIN 2 among SIL
Regression of CIN 1 to normal from HPV infection
0.0959
0.1350
0.7000
0.5000
0.4000
0.2700
0.1000
12 months
12 months
18 months
18 months
18 months
18 months
18 months
Canfell et al17
Calibrated based on Myers et al12 and Canfell et al17
Calibrated based on Myers et al12 and Canfell et al17
12–24
25–29
30–39
40–49
50+
CIN 1
Progression from CIN 1 to CIN 2 – all risk HPV
Canfell et al17
16–34
35+
0.0297
0.1485
0.0301
0.2248
0.1124
0.9000
12 months
12 months
12 months
12 months
12 months
12 months
Progression from CIN 1 to CIN 3 – all risk HPV
Regression to HPV infected state – all risk HPV16–34
35+
Proportion regressing to normal
CIN 2
Progression from CIN 2 to CIN 3
Canfell et al17
16–34
35–44
45+
0.0389
0.0797
0.1062
0.2430
0.1901
12 months
12 months
12 months
12 months
12 months
Regression from CIN 2 to CIN 1
Regression from CIN 2 to uninfected or HPV
infections
Proportion regressing directly to normal 0.900012 months
CIN 3
Regression CIN 3 to CIN 1 – all risk HPV
Regression from CIN 3 to CIN 2 – all risk HPV
CIN 3 to uninfected or HPV infection
Canfell et al17
0.0000
0.0135
0.0135
0.0100
0.5000
0.0127
12 months
12 months
12 months
12 months
12 months
12 months
16–44
45+
Proportion CIN 3 regressing directly to uninfected
Proportion CIN 3 progressing to FIGO I cancer
Cervical cancer
FIGO 1
Progression rates
Probability of symptoms
FIGO 2
Progression rates
Probability of symptoms
Myers et al12
0.9000
0.1850
48 months
12 months
0.9000
0.3000
36 months
12 months

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women with symptomatic warts would receive treatment
and that treatment was 100% effective.
For the base case, women aged 25 to 49 years were
assumed to be screened every 3 years; women aged 50 to
64 years were screened every 5 years consistent with cur-
rent National Guidelines [22]. Differences in screening
coverage by age were modelled using estimates from the
Government Statistical Service (2003). Estimates for the
sensitivity and specificity of conventional cytology and
liquid cytology tests were based on published data [23,24]
and UK specific data [25], with separate estimates of sen-
sitivity used for CIN 1/CIN 2 and CIN 3. Fifty percent of
women were assumed to be screened with LBC and the
rest were assumed to be screened with conventional Pap
smears for the base case. Ten percent of women were esti-
mated to have inadequate Pap smear screening results and
were assumed to undergo repeat screening [26]. Women
with normal Pap smear results were assumed to return to
regular screening. Women with Atypical Squamous Cells
with Unknown Significance (ASCUS) or Low grade Squa-
mous Intraepithelial Lesion (LSIL) Pap smear results were
assumed to undergo repeat screening, with women
referred to colposcopy based on two repeat borderline
results. Women with ≥ High grade Squamous Intraepithe-
lial Lesion (HSIL) were assumed to be referred directly to
colposcopy. Colposcopy and biopsy were assumed to
have 90% sensitivity for detection of CIN [27]. Treatment
of CIN was assumed to be 100% effective. Twenty percent
of women with CIN 1 were assumed to be treated: this
proportion is consistent with the recommendation that
confirmed CIN 1 lesions are monitored via colposcopy
rather than treated [17]. The proportion of women treated
for CIN 2 and 3 was assumed to be 90% [17]. Screening
and treatment parameters are presented in Table 2.
Vaccination to prevent infection with HPV types 6, 11, 16
and 18 was assumed to be 98% effective, using the recent
results from the FUTURE II trial to determine efficacy of
the vaccine in preventing CIN 2–3 [6]. We conservatively
assumed the same efficacy for genital warts [5], but varied
this assumption widely in sensitivity analyses. The vaccine
was assumed to be administered to girls aged 12 years
through a school-based programme. To date, there is evi-
dence of a 5-year duration of vaccine efficacy [28]. We
assumed a lifetime duration of efficacy for the base case
consistent with a recently published analysis of the impact
of an HPV 16–18 vaccine on cervical cancer in the UK [29]
FIGO 3
Progression rates
Probability of symptoms
FIGO 4
Probability of symptoms
0.9000
0.7500
15 months
12 months
0.800012 months
Annual probability of survival after diagnosis, FIGO 1
1 Year survival
2 Year survival
3 Year survival
4 Year survival
5 Year survival
Cancer Research UK 21
0.977
0.978
0.963
0.988
0.988
12 months
12 months
12 months
12 months
12 months
Annual probability of survival after diagnosis, FIGO 2
1 Year survival
2 Year survival
3 Year survival
4 Year survival
5 Year survival
0.830
0.835
0.755
0.870
0.899
12 months
12 months
12 months
12 months
12 months
Annual probability of survival after diagnosis, FIGO 3
1 Year survival
2 Year survival
3 Year survival
4 Year survival
5 Year survival
0.590
0.693
0.778
0.928
0.963
12 months
12 months
12 months
12 months
12 months
Annual probability of survival after diagnosis, FIGO 4
1 Year survival
2 Year survival
3 Year survival
4 Year survival
5 Year survival
0.523
0.782
0.721
0.925
0.956
12 months
12 months
12 months
12 months
12 months
Table 1: Annual transition probabilities for the natural history model (Continued)

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as well as other analyses [30] but varied this assumption
widely in sensitivity analyses. Use of a booster, assumed
to be administered 10 years after the initial vaccine (i.e., at
age 22), to achieve a lifetime duration of efficacy was
examined in a sensitivity analysis [31]. Vaccine coverage
was 85% for the base case based on coverage rates
reported for the hepatitis B vaccine in the UK through a
school programme [32]. Since women can be infected
with multiple HPV types, and these other types can poten-
tially cause replacement CIN and cancer, we examined
this possibility in sensitivity analyses, assuming that 10
percent of women were coinfected with other high-risk
HPV types [33].
We modelled a reduction of approximately 35% for CIN
1, 55% for CIN 2 and 3 and 70% for cervical cancer (all
stages). This reflects the percentage of cervical cancer and
CIN 1–3 attributable to HPV types 6, 11, 16 and 18
[34,35]. Moreover, we assumed that 90% of warts were
attributable to infection with HPV types 6 and 11 [10]. We
Table 2: Screening, vaccine and cost parameters
ParametersBase caseRanges References
Screening characteristics
Screening interval3 years in ages 25–49 years and 5 years
in ages 50–64 years
NHS cervical screening programme 22
Coverage rates of target groups by
age (2003)
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
Inadequate pap smear results
Pap Sensitivity for CIN 1/2 Pap
sensitivity for CIN 1/2 (LBC)
Pap Sensitivity for CIN 3 Pap
Sensitivity for CIN 3 (LBC)
Pap Specificity for no CIN Pap
Specificity for no CIN (LBC)
Colposcopy/Biopsy Sensitivity
Colposcopy/Biopsy Specificity
Vaccine characteristics
Vaccine efficacy for all 6, 11, 16, 18
HPV types
Duration of efficacy
Vaccine coverage
Booster coverage
Costs
Pap smear
74.0%
81.0%
83.7%
84.0%
83.8%
83.2%
81.4%
77.3%
10%
61%
NHS cervical screening programme 22
5% – 20%
51% – 80%Nanda et al23and Karnon et al25
65%65% – 90% Nanda et al23 and Karnon et al25
95.7%90% – 99% Nanda et al25 and Kulasingam et al24
90%
100%
88% – 100%
65% – 100%
Mitchell et al27
Kulasingam et al24 and Karnon et al25
98%85% – 100%Villa et al5 and Future II 6
Lifetime
85%
From 10 years to lifetime
50%–90%
50%
Olsson et al 28 and Villa et al42
Trotter et al31 and Bramley et al32
Trotter et al31
£23.7£18 – £30Brown et al 26
Curtis et al38
Colposcopy (with or without biopsy)
Knife cone biopsy of cervix uteri
CIN 1, CIN 2, CIN 3
FIGO I
£141.69
£290.64
£313.14
£12,142
£113 – £170
£232 – £349
£250 – £376
£9,714 – £14,570Curtis et al38 and Wolstenholme et
al37
FIGO II
FIGO III
FIGO IV
Genital warts
Vaccine cost/dose
Administration cost/dose
Booster cost/dose
Administration cost for booster
Discount rates
Costs
Benefits
£22,061
£21,785
£23,402
£215.73
£75
£ 3.4
£17,649 – £26,473
£17,428 – £26,142
£18,722 – £28,082
£172 – £259
£70 – £80
£0 – £12
£75
£10
Brown et al26 and Curtis et al38
Trotter et al31
Curtis et al38
3.5%
3.5%
0 – 5%
0 – 5%