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n e w e ng l a n d j o u r na l
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special article
A bs t r ac t
Background
Results
On the assumption that the vaccine provided lifelong immunity, the cost-effectiveness ratio of vaccination of 12-year-old girls was $43,600 per quality-adjusted lifeyear (QALY) gained, as compared with the current screening practice. Under baseline
assumptions, the cost-effectiveness ratio for extending a temporary catch-up program for girls to 18 years of age was $97,300 per QALY; the cost of extending vaccination of girls and women to the age of 21 years was $120,400 per QALY, and the
cost for extension to the age of 26 years was $152,700 per QALY. The results were
sensitive to the duration of vaccine-induced immunity; if immunity waned after 10
years, the cost of vaccination of preadolescent girls exceeded $140,000 per QALY, and
catch-up strategies were less cost-effective than screening alone. The cost-effectiveness ratios for vaccination strategies were more favorable if the benefits of averting
other health conditions were included or if screening was delayed and performed at
less frequent intervals and with more sensitive tests; they were less favorable if vaccinated girls were preferentially screened more frequently in adulthood.
Conclusions
The cost-effectiveness of HPV vaccination will depend on the duration of vaccine immunity and will be optimized by achieving high coverage in preadolescent girls, targeting initial catch-up efforts to women up to 18 or 21 years of age, and revising
screening policies.
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Me thods
Analytic Overview
Synthesizing epidemiologic, clinical, and demographic data from the United States, we used empirically calibrated simulation models to estimate
the lifetime costs and benefits of vaccinating 12year-old girls (herein referred to as the vaccination
of preadolescent girls), as well as catch-up programs in girls and women up to 18, 21, or 26 years
of age, in the context of current cytology-based
screening in the United States. The base-case analysis was intended to be relevant to both the bivalent and quadrivalent HPV vaccines and therefore
focused on the outcomes of cervical cancer. To examine the additional benefits of the vaccine for
which empirical data were available, we also assessed the effect of the quadrivalent vaccine on
HPV-6associated and HPV-11associated genital
warts. Although the efficacy of the vaccine against
noncervical HPV-16associated and HPV-18associated cancers and HPV-6associated and HPV11associated juvenile-onset recurrent respiratory
papillomatosis is more uncertain, we assessed the
effect of their inclusion on our results. Although
we assumed lifelong complete protection against
the vaccine-targeted types of HPV in the base-case
analysis, we evaluated the effect of waning vaccineinduced immunity (without and with a booster).
Other uncertainties that we evaluated included
cross-protection of the vaccine against high-risk
types of HPV that did not include HPV-16 and
HPV-18, the increased incidence of high-risk types
of HPV that did not include HPV-16 and HPV-18,
disparities in vaccination and screening coverage,
and revisions in screening practices.
We adopted a societal perspective, discounted
costs and benefits by 3% annually, and expressed
benefits as quality-adjusted life-years (QALYs)
gained. After eliminating strategies that were more
costly and less effective or less costly and less costeffective than an alternative strategy, incremental cost-effectiveness ratios were calculated as the
We used a flexible modeling approach that included a dynamic model to simulate the sexual transmission of HPV-16 and HPV-18 infections between
men and women and an individual-based stochastic model to simulate the cervical carcinogenesis
associated with all types of HPV. Both models have
been described previously.24,25 Briefly, the dynamic
model is an open-cohort, age-structured compartmental model in which women and men form sexual partnerships over time. Women and men enter
the susceptible pool on sexual initiation starting
at 10 years of age, and with each partnership,
HPV-16 or HPV-18 may be transmitted, depending
on the number of new partners, the prevalence of
HPV among the opposite sex, and the probabilities of transmission of HPV-16 and HPV-18 from
an infected partner. After the first HPV infection
and clearance, partial type-specific natural immunity develops, effectively reducing a persons susceptibility to future infections of the same type.
Grade 1 cervical intraepithelial neoplasia (CIN 1)
or grade 2 or 3 CIN (CIN 2/3) can develop in women with HPV-16 or HPV-18 infection, and invasive
cancer may develop in women with CIN 2/3.
The individual-based stochastic model has a
similar structure. However, all types of HPV (categorized as HPV-16, HPV-18, other high-risk types
of HPV, and low-risk types of HPV) are included,
the incidence of HPV is a function of age and individual-level characteristics, it keeps track of each
persons history (e.g., vaccination, screening, treatment, and past abnormalities), and it can accommodate complex screening strategies.25,26 The dynamic model was used to estimate reductions in
the age-specific incidence of HPV-16 and HPV-18
with vaccination, reflecting the direct benefits to
persons who were vaccinated, as well as indirect
benefits, because of herd immunity, to those who
were not vaccinated. The generated reductions in
the incidence of HPV-16 and HPV-18 served as
inputs to the stochastic model, which was used to
compare multiple strategies for the prevention of
cervical cancer. The specific features of the individ-
823
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Values
Reference
Cervical cancer
Incidence (no./100,000 women)
4.262.8
16.592.0
Quality-of-life adjustment
0.480.76
70.0
26,54045,540
Vulvar cancer
Incidence (no./100,000 women)
0.224.9
77.8
Quality-of-life adjustment
0.68
32.0
20,430
Vaginal cancer
Incidence (no./100,000 women)
0.16.0
55.7
0.68
32.0
23,440
Gold et al.39
Parkin and Bray2
Hu and Goldie38
Anal cancer
Incidence (no./100,000 women)
0.05.6
66.2
0.68
82.8
31,300
Gold et al.39
Parkin and Bray2
Hu and Goldie38
Oral cancer
Incidence (no./100,000 women)
0.213.9
62.6
Quality-of-life adjustment
0.68
2.9
37,370
Oropharyngeal cancer
Incidence (no./100,000 women)
0.01.1
62.6
0.68
10.7
37,370
Table 1. (Continued.)
Variable
Values
Reference
Genital warts
Prevalence (no./1000 women)
0.076.20
Quality-of-life adjustment
0.91
Insinga et al.35
Insinga et al.,35 Myers et al.36
100
Lacey et al.10
430
Hu and Goldie38
4.30
Derkay37
Quality-of-life adjustment
0.69
Bishai et al.40
Lacey et al.10
100
Hu and Goldie38
62,010
* Ranges represent age-specific values, and rates are annual rates unless otherwise noted. HPV denotes human papillomavirus.
Incidence rates for cervical cancer were generated by the calibrated stochastic model in the absence of screening or vaccination (i.e., natural
history).
The 5-year survival for cervical cancer varied according to the stage (i.e., 92.0% for local, 55.7% for regional, and 16.5% for distant disease).
The quality-of-life adjustment assumed a health-state utility weight of 0 (death) to 1 (perfect health). The health-state utility weight for cervical cancer varied according to the stage: 0.76 for local cancer, 0.67 for regional cancer for a period of 5 years, and 0.48 for distant cancer
over the lifetime with disease. For noncervical cancers, we assumed an average health-state utility weight of 0.68 over the lifetime with disease in order to reflect a weighted average of stage-specific utility weights and distribution of disease according to stage. For genital warts,
we assumed a health-state utility weight of 0.91 over 3 months. All disease-specific utility weights were multiplied to baseline age-specific
utility weights in order to estimate the overall utility weight (data are from Fryback et al.41).
The cost per case is expressed in 2006 U.S. dollars and represents the average discounted lifetime costs of a new case of disease, including
direct medical costs (i.e., the cost of procedures, hospitalizations, and office visits). The costs of treatment of cervical cancer varied according to stage (e.g., $26,540 for local, $28,430 for regional, and $45,540 for distant disease) and included direct nonmedical costs such as the
patients time and transportation.
births per woman,53 annual incidence rates of juvenile-onset recurrent respiratory papillomatosis
per live child,37 costs per case, and effects on
quality of life.38,40 For both vaccines, we modeled
age-specific incidence rates of HPV-16associated and HPV-18associated noncervical cancer
among women,32 taking into account cancer-specific mortality and health-state utility weights (i.e.,
values from 0 to 1 indicating the quality of a persons state of health, with 0 indicating death and
1 indicating perfect health),32,39 to estimate quality-adjusted life expectancy gained and costs averted (Table 1). Vaccination was assumed to reduce
the proportion of cases attributable to vaccinetargeted types of HPV, and we varied the efficacy
on these conditions from 50% to 100% (see the
Supplementary Appendix for additional details on
noncervical conditions).
R e sult s
Cost-Effectiveness of Vaccination
825
The
Program
n e w e ng l a n d j o u r na l
Age (yr)
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Year 7
Year 8
Year 9
Year 10
76%
of
m e dic i n e
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Strategy
Base Case
Screening only
43,600
34,900
97,300
81,000
120,400
101,300
152,700
133,600
* The values represent incremental cost-effectiveness ratios (i.e., the additional cost divided by the additional health benefit compared with the next-less-costly strategy) expressed as cost per quality-adjusted life-year ($/QALY). All costs are
expressed in 2006 U.S. dollars. HPV denotes human papillomavirus.
All strategies included current cytologic screening (see the Methods section).
The base-case analysis reflected the outcomes related to cervical cancer only.
The analysis included outcomes related to cervical cancer and HPV-6associated and HPV-11associated genital warts
in girls and women.
Since screening only is the baseline strategy, it is not associated with an incremental cost-effectiveness ratio.
QALY) if high coverage can be achieved in the primary target group of 12-year-old girls and if vaccine-induced immunity is lifelong. Under these
conditions, if we are willing to pay $100,000 per
QALY, a catch-up program for girls between 13
and 18 years of age appears to be reasonable, especially when we include the benefits of averting
genital warts (with the use of the quadrivalent vaccine) or the benefits of cross-protection against
other high-risk types of HPV not including HPV16 and HPV-18 (as reported with the bivalent vaccine). Extending the catch-up program to 21 years
of age is less cost-effective, but it also becomes
more favorable when the potential benefits of preventing noncervical HPV-16associated and HPV18associated cancers in women are included.
Extending vaccine coverage to women up to 26
years of age generally exceeds $130,000 per QALY.
This result is not unexpected, since nearly 90% of
women in the United States have had vaginal intercourse by 24 years of age47 and up to 30% of
women may be exposed to HPV in the first year
of intercourse.54 The cost of extending a catch-up
program to women up to 26 years of age is less
than $100,000 per QALY only in the context of
100% lifelong efficacy against other outcomes associated with HPV-16, HPV-18, HPV-6, and HPV-11
in women; these outcomes include cervical cancer,
warts, other cancers, and juvenile-onset recurrent
Discussion
respiratory papillomatosis. The cost of extending
Vaccination against HPV-16 and HPV-18 is expected this program is more than $200,000 per QALY
to be economically attractive (i.e., <$50,000 per when a booster is required to maintain lifelong
827
The
160,000
140,000
120,000
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100,000
80,000
60,000
40,000
20,000
12
1218
1221
1226
Figure 2. Effect of Inclusion of Other Health Conditions on the Cost-Effectiveness of Vaccination Strategies.
1st
RETAKE
AUTHOR:
Kim of the vaccine against
The solid lines represent analyses ICM
in which
the efficacy
human
papillomavirus (HPV) was as2nd
FIGURE:
2
of
2
REG
F
sumed to be 100% among girls and
women
without a previous history of type-specific
infection (for all conditions).
3rd
The dashed lines represent analyses
in which the efficacy of the vaccine was
assumed to be 50% (only for cancers
CASE
Revised
Line
4-C
other than cervical cancer and juvenile-onset
recurrent respiratory
papillomatosis
EMail
SIZE [JORRP]; the efficacy remained
ARTIST: ts
H/T
H/T
100% for cervical cancer and genital
warts)
among
girls
and
women
without a22p3
previous history of type-specific inEnon
Combo
fection. In all analyses, the efficacy of the vaccine was assumed to be 0% among persons with a previous type-speAUTHOR,
PLEASE
NOTE:
cific infection or infections. Including the potential
benefits
of the
vaccine against noncervical HPV-16related and
Figure has been redrawn and type has been reset.
HPV-18related cancers, HPV-6related and HPV-11related
JORRP, or both reduced the cost-effectiveness ratios,
Please check carefully.
but the magnitude of the reduction depended on the specific outcomes included and the assumptions about efficacy. For instance, including otherJOB:
cancers
ratios08-21-08
from 18% to 30% depending on the
35908reduced the cost-effectivenessISSUE:
efficacy of the vaccine, whereas including JORRP had less of an effect. Under all assumptions, the cost of vaccination of preadolescent girls (i.e., 12-year-old girls) remained below $50,000 per quality-adjusted life-year (QALY), and
the cost of catch-up vaccination of girls to 18 years of age was between $50,000 and $100,000 per QALY. The cost of
catch-up vaccination of girls and women to 21 years of age decreased below $100,000 per QALY when other cancers
or all outcomes were included, and the cost of catch-up vaccination to 26 years of age exceeded $100,000 per QALY,
unless all outcomes were included with a vaccine efficacy of 100% for all conditions.
828
ceeded $140,000 per QALY, and all catch-up strategies were less cost-effective than screening alone.
Although immunologic data have provided support
for a strong initial immune response with antibody levels persisting at a level higher than the
level after natural infection,9,55,56 observations in
published reports are limited to 5 years after vaccination. With partial natural immunity to typespecific infection, if a vaccinated girl loses vaccineinduced protection and becomes susceptible at a
Strategy
Base Case
Waning Immunity
at 10 Yr
Booster
at 10 Yr
$/QALY
Screening only**
43,600
144,100
83,300
33,700
97,300
Not cost-effective
140,700
79,300
120,400
Not cost-effective
185,400
102,200
152,700
Not cost-effective
233,500
129,500
* The values represent incremental cost-effectiveness ratios (i.e., the additional cost divided by the additional health
benefit compared with the next-less-costly strategy) expressed as cost per quality-adjusted life-year ($/QALY). A strategy that is not cost-effective is more costly and less effective than another strategy. All costs are expressed in 2006
U.S. dollars. HPV denotes human papillomavirus.
All strategies included current cytologic screening (see the Methods section).
The base-case analysis reflected the outcomes related to cervical cancer only.
The analysis assumed full vaccine-induced protection up to 10 years, after which protection waned completely.
The analysis assumed a vaccine booster was administered to all previously vaccinated persons 10 years after initial
vaccination and provided lifelong protection. The booster was assumed to cost $250 per vaccinated person (including
the cost of the vaccine dose, supplies, wastage, administration, and patients time and transportation, as well as an
additional cost for the booster campaign and outreach efforts).
The efficacy of the vaccine against other high-risk types of HPV (i.e., other than HPV-16 and HPV-18) was assumed to
be 27.1%; data are from Paavonen et al.8
** Since screening only is the baseline strategy, it is not associated with an incremental cost-effectiveness ratio.
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Table 4. Effect of Disparities in Vaccination and Screening Coverage and Revised Cervical-Cancer Screening Policies on Cost-Effectiveness.*
Strategy
Base Case
Vaccine Coverage
Screening Policy
Only Women
Who Will Be
Screened
Only Women
Who Will Be
Screened
Frequently
Cytologic
Screening
(1 yr)
Cytologic
Screening
(2 yr)
Revised
Screening
(3 yr)
$/QALY
Screening only**
43,600
47,900
106,000
118,200
45,800
40,900
97,300
121,900
136,300
186,700
102,400
103,500
120,400
153,300
172,400
250,600
120,600
128,700
152,700
204,700
231,000
324,200
189,700
185,400
* The values represent incremental cost-effectiveness ratios (i.e., the additional cost divided by the additional health benefit compared with
the next-less-costly strategy), expressed as the cost per quality-adjusted life-year ($/QALY). All analyses reflect outcomes related to cervical
cancer only. All costs are expressed in 2006 U.S. dollars. HPV denotes human papillomavirus.
The base-case analysis included current cytologic screening (see the Methods section).
The analysis assumed that women who were never screened were also not vaccinated.
The analysis assumed that women who were screened less frequently (i.e., every 5 years or never) were also not vaccinated.
The analysis assumed the base-case screening test and age for initiation of screening, but the screening interval was changed to every
1 or 2 years, which is consistent with current screening guidelines.
The analysis assumed cytologic screening with HPV DNA testing as triage for equivocal results starting at 25 years of age, with a switch to
combined cytologic and HPV DNA testing starting at 35 years of age.
** Since screening only is the baseline strategy, it is not associated with an incremental cost-effectiveness ratio.
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