Cost-Effectiveness of Primary HPV Testing, Cytology and Co-testing as Cervical Cancer Screening for Women Above Age 30 Years
J Gen Intern Med
Cost-Effectiveness of Primary HPV Testing, Cytology and Co-testing as Cervical Cancer Screening for Women Above Age 30 Years
Xian Wen Jin 2
Laura Lipold 1
Andrea Sikon 2
Jennifer Brainard 6
Jerome Belinson 5
Kelly Nottingham 3 4
Bo Hu 7
Michael B. Rothberg 2 4
0 Cleveland Clinic Lerner College of Medicine, Cleveland Clinic , Cleveland, OH , USA
1 Department of Family Medicine, Cleveland Clinic , Cleveland, OH , USA
2 Department of Internal Medicine, Cleveland Clinic , Cleveland, OH , USA
3 Heritage College of Osteopathic Medicine, Ohio University , Athens, OH , USA
4 Medicine Institute Center for Value Based Care Research, Cleveland Clinic , Cleveland, OH , USA
5 Department of Obstetrics and Gynecology, Cleveland Clinic , Cleveland, OH , USA
6 Department of Pathology, Cleveland Clinic , Cleveland, OH , USA
7 Department of Quantitative Health Science, Cleveland Clinic , Cleveland, OH , USA
BACKGROUND: Cervical cancer screening guidelines for women aged ≥30 years allow for co-testing or primary cytology testing. Our objective was to determine the test characteristics and costs associated with Cytology, HPV and Co-testing screening strategies. MAIN METHODS: Retrospective cohort study of women undergoing cervical cancer screening with both cytology and HPV (Hybrid Capture 2) testing from 2004 to 2010 in an integrated health system. The electronic health record was used to identify women aged ≥30 years who had cotesting. Unsatisfactory or unavailable test results and incorrectly ordered tests were excluded. The main outcome was biopsy-proven cervical intraepithelial neoplasia grade 3 or higher (CIN3+). KEY RESULTS: The final cohort consisted of 99,549 women. Subjects were mostly white (78.4 %), married (70.7 %), never smokers (61.3 %) and with private insurance (86.1 %). Overall, 5121 (5.1 %) tested positive for HPV and 6115 (6.1 %) had cytology ≥ ASCUS; 1681 had both and underwent colposcopy and 310 (0.3 %) had CIN3+. Sensitivity for CIN3+ was 91.9 % for Primary Cytology, 99.4 % for Co-testing, and 94.8 % for Primary HPV; specificity was 97.3 % for Co-testing and Primary Cytology and 97.9 % for Primary HPV. Over a 3-year screening interval, Primary HPV detected more cases of CIN3+ and was less expensive than Primary Cytology. Co-testing detected 14 more cases of CIN3+ than Primary HPV, but required an additional 100,277 cytology tests and 566 colposcopies at an added cost of $2.38 million, or $170,096 per additional case detected. CONCLUSIONS: Primary HPV was more effective and less expensive than Primary Cytology. Primary HPV screening appears to represent a cost-effective alternative to Co-testing.
Cervical cancer is the fourth leading cause of cancer death in
women worldwide, with an estimated 275,000 deaths each
year.1,2 Incidence of cervical cancer in the US has decreased
>50 % because of the success of the Papanicolaou (Pap) test
(cytology screening). As a result, cervical cancer mortality has
also declined by half.3 The American Cancer Society
estimates 4100 cervical cancer deaths in the US in 2015, most
due to lack of screening or follow-up from abnormal testing.4
Elucidation of the role of high-risk human papillomavirus
(HPV) in cervical cancer pathogenesis has led to incorporation
of HPV testing into primary screening strategies for women
age 30 and older.5 When cytology and HPV tests are used
together (co-testing), sensitivity approaches 100 %,6 and the
5year risk of cervical intraepithelial neoplasia grade 3 or higher
(CIN3+) after a negative co-test is far below that with negative
cytology alone, supporting longer testing intervals.7,8 For this
age group, multiple organizations now recommend co-testing
every 5 years as an alternative to cytology.5,9–11 The American
Cancer Society, The American Society of Colposcopy and
Cervical Pathology (ASCCP) and the American Society of
Clinical Pathology recommend co-testing as a Bpreferred^
screening strategy,5 although the appropriateness of this
recommendation has been questioned.12 The US Preventive
Service Task Force (USPSTF) recommends cytology or
cotesting as acceptable screening. Co-testing is more expensive,
but estimates of cost-effectiveness are lacking in the US.13
Several studies support the use of primary HPV testing
(HPV followed by cytology for positive HPV results) due to
its high sensitivity and negative predictive value.6,14–22 One
systematic review suggests that co-testing has only marginal
benefit over primary HPV testing, with significantly increased
cost.23 In 2014, the Food and Drug Administration (FDA)
approved the cobas® HPV Test (Roche Molecular Systems)
for primary screening in women age 25 and older, and an
interim guidance panel of the ASCCP and the Society of
Gynecologic Oncology (SGO) stated that high-risk HPV
testing could be considered an alternative to
Despite FDA approval, a number of concerns remain. Some
worry that primary HPV testing may not be sufficiently
sensitive and cases will be missed, especially because it has not been
studied in routine practice.25 Many institutions do not use the
cobas® Test and may be reluctant to change based on a single
trial. Finally, the cost-effectiveness of primary HPV screening is
unknown. To investigate the utility of primary HPV screening
strategies in clinical practice, we compared the expected
outcomes and cost of a Primary HPV strategy using the most
widely used HPV test (Hybrid Capture 2) to those of Co-testing
and Primary Cytology in an integrated health system.
We conducted a retrospective cohort study of women
≥30 years of age who had co-testing with HPV DNA and
cytology for primary cervical cancer screening in an integrated
health system from 2004 to 2010. This study was approved by
the Cleveland Clinic Institutional Review Board. Patients who
had diagnostic tests incorrectly ordered as screening or whose
HPV or cytology results were unsatisfactory or unavailable
were excluded. The electronic health record (Epic® EHR) was
queried to identify eligible patients and extract demographics.
The primary outcome of histologically confirmed CIN3+ was
chosen because it is reliably diagnosed,26–28 has a low
likelihood of regression29,30 and is a surrogate for cancer.7 A
supplemental analysis was performed using the outcome of
CIN2+.6 CIN3+ was identified from the pathology reporting
system (CoPath). HPV and cytology results were obtained
through chart review. For women with CIN3+ lesions, the
results of the co-test immediately preceding cervical biopsy
were recorded. For women without histologically confirmed
CIN3+ lesions, we recorded the results of the most recent
cotest. To accurately determine prevalence, positive and negative
predictive values, patients with abnormal screening tests who
did not undergo colposcopy were identified and their
outcomes assigned using multiple imputation.
Cytology specimens were analyzed by the ThinPrep
Imaging System™ (Hologic). Results were reported according to
the 2001 Bethesda System.31 HPV status was determined
utilizing Hybrid Capture 2 (Qiagen) as either positive or
negative for HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51,
52, 56, 58, 59 and 68.32 HPV-16/HPV-18 genotypes were not
distinguished from other genotypes.
Using HPV and cytology results, we modeled three primary
screening strategies (Fig. 1) from the payer perspective. The first
two, Primary Cytology and Co-testing, reflect current
recommendations for women age 30 and older.5,9,10,13 In the third strategy,
Primary HPV, positive HPV results are followed by cytology,
while negative HPV results prompt no testing for 5 years.
In the model, only patients with positive HPV and cytology
≥ atypical squamous cells of undetermined significance
(ASCUS) are referred to colposcopy. Patients with positive
HPV and normal cytology receive repeat co-testing in 1 year.
Patients remaining HPV positive or ≥ ASCUS at 1 year are
referred to colposcopy. Referred patients who do not undergo
colposcopy do not incur colposcopy costs and cannot have
CIN3+ detected, even if present. Sensitivity, specificity and
predictive values of the strategies were based on observed
results, without imputation. To determine the costs associated
with detection of a case of CIN3+ we performed a simulation
based on the results of the recorded HPV test, cytology test and
the known CIN3+ outcome. We assumed that all patients with a
follow-up test would have CIN3+ detected if present. For
patients who were HPV negative in the primary HPV strategy,
or HPV negative and cytology negative in the co-test strategy,
we assumed no further testing, and CIN3+ would not be
detected, even if present. In reality, two of these women had
additional testing (e.g., repeat cytology or HPV test in <3 years)
and were found to have CIN3+, so no strategy detected all
cases. To determine costs, we summed the number of HPV
tests, cytology tests and colposcopies for each strategy over a
3year interval and assigned costs using current Medicare
National Facility Prices (eTable 1).33 For Co-testing and Primary HPV,
we multiplied the cost of the 5-year interval by 3/5. Office visit
costs were not included because we assumed that testing would
be conducted during an annual examination. For the Primary
Cytology and Primary HPV strategies, we assumed that both
HPV and cytology specimens would be collected but the
secondary specimen would be processed only in the case of a
positive primary result. Costs to store unprocessed cytology
specimens could not be ascertained and were not included.
The collection kit represents approximately 10 % of the cost
of the test. In a sensitivity analysis, we varied the storage cost
from 10 to 30 % of the cost of cytology. We estimated
Single/Widowed and age <50
Married/domestic partner/widowed and age ≥50
colposcopy costs based on a weighted average of Medicare
prices for colposcopy procedure codes in our study population.
This analysis was limited to one round of screening and did not
include the cost of surveillance following colposcopy.
Baseline characteristics were summarized as frequencies and
percentages. Characteristics of patients who were referred and
did or did not undergo colposcopy were compared using the
chi-squared test. For referred patients who did not undergo
colposcopy (n = 375), CIN3+ results were imputed based on a
logistic regression model that used the observed CIN3+ results
among the entire cohort as outcomes and baseline
characteristics and HPV and cytology results as predictors. Results were
imputed five times and summarized using Rubin’s rule.
Similar analyses were performed to impute CIN2+ results.
Prevalence of CIN2+/CIN3+ was estimated as percentages
with 95 % confidence intervals. Test characteristics were
estimated for the initial round of screening. Analyses were
conducted using SAS 9.3 (Cary, NC) and R 3.0.2 (cran.r-project.org).
We identified 101,889 patients who met the inclusion criteria.
We excluded patients with diagnostic testing ordered as
screening (N = 35) and those with unsatisfactory or
unavailable test results (N = 2305), resulting in a final cohort of
99,549 patients. Patient characteristics appear in Table 1.
Subjects were mostly under age 60 (84.6 %), white (78.4 %),
married (70.7 %), never smokers (61.3 %) and with private
insurance (86.1 %). A total of 8836 patients (8.9 %) had a
positive test by either HPV (N = 5121, 5.1 %) or cytology
(N = 6115, 6.1 %). Of these, 1681 underwent colposcopy, and
310 (0.3 %) had CIN3+ lesions (Table 2). Both positive HPV
and CIN3+ were more common among women who were
younger, black, single and smokers. Additionally, 375 patients
had positive cytology but did not undergo colposcopy. These
patients were not different in age or marital status from those
who underwent colposcopy; however they were more likely to
be white, to smoke and to not have private insurance
(p < 0.001) (eTable 2). Of these patients, we imputed 139
cases of CIN2+ and 74 cases of CIN3+. Eleven cancers were
reported—two metastatic breast and nine cervical (1
squamous, 8 adenocarcinoma).
The incidence of CIN3+ by HPV and cytology status
appears in Table 2. CIN3+ was more common with positive than
negative HPV results (5.7 % vs. 0.02 %, p < 0.001).
HPVpositive patients with abnormal cytology had high rates of
CIN3+ (≥4.6 %). Of patients who were HPV negative, only
those with cytology indicating ASC-H, HSIL and cancer had
rates of CIN3+ >0.6 %. Only two HPV-negative patients with
any other cytology result had CIN3+.
Test characteristics appear in Table 3. Sensitivity of Co-testing
(99.4 %) was greater than for Primary HPV (94.1 %) and
Primary Cytology (90.7 %). Primary HPV was slightly more
specific (98.1 %) than the other strategies (both 97.6 %) and had
the greatest positive predictive value (12.1 % vs. 9.6 % for
Primary Cytology and 10.3 % for Co-testing). All strategies
had negative predictive values exceeding 99.9 %.
Over a 3-year period, Primary HPV was the least expensive,
detecting 294 cases of CIN3+ with 2422 colposcopies per
99,549 screened at a cost of $3.47 M. Primary Cytology
detected nine fewer cases of CIN3+ but cost more. Co-testing
detected 14 additional cases of CIN3+ than Primary HPV but
would require 100,277 more cytology tests and 566 more
colposcopies at an additional cost of $2.38 million, or
HPV human papillomavirus, CIN3+ cervical intraepithelial neoplasia 3
or worse, ASCUS atypical squamous cells of undetermined significance,
ASC-H atypical squamous cells—cannot exclude high-grade
intraepithelial lesion, AGC atypical glandular cells, LSIL low-grade
squamous intraepithelial lesion, HSIL high-grade squamous
*375 patients without histological results excluded (no imputed data)
$170,096 per case detected (Table 4). In sensitivity analysis,
this marginal cost ranged from $166,864–$173,327 as the cost
of the HPV test was varied from 50 to 150 % of the current
Medicare National Facility Price (eTable 6). Increasing the
cost of cytology made Co-testing even more expensive,
whereas including costs for cytology storage in the Primary
HPV strategy decreased the marginal cost of Co-testing.
Varying the storage cost from 10 to 30 % of the cost of cytology
produced marginal costs of $157,566 to $132,506. Results
were similar for patients with CIN2+ (eTables 3–6).
The FDA approval of a primary HPV screening test as an
alternative to cytology has introduced complexity into an
evolving field and stirred considerable debate over the
appropriate screening strategy.12,25,34 In this retrospective cohort
study of 99,549 patients undergoing primary cervical cancer
screening in an integrated health system, we found that
Primary HPV screening was more effective and less expensive
than Primary Cytology. Co-testing was only slightly more
effective than Primary HPV testing and was substantially
more expensive, costing approximately $170,000 for each
additional case of CIN3+ identified.
Three large prospective, population-based studies of cervical
cancer screening have been conducted in North America. All
reported rates of HPV infection and cervical abnormalities similar
to ours.6,7,16,35–37 In contrast, test characteristics of the strategies
varied widely. The sensitivity of HPV testing ranged from 48 to
87 %, and cytology ranged from 51 to 90 %. Specificity varied
less, ranging from 92 to 99 % for HPV and 88 % to 99 % for
cytology. In our cohort, all testing modalities had high sensitivity
(>90 %) and specificity (>97 %). In contrast, the ATHENA study
and Canadian Cervical Cancer Screening Trial reported
sensitivities below 60 % for all modalities, because their rates of
abnormal cytology (which was necessary for advancing to colposcopy
in any strategy) were much lower than ours. It is unclear whether
this difference was due to sample collection or pathological
The superior cost-effectiveness of cervical cancer screening
strategies involving HPV testing over cytology alone has been
reported in a variety of settings.38–44 Although Co-testing is
preferred over Primary Cytology by some guidelines,5 this
recommendation has been questioned.12 Our analysis supports
a Primary HPV strategy over Primary Cytology, because it
detected more cases of CIN3+ at lower cost. The higher
specificity of Primary HPV meant almost 20 % fewer unnecessary
colposcopies—a savings of $1.3 million over the study period.
Compared to Co-testing, Primary HPV avoided most Pap
smears and many colposcopies. Because both strategies
included HPV testing, the analysis was relatively insensitive to the
cost of HPV testing.
To our knowledge, no studies have directly compared
3year Primary HPV and Co-testing strategies, and none have
HPV human papillomavirus, CIN3+ cervical intraepithelial neoplasia 3 or worse
*We assume that the tests conducted after year 1 are perfect in the sense that all test positives are true CIN3+ cases, and all negatives are true negatives
†Numerators and denominators rounded to nearest integers
‡Includes imputed data for patients with missing colposcopy results
§p < 0.001 vs. Primary Cytology and Primary HPV, other comparisons not significant
‖p < 0.001 vs. Primary Cytology and Co-testing, other comparisons not significant
¶p < 0.001 for all comparisons
included US populations. Several studies utilized
mathematical models to simulate the natural history of cervical cancer
and evaluate the cost-effectiveness of screening strategies.
One Canadian study compared a primary HPV strategy with
a 3-year screening interval and a co-testing strategy to
cytology alone.38 However, they did not directly compare these
strategies to each other, and an incremental cost-effectiveness
could not be ascertained. Another Canadian study found that
compared to primary HPV, bi-annual co-testing beginning at
age 18 had an incremental cost-effectiveness ratio
of >$400,000 per life year gained.45 Similar findings have
been demonstrated in Europe.46–49 Because our findings
cannot be translated into life years saved, the incremental
costeffectiveness of co-testing may be difficult to interpret. What
is a reasonable cost for the health care system to bear to detect
one additional case of CIN3+? Specifically, is the detection of
14 cases per 100,000 women screened worth $170,096 per
case detected, in addition to the inconvenience of an additional
100,277 cytology tests and 566 colposcopies?
Our cohort represents a low-risk population, as evidenced by
the lower incidence of LSIL (0.88 %) and HSIL (0.22) than the
national median (2.5 % and 0.5 %, respectively).50 Our study is
instructive for other integrated health systems seeking to
provide high-value care to similar populations. Given the low rates
of disease, the redundancy of co-testing appears to be
unnecessary. This conclusion cannot be generalized to high-risk centers,
where patients struggle with access to care, and where most
cases of cervical cancer occur. In that context, the emphasis
must be on consistent screening and assuring timely follow-up.
Our study has several other important limitations. First, for
women who did not receive follow-up care, we used
imputation to assign outcomes, which may not accurately
represent the incidence of CIN3+. The population with
imputed results was small, but differed in race, smoking status and
insurance from those who underwent colposcopy. Imputation
was used only for determining the positive and negative
predictive value, so it had no impact on other test
characteristics or the cost-effectiveness calculations. Second, without
being able to determine the histological status of patients with
both negative HPV and cytology tests, our study is susceptible
to verification bias; however, other studies have demonstrated
negligible incidence of CIN2+ and CIN3+ in the setting of
negative co-testing results.6,51,52 We used only a single co-test,
while the importance of assessing screening over at least two
rounds has been suggested.53 Additionally, because all tests
were conducted in a high-functioning health care system, test
sensitivity may be superior to other settings. Finally, because
we used surrogate outcomes, we could not estimate the cost
per case of cervical cancer prevented or life years saved.
Our cost-effectiveness analysis is limited to a 3-year
screening interval. Because of the difference in screening intervals
(3 years for Primary Cytology and 5 years for Primary HPV
and Co-testing), we had to estimate the cost of a 3-year interval
for the HPV-based strategies in order to compare like
outcomes. The cost of storing specimens was considered only in
sensitivity analysis. Including such costs would improve the
cost-effectiveness of Co-testing. It is also important to note
that we used current National Medicare Facility Prices. While
the prices paid by private insurance may be higher, our
marginal costs of Co-Testing over Primary HPV were relatively
insensitive to the cost of HPV testing. Higher cytology prices
would make Co-Testing less favorable. Our analysis was
HPV human papillomavirus, CIN3+ cervical intraepithelial neoplasia 3 or worse
*Total cost of Primary HPV and Co-testing strategies multiplied by 3/5 to compare cost of 3-year screening interval for all strategies
conducted from the payer perspective. Patients, depending on
their co-pays and financial means, might feel differently about
which strategy they prefer. Finally, we excluded patients who
had equivocal HPV results. Including the cost of these tests
would not affect the outcome because the number would be
the same for both strategies.
The cobas® HPV Test was recently approved for
primary cervical cancer screening based on the ATHENA
trial.21,54 Like the Hybrid Capture 2 used in this study,
the cobas® Test detects 14 high-risk HPV genotypes.
However, the cobas® Test also detects genotype 66 and
indicates specifically whether the specimen is positive or
negative for HPV-16 or HPV-18.55 The strong association
of cervical cancer with these two genotypes is the basis
for a primary HPV screening strategy in which women
who test positive for HPV-16/HPV-18+ genotypes are
triaged directly for colposcopy. In ATHENA, genotyping
for HPV-16/HPV-18 improved the sensitivity for CIN3+
and required far fewer cytology tests with only a marginal
increase in colposcopies over co-testing.35 This should
make Primary HPV testing even more cost-effective.
However, because of the differences between these tests,
our Primary HPV strategy is not directly comparable to
screening with cobas®.
The findings from this large cohort of women in routine
care shed light upon the changing landscape of cervical cancer
screening. Primary HPV testing appears to offer an attractive
tradeoff between cost and effectiveness. Additional factors
may be taken into consideration when selecting the
appropriate screening strategy for individual patients, but as
valuebased care becomes increasingly important, cost and
convenience will contribute more to decision making. Overall, the
findings from this study provide support for the
implementation of primary HPV screening with reflex cytology as a
potentially cost-effective strategy in low-risk women age 30
Author Contributions: Dr. Jin and Sarah Schramm had full access to
all of the data in the study and take responsibility for the integrity of the
data and the accuracy of the data analysis.
Study concept and design: Jin, Sikon, Lipold, Belinson
Acquisition of data: Schramm, Nottingham, Brainard
Analysis and interpretation of data: Hu, Jin, Lipold, Sikon, Rothberg,
Drafting of the manuscript: Jin, Foucher, Rothberg, Sikon, Lipold
Critical revision of the manuscript for important intellectual content: All
Statistical analysis: Hu
Administrative, technical, or material support: Schramm, Nottingham
Study supervision: Schramm, Nottingham, Jin, Sikon, Lipold
Role of the Sponsor: The sponsors provided funding only and played
no role in the design and conduct of the study; collection, management,
analysis, and interpretation of the data; preparation, review, or
approval of the manuscript; or decision to submit the manuscript for
Additional Contributions: The following individuals contributed to
acquisition of data: Jacqueline Fox, RN, BSN; Pamela Mason, RN, BSN,
MBA; Fabrizio Galimberti, PhD; Yumeng Li, BS; Yue Zhao, BS; Joanna
Zhou, BS; Mir Lim; Shoshana Weiner, MD; Harsha Alexander, MD
Previous Presentation: Oral Presentation at the Society of General
Internal Medicine Annual Meeting, San Diego, April
Corresponding Author: Xian Wen Jin, MD, PhD; Department of
Internal MedicineCleveland Clinic, Cleveland, OH, USA
Compliance with Ethical Standards:
Funding/Support: This study was funded internally by the Cleveland
Clinic Research Program Committees, award number 2010-1050-R1.
Conflict of Interest: Xian Wen Jin MD, PhD: Speaking Bureau for
Qiagen and Merck. Jerome Belinson MD: Support in kind (reagents
and testing) and funds for direct support and research, under the
auspices of Preventive Oncology International Inc., from Hologic Inc.,
Qiagen, Gen-Probe, Merck Inc., BGI Shenzhen, and GE Healthcare.
None of the support described above was for the research described
in this manuscript. All remaining authors declare that they do not have
a conflict of interest.
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