Research www. AJOG.

org

GENERAL GYNECOLOGY
Comparison of cervical cancer screening strategies
incorporating different combinations of cytology,
HPV testing, and genotyping for HPV 16/18:
results from the ATHENA HPV study
J. Thomas Cox, MD; Phillip E. Castle, PhD, MPH; Catherine M. Behrens, MD, PhD; Abha Sharma, PhD;
Thomas C. Wright Jr, MD; Jack Cuzick, PhD; and the Athena HPV Study Group

OBJECTIVE: The objective of the study was to compare 9 cervical can-
cer screening strategies to the current screening standard (cytology
with human papillomavirus [HPV] triage of atypical squamous cells of
undetermined significance) for the detection of high-grade cervical
disease.
STUDY DESIGN: Women (n ⫽ 34,254) aged 30 years or older from the
Addressing the Need for Advanced HPV Diagnostics (ATHENA) study
underwent screening with cytology and HPV testing with simultaneous
HPV16/18 genotyping; those with atypical squamous cells of undeter-
mined significance cytology or greater or HPV-positive status were re-
ferred for colposcopy.
RESULTS: In general, screening strategies that offered greater sensitiv-
ity also required more referral to colposcopy. HPV testing was more
sensitive than cytology for detection of cervical intraepithelial neoplasia
grade 2 or greater, but strategies that depended on cytology for triage of
HPV-positive women decreased this sensitivity. Various strategies of
cotesting with cytology increased sensitivity but did so by increasing
testing. Strategies that included integrated HPV16/18 testing provided
more efficient referral to colposcopy.
CONCLUSION: Strategies that maximize detection of women at greatest
risk of cervical intraepithelial neoplasia grade 3 or greater by immediate
referral to colposcopy, with follow-up testing of women at intermediate
risk, maximize the benefits of cervical cancer screening while decreas-
ing the potential harm. Incorporating screening with HPV and triage of
HPV-positive women by a combination of genotyping for HPV16/18 and
cytology provided a good balance between maximizing sensitivity (ben-
efit) and specificity by limiting the number of colposcopies (potential
harm).
Key words: Addressing the Need for Advanced HPV Diagnostics,
atypical squamous cells of undetermined significance, cotesting,
human papillomavirus, human papillomavirus 16/18, low-grade
squamous intraepithelial lesion

Cite this article as: Cox JT, Castle PE, Behrens CM, et al. Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV
testing, and genotyping for HPV 16/18: results from the ATHENA HPV study. Am J Obstet Gynecol 2013;208:184.e1-11.

I n March 2012, new primary cervical

screening guidelines were jointly is-
sued by the US Preventative Services
Task Force (USPSTF)1 and a consortium
of the American Cancer Society (ACS),
the American Society for Colposcopy
and Cervical Pathology (ASCCP), and
the American Society of Clinical Pathol-
ogists (ASCP).2 Based on the evidence

From Student Health, University of California, Santa Barbara (retired), Santa Barbara, CA (Dr Cox); Albert Einstein College of Medicine, Bronx, NY (Dr
Castle); Roche Molecular Systems, Pleasanton, CA (Drs Behrens and Sharma); the Department of Pathology, Columbia University Medical Center,
New York, NY (Dr Wright); and the Center for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London,
London, UK (Dr Cuzick).
Received July 20, 2012; revised Oct. 12, 2012; accepted Nov. 14, 2012.
This study was supported by Roche Molecular Systems.
J.T.C. and P.E.C. are compensated for their services as members of a Data Monitoring Board for HPV vaccines for Merck. J.T.C. has received
honoraria from Roche for assistance in the development of an educational slide set and for speaking on the cobas HPV Test. He has also received
honoraria for service on the scientific advisory board for Gen-Probe and advisory boards for Graceway and Bradley Pharmaceuticals. P.E.C. has
received HPV tests and testing for research at a reduced or no cost from Roche and Qiagen. T.C.W. is compensated for his services as a reference
pathologist, clinical adviser, and speaker for Roche, Gen-Probe, BD Diagnostics, and Ikonisys. He has received honoraria for serving on a scientific
advisory board for HPV vaccines for Merck. J.C. has served on advisory boards for Roche, Gen-Probe, Abbott, and Qiagen. C.M.B. and A.S. are
employees of Roche Molecular Systems.
Presented at EUROGIN 2012, Prague, Czech Republic, July 8-11, 2011.
Reprints: J. Thomas Cox, MD, 3345 Numancia St., Santa Ynez, CA 93460. tomcoxmd@aol.com.
0002-9378/$36.00 • © 2013 Mosby, Inc. All rights reserved. • http://dx.doi.org/10.1016/j.ajog.2012.11.020

See Journal Club, page 235

184.e1 American Journal of Obstetrics & Gynecology MARCH 2013

www.AJOG.org
that human papillomavirus (HPV) test-
ing is more sensitive and therefore pro-
vides better negative predictive values
(NPV) than cytology, these new guide-
lines recommend that women aged 30
years and older be screened every 3 years
using cervical cytology alone or every 5
years using a combination of cervical cy-
tology and high-risk HPV testing (re-
ferred to as cotesting).
The better NPV of HPV testing per-
mits a safe extension of the screening in-
terval, thereby reducing harms caused
by screening. The ACS/ASCCP/ASCP
guidelines endorsed the cotesting option
as the preferred approach for women
aged 30 years and older,2 whereas the
USPSTF endorsed it as acceptable,1 and
the American College of Obstetricians
and Gynecologists (ACOG) expressed
support of these recommendations.3
The ACS/ASCCP/ASCP guidelines rec-
ommend that cytology-negative/HPV-
positive women undergo follow-up in 12
months with repeat cytology and HPV
testing or, alternatively, cytology-negative/
HPV-positive women can be genotyped
for HPV 16 and HPV 18.2 With the latter
option, women who are found to have ei-
ther HPV 16 or HPV 18 are referred for
colposcopy, whereas those without these
highest-risk HPV types are cotested again
in 12 months.
The Addressing the Need for Ad-
vanced HPV Diagnostics (ATHENA)
HPV study is a prospective 3 year cervi-
cal cancer screening trial designed to
compare the performance of the newly
introduced cobas HPV Test (Roche Mo-
lecular Diagnostics, Pleasanton, CA)
both alone and in combination with cer-
vical cytology among women aged 21
years and older in the United States.
Based on the cross-sectional data from
the ATHENA trial, the US Food and
Drug Administration recently approved
for use in the United States the cobas
HPV Test, which detects 11 pooled high-
risk HPV genotypes (HPV 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, and 68) and 1 pos-
sible high-risk type (HPV 66) and con-
currently provides separate results for
HPV 16 and HPV 18.4-7
The current manuscript further ana-
lyzes the enrollment results of the
ATHENA trial to investigate alternative
General Gynecology
screening strategies to those endorsed by
the most recent US cervical cancer
screening guidelines. Ten different cervi-
cal cancer screening strategies, including
several that use HPV testing alone as the
initial screening method, were investi-
gated. The performance of each strategy
for detection of cervical intraepithelial
neoplasia grade 2 (CIN2) or more severe
or CIN3 or more severe was explored, as
was the potential harm estimated by the
number of tests and the number of col-
poscopies (a metric used by the recent
guideline process) needed to detect each
high-grade lesion at baseline. These
strategies included results of testing with
cytology and/or various combinations of
HPV testing, including HPV genotyping
for HPV 16 and HPV 18.
M ATERIALS AND M ETHODS
Study protocol
As previously described, the ATHENA
HPV study enrolled more than 47,000
women aged 21 years and older who pre-
sented for cervical cancer screening; all
eligible participants had both Papanico-
laou testing (by liquid-based cytology,
ThinPrep; Hologic, Bedford, MA) and
HPV testing (by Amplicor HPV test, Lin-
ear Array high-risk HPV genotyping test,
and the cobas HPV Test, all from Roche
Molecular Systems).6 The protocol was
approved by the institutional review
boards at all study sites, and all women
provided written informed consent be-
fore undergoing any study procedures.
The current analysis focuses only on the
subset of women aged 30 years old and
older to compare alternative manage-
ment strategies with those endorsed in
the current guidelines.
All women in this subset who had ei-
ther abnormal cytology (atypical squa-
mous cells of undetermined significance
[ASC-US] or greater) or who tested pos-
itive for HPV (by Amplicor or Linear Ar-
ray test) were scheduled for colposcopy.
In addition, to adjust for ascertainment
bias, a randomly selected subset of
women who tested negative for both cy-
tology and HPV had colposcopy. Colpo-
scopic biopsies were performed accord-
ing to a standardized protocol, and a
random biopsy was required in all
MARCH 2013 American Journal of Obstetrics & Gynecology
Research
women with adequate colposcopy in
whom no lesion was seen; patients and
colposcopists were blinded to the cytol-
ogy and HPV results.
An expert central pathology review
(CPR) panel of 3 pathologists read all bi-
opsies masked to any clinical data.
Women achieving the study endpoint of
CIN2 or more severe by CPR exited the
study; those who did not reach this end-
point proceeded to the 3 year follow-up
phase of the study, scheduled to con-
clude December 2012. The current anal-
ysis is restricted to disease detected at en-
rollment; disease detected over the
subsequent 3 years of follow-up will be
analyzed separately.
Screening strategies
The 10 screening strategies were evalu-
ated based on review of the published
cervical cancer screening literature and
appear to be the strategies most likely to
be considered potentially attractive by
the clinical and public health commu-
nities. Strategies 1 and 2 are cytology
screening strategies (Figure 1). Strategy
1 consists of screening with cytology
with reflex HPV testing (pooled high-
risk HPV test for 14 genotypes) of
ASC-US and referral of all women with
HPV-positive ASC-US or low-grade
squamous intraepithelial lesion (LSIL)
or greater to colposcopy. Because this is
the strategy most widely used in the
United States, it serves as the comparator
for the other 9 strategies.
Strategy 2 consists of screening with
cytology alone, with referral of all
women with ASC-US or greater to col-
poscopy. Strategies 3, 4, and 5 (Figure 2)
incorporate cotesting with both cytology
and HPV testing. They vary as to
whether genotyping for HPV 16 and
HPV 18 is used and by the cytological
threshold for referral to colposcopy.
Strategies 6 through 10 (Figure 3) use
HPV testing alone (pooled high-risk
HPV test with, or without, genotyping
for HPV 16/18) as the initial screening
test and differ by which triage tests are
used to evaluate HPV-positive women.
In the strategies described, women who
did not meet the criteria for either imme-
diate colposcopy or return to routine
screening would be deferred to a 1 year
184.e2
Research General Gynecology
follow-up per the current guidelines2 as
indicated in Figures 2 and 3.
Statistical analysis
For each screening strategy, the number
of tests (cytology and/or HPV test with
or without integrated HPV 16/18 geno-
type detection) required at baseline was
calculated, as was the number of colpos-
copies required to detect 1 case of CIN2
or more severe or CIN3 or more severe.
From the total catchment of CIN2 or
more severe and CIN3 or more severe
detected, the number of cases not iden-
tified at baseline, and an estimate of the
number that could potentially be identi-
fied by each strategy at 12 month fol-
low-up were calculated. The crude sensi-
tivity and specificity for detection of
CIN2 or more severe or CIN3 or more
severe and its sensitivity and specificity
relative to strategy 1 were also deter-
mined (Tables 2 and 3).
The cobas HPV Test results were cate-
gorized as follows: HPV positive (posi-
tive for any of 14 high-risk HPV types);
HPV negative (negative for all 14 high-
risk HPV types); HPV 16/18 positive
(positive for HPV 16 and/or HPV 18, re-
gardless of the presence or absence of 12
other HPV types); positive for 12 other
HPV types (positive for 1 or more of the
12 other HPV types and negative for
HPV 16 and HPV 18).
For calculations of sensitivity and
specificity, only those cases in which col-
poscopy was performed and a valid bi-
opsy result was obtained were consid-
ered. Crude estimates are given because
the intent was to report on the utility of
the strategies as would be observed in a
clinical situation. Verification bias ad-
justment would not change the relative
sensitivities or specificities of the various
strategies or represent what happens in
clinical practice.
R ESULTS
A total of 34,254 women aged 30 years or
older were eligible for this analysis; the
mean age was 44.7 years, and the demo-
graphics are shown in Table 1. Among
the eligible women, 2872 (8.4%) tested
positive with the cobas HPV Test, and
1966 (5.7%) had abnormal cytology; 280
women were diagnosed with CIN2 or
184.e3 American Journal of Obstetrics & Gynecology MARCH 2013
www.AJOG.org
FIGURE 1
Cytology primary screening options
Strategy 1: Cytology with reflex HPV (ASC-US triage)
Routine follow-up
NILM
>ASC-US
Pap Test Colposcopy
Routine
Neg
ASC-US follow-up
HPV Test
Pos Colposcopy
Strategy 2: Cytology Alone
NILM Routine screening
Pap Test
Colposcopy
ASC-US
Strategies 1 and 2 screened initially with cytology only. Strategy 1, a recommended screening option
for women aged 21 years or older, triages ASC-US by reflex HPV testing, sending to colposcopy
ASC-US/HPV positive and more severe than ASC-US (ie, ASC with possible HSIL [ASC-H], LSIL,
atypical glandular cells [AGC], and HSIL). Women with normal cytology or ASC-US/HPV negativity
continued with routine screening. Strategy 2 sent all women with any abnormal cytology (ie, ASC-US
or more severe) to colposcopy, and all women with normal cytology continued with routine screening.
This is not a recommended screening option but is included in this study for comparison with other
options.
ASC-US, atypical squamous cells of undetermined significance; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial
lesion; LSIL, low-grade squamous intraepithelial lesion.
Cox. Cervical cancer screening strategies: evaluation of results from the ATHENA HPV study. Am J Obstet Gynecol 2013.
more severe and 189 with CIN3 or more more severe. These included cytology
severe. The most sensitive screening with HPV triage of ASC-US (strategy 1;
strategy was screening with HPV alone 51.4% and 56.1%, respectively) and cy-
(pooled 14 high-risk types) with referral tology alone (strategy 2; 53.2% and
of all HPV-positive women to colpos- 57.7%, respectively). Strategy 3 was also
copy (strategy 6), detecting 242 of CIN2 cytology based because it screened with
or more severe lesions (86.4%) and 170 cytology and HPV testing (cotesting) but
(89.9%) of the CIN3 or more severe le- used only the results of cytology and re-
sions (Tables 2 and 3). However, this flex HPV testing of ASC-US to deter-
strategy also had the highest false-posi- mine immediate referral to colposcopy.
tive rate for CIN3 or more severe Therefore, this strategy had an identical
(38.0%). In terms of the utilization of performance to strategy 1 during the first
colposcopy resources, it was almost as round of screening, except that cotesting
inefficient as the strategy of screening also identified cytology-negative/HPV-
with cytology alone and referring all positive women in need of additional
woman with ASC-US or more severe to follow-up in 12 months2 from which 72
colposcopy (strategy 2) since it required additional cases of CIN3 or more severe
9.7 colposcopic evaluations to find a sin- could potentially be detected (subse-
gle case of CIN2 or more severe and 13.8 quently described as “cases identified for
to find a single case of CIN3 or more 12 month f/u” [Tables 2 and 3]). HPV
severe. alone with cytology triage of HPV-posi-
All strategies depending on cytology tive women (strategy 7) had the lowest
alone or on cytology as the sole reflex test cross-sectional sensitivity because the
had the lowest sensitivities for detection triage test negates the increased sensitiv-
of CIN2 or more severe and CIN3 or ity of HPV testing. In contrast to the
www.AJOG.org General Gynecology Research

lower sensitivity of each of these strate-

FIGURE 2
gies, all but strategy 2 were among the
Cotesting primary screening options most specific, with false-positive rates
Strategy 3: Cotesting with reflex for ASC-US for detection of CIN3 or more severe be-
tween 8.7 (strategy 7) and 12.4 (strate-
Both Negative or Routine screening gies 1 and 3).
ASC-US/HPV- All 3 cotesting options approximately
HPV and ASC-US/HPV+
doubled the number of initial screening
Pap Test & >ASC-US
Colposcopy tests compared with the remaining
(Cotesting) strategies. Of the cotesting options,
NILM/HPV+ cotesting with genotyping triage and
Repeat cotest an ASC-US threshold (strategy 4) de-
in 12 mo. tected the most CIN2 or more severe
and CIN3 or more severe, with the
highest sensitivity (67.5% and 76.2%,
Strategy 4: Cotesting with genotyping and cytology triage:
respectively). However, because this
HPV 16/18 & ASC-US HPV+ threshold option required 32% more colposco-
pies than cotesting alone (strategy 3),
Both Negative or Routine screening the number of colposcopic evaluations
ASC-US/HPV- to detect 1 CIN2 or more severe (ap-
HPV with proximately 6) and 1 CIN3 or more se-
16/18 ASC-US/HPV+ or
>ASC-US or vere (approximately 8) was similar. Of
genotyping Colposcopy the cotesting options, strategy 4 also
and Pap Test NILM HPV16/18+
had the highest relative sensitivity for
(Cotesting)
NILM/HPV+ CIN2 or more severe and CIN3 or
but not 16/18 Repeat cotest more severe (1.31 and 1.36, respec-
in 12 mo. tively) but also had the highest false-
positive rate for CIN3 or more severe
(18.5%). Strategy 5 was similar to
Strategy 5: Cotesting with genotyping and cytology triage: strategy 4 but triaged non-HPV 16/
HPV 16/18 & LSIL threshold HPV 18 pooled positive women to col-
poscopy using an LSIL threshold rather
Both Negative or Routine screening than an ASC-US threshold; this strat-
HPV-/ASC-US egy was 5.3% less sensitive for CIN3 or
HPV with more severe than strategy 4 but re-
16/18 ≥LSIL or NILM
or ASC-US duced the number of colposcopies by
genotyping Colposcopy 14.3% (1030 vs 1202). The cotesting
and Pap Test HPV16/18+
strategies required between 5 and 6
(Cotesting) colposcopies to detect 1 CIN2 or more
ASC-US or
NILM/HPV+ severe, approximately the same as cy-
Repeat cotest
but not 16/18 tology with HPV triage of ASC-US
in 12 mo.
(strategy 1).
Strategies 3-5 screened initially with both cytology and testing for high-risk HPV. Strategies 4 and 5 All of the screening strategies based on us-
also utilized the information provided when the HPV test also included separate results for HPV 16 and ing HPV alone (pooled 14 high-risk types,
HPV 18 genotyping or, if not, when reflex genotyping could be done. Strategy 3, 1 of 2 recommended with or without HPV 16/18 genotyping) as
cotesting options for women aged 30 years or older, referred to colposcopy women with ASC-US HPV the initial test required similar numbers of
positivity and LSIL or more severe, irrespective of HPV result, whereas women with cytology-nega- testscomparedwiththecytology-basedstrat-
tivity/HPV positivity had repeat cotesting in 12 months and women who were cytology negative/HPV egies (from 34,254 to 37,126). Of the 5 HPV
negative and ASC-US/HPV negative continued routine screening. Strategy 4, also a recommended
cotesting strategy, referred to colposcopy women who were ASC-US/HPV positive and LSIL or more 4™™™™™™™™™™™™™™™™™™™™™™™
severe irrespective of HPV result, as well as all women who were cytology negative/HPV 16/HPV 18 not HPV 16/HPV 18 positive had 12 month fol-
positive. Women who were cytology negative/HPV positive but not positive for HPV 16 or HPV 18 had low-up.
repeat cotesting in 12 months, and women who were cytology negative/HPV negative and ASC-US/ ASC-US, atypical squamous cells of undetermined significance;
HPV negative continued with routine screening. Strategy 5 was similar to strategy 4 except that the HPV, human papillomavirus; LSIL, low-grade squamous intraepi-
thelial lesion.
threshold for referral to colposcopy was LSIL or more severe or cytology negative/HPV 16/HPV 18 Cox. Cervical cancer screening strategies: evaluation of results
positive or ASC-US/HPV 16/HPV 18 positive, whereas ASC-US or negative cytology/HPV positive but from the ATHENA HPV study. Am J Obstet Gynecol 2013.

MARCH 2013 American Journal of Obstetrics & Gynecology 184.e4

Research General Gynecology www.AJOG.org

strategies, HPV alone (strategy 6) had the

FIGURE 3
highest relative sensitivity and lowest relative
HPV screening algorithms specificity for CIN2 or more severe (1.68 and
Strategy 6: HPV alone 0.71, respectively), whereas HPV with cytol-
ogy triage (strategy 7) and HPV with geno-
Neg Routine screening typing triage (strategy 8) had the highest rel-
HPV Test ative specificity (each 1.04) but the lowest
Pos Colposcopy relative sensitivity (0.92 and 0.85, res-
pectively).
Strategy 7: HPV with reflex to cytology Using genotyping to triage HPV-pos-
itive women to colposcopy (strategy 8)
slightly decreased sensitivity for CIN2 or
Neg Routine screening
Follow-up more severe compared with using cytol-
HPV Test NILM in 12 mo. ogy at an ASC-US threshold (strategy 7;
Pos Pap Test 43.6% vs 47.5%) but increased sensitiv-
≥ASC-US Colposcopy ity for CIN3 or more severe (53.4% vs
51.9%), indicating a trend toward in-
Strategy 8: HPV with genotyping creased predictive value of HPV 16/HPV
18 genotyping as a triage test compared
Routine screening with cytology.
Neg Of all the screening strategies, HPV
HPV Test with cytology triage (strategy 7) and
and 16/18 Colposcopy
Genotyping HPV16+/18+ HPV with genotyping triage (strategy 8)
12 Other
required both the least number of col-
HR+ Follow-up poscopies (596 and 580, respectively)
in 12 mo.
and the least number of colposcopies to
detect 1 CIN2 or more severe (approxi-
Strategy 9: HPV with genotyping and reflex cytology: ASC-US threshold
mately 5). However, both strategies had
relatively low baseline sensitivity.
Routine screening Strategies 8, 9, and 10 used HPV alone
Neg
HPV Test as the initial screen and incorporated
and 16/18 Colposcopy genotyping triage for HPV-positive
HPV16+/18+
Genotyping Follow-up women. Strategies 9 and 10 added cytol-
12 Other NILM in 12 mo.
HR+ Pap Test ogy triage for HPV-positive women who
were HPV 16/HPV 18 negative to in-
≥ASC-US Colposcopy crease baseline detection of CIN2 or
more severe caused by the other 12 HPV
Strategy 10: HPV with genotyping and reflex cytology: LSIL threshold
4™™™™™™™™™™™™™™™™™™™™™™™
Routine screening Women with any abnormal cytology ASC-US or
Neg more severe were also referred to colposcopy,
HPV Test whereas women who were cytology negative/
and 16/18 Colposcopy
HPV16+/18+ NILM & HPV positive for non–HPV 16/HPV 18 had 12
Genotyping Follow-up
ASC-US
12 Other in 12 mo. month follow-up. Strategy 10 screened initially
HR+ Pap Test with a panel of HPV plus genotyping for HPV 16 and
≥LSIL Colposcopy HPV 18, referring all women who were HPV 16/HPV
18 positive to colposcopy and reflex testing by cy-
Strategies 6-10 screened initially with HPV testing. Strategy 6 referred all HPV-positive women to tology those HPV positive but not positive for HPV
colposcopy and all HPV-negative women to routine screening. Strategy 7 reflex tested all HPV- 16/HPV 18. Women with LSIL or more severe were
positive women with cytology, referring to colposcopy only those with ASC-US or more severe, also referred to colposcopy, whereas women who
whereas those with negative cytology had follow-up in 12 months. Strategy 8 screened initially with were cytology negative/HPV positive and ASC-US/
a panel of HPV plus genotyping for HPV 16 and HPV 18, referring to colposcopy all women testing HPV positive for non–HPV 16/HPV 18 had 12
positive for HPV 16 and/or HPV 18 and to 12 month follow-up women positive for other HPV month follow-up.
genotypes but not positive for HPV 16/HPV 18. Strategy 9 screened initially with a panel of HPV plus ASC-US, atypical squamous cells of undetermined significance;
genotyping for HPV 16 and HPV 18, referring all women who were HPV 16/HPV 18 positive to HPV, human papillomavirus.
Cox. Cervical cancer screening strategies: evaluation of results
colposcopy and reflex testing by cytology those HPV positive but not positive for HPV 16/HPV 18. from the ATHENA HPV study. Am J Obstet Gynecol 2013.

184.e5 American Journal of Obstetrics & Gynecology MARCH 2013

www.AJOG.org General Gynecology Research
The 4 strategies in the middle group
TABLE 1 (strategies 4, 5, 9, and 10) demonstrated
Demographic and clinical characteristics of ATHENA a narrow range of sensitivity (66.7–
population aged 30 years or older at baseline 76.2%) but varied by 33% in the number
Evaluable subjects of colposcopies (810 –1202). Within this
Characteristics (n ⴝ 34,254) group, cotesting with genotyping and cy-
Age, y tology triage at the ASC-US HPV-posi-
...................................................................................................................................................................................................................................
Mean ⫾ (SD) 44.7 ⫾ (10.1) tive threshold (strategy 4) was the most
...................................................................................................................................................................................................................................
sensitive but also required the most col-
30-39, n (%) 12,248 (35.8)
................................................................................................................................................................................................................................... poscopies. HPV with genotyping and cy-
ⱖ40, n (%) 22,006 (64.2) tology triage at the LSIL threshold (strat-
............................................................................................................................................................................................................................................
Race, n (%) egy 10) was the least sensitive and
...................................................................................................................................................................................................................................
White 28,821 (84.1) required the fewest colposcopies. Cotest-
...................................................................................................................................................................................................................................
ing with genotyping and cytology triage
Black or African American 4503 (13.1)
................................................................................................................................................................................................................................... with LSIL (strategy 5) and HPV with
Asian 503 (1.5) genotyping and reflex cytology triage
...................................................................................................................................................................................................................................
American Indian or Alaskan native 184 (0.5) with ASC-US (strategy 9) were very sim-
...................................................................................................................................................................................................................................
Native Hawaiian or other Pacific 78 (0.2) ilar in both sensitivity and number of
Islander colposcopies, but strategy 5 required
...................................................................................................................................................................................................................................
a nearly twice the number of initial screen-
Any combination/missing 165 (0.5)
............................................................................................................................................................................................................................................ ing tests (Tables 2 and 3).
Ethnicity, n (%)
...................................................................................................................................................................................................................................
Hispanic or Latino 6144 (17.9)
...................................................................................................................................................................................................................................
C OMMENT
Postmenopausal, n (%) 12,743 (37.2)
...................................................................................................................................................................................................................................
The ideal cervical cancer screening strat-
HPV vaccine, n (%) 50 (0.1)
............................................................................................................................................................................................................................................ egy would provide maximum sensitivity
Immunocompromised or 224 (0.7) to minimize missing disease as well as
immunosuppressed, n (%)
............................................................................................................................................................................................................................................ maximum specificity to minimize false
Family history of cervical disease positive results and overreferral. Unfor-
related to cervical cancer, n (%)
................................................................................................................................................................................................................................... tunately, cervical cancer screening strat-
Yes 1920 (5.6) egies that maximize both sensitivity and
...................................................................................................................................................................................................................................
No 31,988 (93.4) specificity have proven elusive because
...................................................................................................................................................................................................................................
Unknown 346 (1.0) strategies that maximize sensitivity have
............................................................................................................................................................................................................................................
typically produced relatively poor speci-
Pap cytology test in past 5 y, n (%) 31,089 (90.8)
............................................................................................................................................................................................................................................ ficity. The development of invasive cer-
ATHENA, Addressing the Need for Advanced HPV Diagnostics; Pap, Papanicolaou. vical cancer is typically a slow process
a
“Any combination/missing” refers to participants who selected more than 1 race or for whom the information was missing.
that takes decades rather than years to
Cox. Cervical cancer screening strategies: evaluation of results from the ATHENA HPV study. Am J Obstet Gynecol
2013. occur.8 This fact reduces the relative
benefits of achieving maximum sensitiv-
ity if poor specificity can lead to potential
types, thereby reducing the number of Figure 4 demonstrates in graphical harm.
cases deferred for identification to 12 form the trade-offs between sensitivity The recent ACS/ASCCP/ASCP cervi-
month follow-up. This produced a gain for CIN3 or more severe and the number cal cancer screening guidelines specifi-
in sensitivity of approximately 14-20% of colposcopies that each strategy would cally acknowledge that the benefits of
when compared with that achieved by produce. Presenting the data in this screening should be balanced against the
strategy 8. Of these 2 strategies, strategy 9 manner delineates 3 groups. One in- potential harms, with the total number
cludes a single strategy, HPV alone, of colposcopies serving as the primary
was more sensitive than strategy 10 for
which was significantly more sensitive measure of harm.2 Colposcopy was cho-
CIN2 or more severe (63.6% vs 57.9%)
than all the other strategies but is also the sen as the measure of harm because it has
and CIN3 or more severe (72.0% vs
least efficient, as measured by the num- been shown to be associated with consid-
66.7%) but slightly less specific (85.2% ber of colposcopies. In contrast, the 5 erable psychological distress, physical
vs 88.0% and 85.7% vs 88.5%, respec- strategies grouped with the lowest sensi- discomfort during the procedure, and
tively, for CIN2 or more severe and CIN3 tivity for CIN3 or more severe (strategies the potential to lead to more invasive
or more severe) because of the lower 1, 2, 3, 7, and 8) required the lowest treatments with short- and long-term
threshold for referral to colposcopy of number of colposcopies overall, with the risks.2 The baseline data from the
ASC-US, as opposed to LSIL. exception of cytology alone (strategy 2). ATHENA study provide us with an ex-

MARCH 2013 American Journal of Obstetrics & Gynecology 184.e6

Research General Gynecology www.AJOG.org

TABLE 2
Clinical outcomes of different strategies for detection of CIN2 or more severe
Colposcopies Cases identified Sensitivity Specificity
Tests to detect 1 CIN2 or more for 12 month relative to False- relative to
Strategy number and performed, Colposcopies CIN2 or more severe cases follow-up Sensitivity, ASC-US positive ASC-US
name n performed, n severe, n identified, n (estimated), n % triage rate, % triage
1 Cytology with reflex 35,546 816 5.7 144 0 51.4 1.00 12.0 1.00
HPV (ASC-US triage)
................................................................................................................................................................................................................................................................................................................................................................................
2 Cytology alone 34,254 1644 11.0 149 0 53.2 1.03 26.6 0.83
................................................................................................................................................................................................................................................................................................................................................................................
3 Cotesting with reflex 68,508 816 5.7 144 109 51.4 1.00 12.0 1.00
for ASC-US
................................................................................................................................................................................................................................................................................................................................................................................
4 Cotesting with 68,508 1202 6.4 189 64 67.5 1.31 18.0 0.93
genotyping and
cytology triage: HPV
16/HPV 18 and ASC-
US HPV-positive
threshold
................................................................................................................................................................................................................................................................................................................................................................................
5 Cotesting with 68,508 1030 6.0 173 80 61.8 1.20 15.2 0.96
genotyping and
cytology triage: HPV
16/HPV 18 and LSIL
threshold
................................................................................................................................................................................................................................................................................................................................................................................
6 HPV alone 34,254 2341 9.7 242 0 86.4 1.68 37.3 0.71
................................................................................................................................................................................................................................................................................................................................................................................
7 HPV with reflex to 37,126 596 4.5 133 109 47.5 0.92 8.2 1.04
cytology
................................................................................................................................................................................................................................................................................................................................................................................
8 HPV with genotyping 34,254 580 4.8 122 120 43.6 0.85 8.1 1.04
................................................................................................................................................................................................................................................................................................................................................................................
9 HPV with genotyping 36,423 982 5.5 178 64 63.6 1.24 14.3 0.97
and reflex cytology:
ASC-US threshold
................................................................................................................................................................................................................................................................................................................................................................................
10 HPV with genotyping 36,423 810 5.0 162 80 57.9 1.13 11.5 1.00
and reflex cytology:
LSIL threshold
................................................................................................................................................................................................................................................................................................................................................................................
ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LSIL, low-grade squamous intraepithelial lesion.
Cox. Cervical cancer screening strategies: evaluation of results from the ATHENA HPV study. Am J Obstet Gynecol 2013.

ceptional opportunity to evaluate both more severe and potential for harm be- CIN3 or more severe with only a modest
the benefit and potential harms that cause it results in 2-3 times more colpos- (less than 2-fold) increase in the required
would be produced during a single copies than the other strategies. Like- number of colposcopies compared with
round of screening using cervical cancer wise, the 5 strategies in the lowest tier the less sensitive strategies. All 4 of the
screening strategies based on various that are the least sensitive for detection of strategies that occupy the middle portion
combinations of cytology, pooled testing CIN3 or more severe would appear to be of the scatterplot use HPV testing with
for 12 high-risk HPV types, and geno- less attractive options for clinicians and genotyping for HPV 16/HPV 18, and 2
typing for HPV 16 and HPV 18. policy makers, despite the fact that all are cotesting strategies. Of these, cotest-
To evaluate trade-offs between sensi- but 1 strategy (cytology alone) offer the ing with genotyping triage (strategy 4)
tivity and potential harms of the differ- least potential for harm by requiring the is the most sensitive strategy but re-
ent screening strategies, we used a scat- lowest number of colposcopies. How- quires the most colposcopies and twice
terplot of each strategy’s sensitivity for ever, the low sensitivity of these strate- the initial tests as the non– cotesting
CIN3 or more severe vs the number of gies for detection of CIN3 or more severe options in this group, strategies 9 and
colposcopies required. The scatterplot at baseline increases the burden of cases 10. HPV with genotyping and cytology
delineates 3 tiers in the balance between that are missed at baseline and that bur- triage with LSIL (strategy 10) requires
sensitivity for CIN3 or more severe, or den would depend on potential identifi- the fewest colposcopies and therefore
benefit of each screening strategy, and cation for those strategies that have 12 would be most applicable in settings in
the number of colposcopies, a measure month follow-up. which potential harm from colposcopy
of potential harm. The most attractive strategies from the is of greater concern than benefit.
The most sensitive strategy, HPV perspective of a benefit-vs-harm analysis The 2 strategies within this tier that
alone with referral of all HPV-positive appear to be the 4 strategies occupying seem to optimize the balance between
women to colposcopy (strategy 6), does the middle portion of the scatterplot. sensitivity and specificity are cotesting
not appear to offer the right balance be- These strategies all combine what we with genotyping and cytology triage with
tween maximum detection of CIN3 or consider to be a reasonable sensitivity for LSIL (strategy 5) and HPV with genotyp-

184.e7 American Journal of Obstetrics & Gynecology MARCH 2013

www.AJOG.org General Gynecology Research

TABLE 3
Clinical outcomes of different strategies for the detection of CIN3 or more severe
Colposcopies Cases identified Sensitivity Specificity
Tests to detect 1 CIN3 or more for 12 month relative to False- relative to
Strategy number and performed, Colposcopies CIN3 or more severe cases follow-up Sensitivity, ASC-US positive ASC-US
name n performed, n severe, n identified, n (estimated), n % triage rate, % triage
1 Cytology with reflex 35,546 816 7.7 106 0 56.1 1.00 12.4 1.00
HPV (ASC-US
triage)
................................................................................................................................................................................................................................................................................................................................................................................
2 Cytology alone 34,254 1644 15.1 109 0 57.7 1.03 26.8 0.84
................................................................................................................................................................................................................................................................................................................................................................................
3 Cotesting with 68,508 816 7.7 106 72 56.1 1.00 12.4 1.00
reflex for ASC-US
................................................................................................................................................................................................................................................................................................................................................................................
4 Cotesting with 68,508 1202 8.3 144 34 76.2 1.36 18.5 0.93
genotyping and
cytology triage: HPV
16/HPV 18 and
ASC-US HPV-
positive threshold
................................................................................................................................................................................................................................................................................................................................................................................
5 Cotesting with 68,508 1030 7.7 134 44 70.9 1.26 15.7 0.96
genotyping and
cytology triage: HPV
16/HPV 18 and LSIL
threshold
................................................................................................................................................................................................................................................................................................................................................................................
6 HPV alone 34,254 2341 13.8 170 0 89.9 1.60 38.0 0.71
................................................................................................................................................................................................................................................................................................................................................................................
7 HPV with reflex to 37,126 596 6.1 98 72 51.9 0.92 8.7 1.04
cytology
................................................................................................................................................................................................................................................................................................................................................................................
8 HPV with 34,254 580 5.7 101 69 53.4 0.95 8.4 1.05
genotyping
................................................................................................................................................................................................................................................................................................................................................................................
9 HPV with 36,423 982 7.2 136 34 72.0 1.28 14.8 0.97
genotyping and
reflex cytology:
ASC-US threshold
................................................................................................................................................................................................................................................................................................................................................................................
10 HPV with 36,423 810 6.4 126 44 66.7 1.19 12.0 1.01
genotyping and
reflex cytology:
LSIL threshold
................................................................................................................................................................................................................................................................................................................................................................................
ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LSIL, low-grade squamous intraepithelial lesion.
Cox. Cervical cancer screening strategies: evaluation of results from the ATHENA HPV study. Am J Obstet Gynecol 2013.

ing and cytology triage with ASC-US at enrollment by a given screening test with cytology alone almost doubling the
(strategy 9). The latter strategy results in would be detected on subsequent screen- number of required colposcopies.
a 50% reduction in the number of re- ing or follow-up. Multiple cost-effectiveness analyses
quired screening tests and is also slightly In a setting in which it would be consid- and metaanalyses have previously docu-
more sensitive and requires slightly ered unethical to follow up women with mented the attractiveness of cytology
fewer colposcopies to detect 1 CIN3 or known CIN3 or more severe lesions, a ran- with triage of ASC-US by HPV over a
more severe case. domized trial in which women are as- strategy of cytology with referral of all
An obvious limitation of this analysis signed to each of the different screening women with abnormal cytology results
is that it uses only the baseline data from strategies would be required to determine
to colposcopy.9-12 Likewise, the group of
the ATHENA trial and does not include exactly how subsequent rounds of fol-
screening strategies that appear to be the
the results of those women identified as low-up or screening would perform. We
most attractive after comparing benefits
needing 12 month follow-up. Because therefore consider it reassuring that our
the design of the ATHENA study re- approach of comparing benefits and and harms includes the strategy recently
ferred all women with abnormal screen- harms of different screening strategies ar- classified by the ACS as the preferred
ing test results at enrollment for colpos- rived at many of the same conclusions as strategy when screening women aged 30
copy, many women with CIN2 or more have analyses incorporating multiple years or older (cotesting).2
severe lesions missed by a given screen- rounds of screening and mathematical However, of the 2 cotesting strategies
ing test were identified by the other modeling studies. For example, in this recommended by the ACS/ASCCP/ASCP,
screening test, and their CIN2 or more analysis, a strategy of cytology with HPV cotesting with genotyping triage (strategy
severe lesions were treated. Therefore, it triage of ASC-US (strategy 1) is clearly su- 4) detects 26.4% more CIN3 or more se-
is impossible to know what percentage of perior to cytology alone (strategy 2) be- vere than cotesting with 12 month fol-
the CIN2 or more severe lesions missed cause both have similar sensitivities but low-up of all cytology-negative/HPV-posi-

MARCH 2013 American Journal of Obstetrics & Gynecology 184.e8

Research General Gynecology www.AJOG.org

FIGURE 4
Sensitivity for CIN3 or more severe and number of colposcopies
Primary Screening Strategies For CIN3+ Endpoint

100.0

90.0 Strategy 6

80.0
Strategy 4
Strategy 9
70.0 Strategy 5
Strategy 10

60.0
Sensitivity (%)

Strategy 2
Strategy 1 or 3
Strategy 8
Strategy 7
50.0

40.0 Colposcopies, Initial tests

Strategy n Sensitivity, % performed, n
Strategy 1 816 56.1 35,546
30.0 Strategy 2 Cytology alone 1644 57.7 34,254
Strategy 3 816 56.1 68,508
Strategy 4 1202 76.2 68,508
20.0 Strategy 5 Cotesting with genotyping and cytology triage: HPV 16/18 and LSIL threshold 1030 70.9 68,508
Strategy 6 HPV alone 2341 89.9 34,254
Strategy 7 HPV with cytology triage 596 51.9 37,126
10.0 Strategy 8 HPV with genotyping triage 580 53.4 34,254
Strategy 9 HPV with genotyping and reflex cytology: ASC-US threshold 982 72.0 36,423
Strategy 10 HPV with genotyping and cytology (LSIL cut-off) triage 810 66.7 36,423
0.0
0 500 1000 1500 2000 2500

Number of Colposcopies
Scatterplot of sensitivity for CIN3 or more severe and number of colposcopies for each screening strategy. Clear outliers as measured by numbers of
colposcopies are in red. Strategies with the lowest sensitivity but also the lowest number of initial colposcopies are in black and those with intermediate
sensitivity and number of colposcopies are in blue. Strategies that are presently recommended in the American Society for Colposcopy and Cervical
Pathology guidelines are in bold.
ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LSIL, low-grade squamous intraepithelial lesion.
Cox. Cervical cancer screening strategies: evaluation of results from the ATHENA HPV study. Am J Obstet Gynecol 2013.

tive women (strategy 3) but requires
nearly 50% more colposcopies at the ini-
tial round of screening. Although this
would appear to significantly increase
potential harm when compared with
cotesting without genotyping, this op-
tion obviates the need for repeat cotest-
ing in 12 months for women positive for
HPV 16/18 and reduces the risk of de-
layed diagnosis and or loss to follow-up
of women with significant disease.13,14
Moreover, approximately half of the
women who are followed up and un-
dergo cotesting 12 months later will re-
quire colposcopy because of persistent
high-risk HPV infections.15
Previous studies have shown other
screening strategies to be effective.14,16-21
Analysis of data from a Finnish screening
trial demonstrated that triage of HPV-
positive women by cytology (strategy 7),
as in the ATHENA trial, was more spe-
cific than conventional cytology screen-
ing and decreased colposcopy referrals
but, in contrast to our results, was also
more sensitive.17 Naucler et al18 evaluated
11 screening strategies using data from a
Swedish screening trial and found that
HPV with cytology triage and repeat HPV
testing at 1 year of cytology-negative/
HPV-positive women was the most feasi-
ble of the screening strategies. Similarly, a
large population-based screening trial in
The Netherlands (VUSA-Screen Study)
also found HPV with cytology triage and 1
year follow-up by repeat cytology of HPV-

184.e9 American Journal of Obstetrics & Gynecology MARCH 2013

www.AJOG.org
positive women to be a feasible alternative
to cytology screening.14
It is difficult to compare these analyses
with ours because they are based on 1-5
year follow-up data, and each of these
studies had quite different study designs
compared with ATHENA. Moreover,
neither the Finnish nor The Netherlands
trials evaluated strategies that included
HPV 16/HPV 18 genotyping. It should be
stressed, however, that the ATHENA base-
line data do not support a conclusion that
HPV with cytology triage is competitive
with any of the HPV 16/HPV 18 genotyp-
ing strategies that include cytology, unless
an absolute reduction in baseline colpos-
copies is the primary goal. In addition, an-
other recent report from a large screening
population in The Netherlands (Popula-
tion-Based Screening Study Amsterdam
[POBASCAM]) has documented that
early detection of CIN3 or more severe as-
sociated with HPV 16 was a major compo-
nent of the benefit of testing for HPV.19
Other more complex HPV genotype–
based approaches may further improve
upon these strategies. In particular, sev-
eral studies, including ATHENA, have
shown that HPV 16 has a much higher
baseline positive predictive value (PPV)
than the other high-risk types and that,
at least cross-sectionally, HPV 18 has a
similar PPV to the pool of 12 other high-
risk types.4,5,7 This raises the question as
to whether HPV 18 –positive women
would be more efficiently managed by
short-term (6-12 months) repeat testing
for HPV 18 to establish persistence be-
fore referral to colposcopy, similar to the
management of women positive for one
of the other 12 high-risk HPV types.
However, HPV 18 is associated more
with cancer than these other types22 and
also is associated with endocervical le-
sions that are difficult to detect.
In ATHENA, 3 of the 6 cancers de-
tected at baseline were HPV 18 positive,
as were 8 of the 16 adenocarcinoma in
situ cases and 1 cancer detected in fol-
low-up.6 So although the PPV for CIN3
or more severe of a positive HPV 18 test
at baseline is lower than typically recom-
mended for immediate colposcopy, the
greater severity of the disease burden
substantiates this approach. Other ques-
tions related to the behavior of different
General Gynecology
HPV types also need to be addressed,
such as whether HPV 45, which shows a
similar predilection for adenocarcinoma
as HPV 18, should be managed in the
same way as HPV 18.
The strategies with 12 month follow-up
for women at intermediate risk will in-
crease both the ultimate sensitivity of each
of these strategies as well as the total num-
ber of colposcopies and must also take into
account loss to follow-up. Hence, any
strategy selected should consider the trade-
offs of sensitivity and specificity in the con-
text of real-world clinical practice. As illus-
trated by Kitchener et al,23 poor follow-up
of HPV-positive women not sent immedi-
ately to colposcopy could negate some of
the benefits of HPV testing to identify
women at risk for CIN2 or more severe
while leaving unaffected the added safety
of a negative HPV test. Within the context
of poor follow-up of screen-positive pa-
tients, more sensitive methods of manag-
ing HPV-positive women may be pre-
ferred over methods with increased
specificity and PPV, so that the opportu-
nity for immediate detection and treat-
ment of precancerous lesions will not be
missed.
In conclusion, this analysis demon-
strates that multiple cervical cancer
screening strategies are more effective
than the present standard of cytology
screening with ASC-US triage. Strategies
that maximize early detection of CIN3 or
more severe without excessive increases
in initial screening tests and colposco-
pies, yet also identify women at interme-
diate risk in need of 12 month follow-up,
would appear to provide optimal bal-
ance between benefit and harms. Of
these options, strategies that incorporate
initial screening with HPV and triage of
HPV-positive women by a combination
of genotyping for HPV 16/HPV 18 and
cytology may best fulfill these require-
ments for more balanced screening, al-
though other options may also be com-
pelling in different settings. When the 3
year follow-up data from ATHENA be-
come available, formal cost-effectiveness
modeling can be performed to better de-
termine the benefits of cervical cancer
screening strategies that incorporate
HPV with genotyping for HPV 16/HPV
18 and cytology. f GA; Fellows Research Alliance, Hilton Head,
MARCH 2013 American Journal of Obstetrics & Gynecology
Research
ACKNOWLEDGMENTS
We thank Teresa Wright, MD, for her valuable
contributions to the design and execution of the
ATHENA HPV Study and for assistance in the
analysis of data. The ATHENA study testing
sites and participants include the following:
United States, Comprehensive Clinical Trials,
West Palm Beach, FL; Green Clinic, Ruston,
LA; Philadelphia Clinical Research, Philadel-
phia, PA; Visions Clinical Research, Boynton
Beach, FL; Women’s Health Specialist, Costa
Mesa, CA; Mount Vernon Clinical Research, At-
lanta, GA; Tennessee Women’s Care, Nash-
ville, TN; Chattanooga Medical Research, Chat-
tanooga, TN; OB/GYN Specialists of the Palm
Beaches, West Palm Beach, FL; Segal Institute
for Clinical Research, North Miami, FL; South
Carolina Clinical Research Center, Columbia,
SC; Bluegrass Clinical Research, Louisville, KY;
Delaware Valley OB-GYN and Infertility Group,
Plainsboro, NJ; Advanced Research Associ-
ates, Corpus Christi, TX; Advanced Clinical
Concepts, West Reading, PA; Miami Research
Associates, Miami, FL; Center for Women’s
Health of Lansdale, Lansdale, PA; Blue Skies
Center for Women, Colorado Springs, CO; Vi-
sions Clinical Research, Tucson, AZ; Impact
Clinical Trials, Las Vegas, NV; Physicians’ Re-
search Options, Lakewood, CO; Four Rivers
Clinical Research, Paducah, KY; Medical Net-
work for Education and Research, Decatur, GA;
Women’s Health Research, Phoenix, AZ; Im-
pact Clinical Trials, Los Angeles, CA; HWC
Women’s Research Center, Englewood, OH;
Texas Medical Center, Houston, TX; Mobile
OB/GYN, Mobile, AL; Altus Research, Lake
Worth, FL; Tacoma Women’s Specialist, Ta-
coma, WA; Phoenix OB-GYN Association,
Moorestown, NJ; The Woman’s Clinic, Boise,
ID; Impact Clinical Trials, Los Angeles, CA;
eCast Corp, North Charleston, SC; State of
Franklin Healthcare Associates Research,
Johnson City, TN; Quality of Life Medical and
Research Center, Tucson, AZ; Eastern Carolina
Women’s Center, New Bern, NC; Tidewater
Clinical Research, Virginia Beach, VA; St John’s
Center for Clinical Research, Jacksonville, FL,
R. Myers; M and O Clinical Research, Ft. Lau-
derdale, FL; Lyndhurst Gynecologic Associ-
ates, PA, Winston-Salem, NC; Enterprise
Women’s Center, Enterprise, AL; Salt Lake Re-
search, Salt Lake City, UT; Women’s Health
Care at Frost Street, San Diego, CA; Atlanta
North Gynecology Center for Research, Ro-
swell, GA; Women’s Clinical Research, New-
burgh, IN; Jacksonville Center for Clinical Re-
search, Jacksonville, FL; Women’s OB-GYN,
Saginaw, MI; Clinical Research Consultants,
Hoover, AL; Edinger Medical Group Research
Center, Fountain Valley, CA; Health Awareness,
Jupiter, FL; Physician Care Clinical Research,
Sarasota, FL; Woman’s Health Practice, Cham-
paign, IL; Clinical Trials Management, Coving-
ton, LA; Advanced Research Associates, Dal-
las, TX; Fellows Research Alliance, Savannah,
184.e10
Research General Gynecology
SC; Women’s Care Florida, Tampa, FL; Ad-
vanced Research Associates, McAllen, TX; Pre-
cision Trials, Phoenix, AZ; and Yassear Clinical
Research, Carmichael, CA.
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