J Med Screen OnlineFirst, published on October 14, 2015 as doi:10.

1177/0969141315604863

Original Article

Evaluation of The Cervista HPV A9 group

In Screening Patients for Cervical Cancer

J Med Screen
0(0) 16
! The Author(s) 2015
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DOI: 10.1177/0969141315604863
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Jinghui Zhao1, Hui Du1,2, Jerome L Belinson3, Xinfeng Qu3,

Wei Zhang1,2, Jing Mei1, Bin Yang4, Chun Wang1,2, Lijie Zhang1,2 and
Ruifang Wu1,2

Abstract
Objective: To exploit the prevalence of HPV genotypes 52/58 in a Chinese population, we evaluated algorithms that the use
the Cervista Assay A9 group for primary cervical cancer screening.
Methods: The SHENCCAST II trial database was re-analyzed, focussing on the A9 pool of the Cervista HR-HPV Assay. Results
for the detection CIN2 and CIN3 were correlated with a genotyping assay (MALDI-TOF) and cervical cytology to explore
various screening algorithms.
Results: This analysis included 8,556 women with a mean age of 38.9. CIN 2 rates were 2.7% (233/8556); CIN 3 rates were
1.7% (141/8556). Overall HPV infection rates were 11.1% (950/8556) for Cervista, in which A5/A6, A7 and A9 groups were
26.5% (227/950), 22.9% (218/950) and 67.8% (644/950), respectively. The HPV A9 group is highly predictive of high-grade
cervical lesions (CIN2 OR 103.61, CIN3 OR 128.059). Sensitivity and specificity for Cervista A9 group for CIN 2 was
85.4% and 94.7%, and for CIN 3 89.4% and 93.8% respectively. Cervista A9 Assay followed by triage cytology for non-A9
positives has sensitivity and specificity for CIN2 of 91.5% of 93.5%, and for CIN 3 94.3% and 92.6%.
Conclusion: Using the Cervista A9 as the primary screen instead of the full Cervista assay, the percentage referred to
colposcopy would decrease from 11.1% to 8.8% and percentage requiring cytology would decrease from 11.1% to 3.6%.
Sensitivity of detecting CIN 2(91.5%), CIN3(94.3%) would remain similar to the complete Cervista HR-HPV assay for
CIN 2(93.1%), CIN3(95.0%).
Keywords
Cervista, Human Papillomavirus (HPV), HPV A9 group, Cervical Cancer
Date received: 30 January 2015; accepted: 18 August 2015

Introduction
It is well accepted that testing women for the presence of
high-risk types of the human papillomavirus (HPV) is the
most sensitive primary screening method for the detection
and prevention of cervical cancer.1,2 As the majority of
women testing positive will have non-neoplastic HPV
infections that will spontaneously resolve or not progress,
the search for assays with higher specicity to use in a
triage role, or possibly even for primary screening is an
important objective in contemporary HPV research.3
Potential secondary biomarkers include HPV genotyping
(for HPV16 or HPV16/18)4,5, HPV mRNA testing6, and/
or detection of other non-HPV biomarkers (eg.
p16INK4A).7 All have aimed to improve specicity, but
population based data regarding the test performance of
these biomarkers are limited.
From April 2009 to April 2010 we conducted the
Shenzhen Cervical Cancer Screening Trial II
(SHENCCAST II) in Shenzhen, China and surrounding
rural communities.8 Among the various new technologies
studied in this population based screening trial, we tested

the now Food and Drug Administration (FDA) approved

Cervista High-Risk HPV Assay (Hologic Inc., Bedford,
Mass, USA) and the polymerase chain reaction
(PCR)-based MassARRAY (Sequenom, San Diego, CA)
matrix-assisted laser desorption/ionization time-of-ight
mass spectrometry system (MALDI-TOF).9 This trial of
10,000-paired specimens demonstrated a non-signicant
dierence to detect CIN3 between the new Cervista
assay and HC2 (Hybrid Capture II, Qiagen, USA).
These results were conrmed by others.10,11 We also
demonstrated at the established cut-points for the two
1

Peking University Shenzhen Hospital, Shenzhen, PR China

Shenzhen Key Laboratory on Technology for Early Diagnosis of Major
Gynecological diseases, Shenzhen, PR China
3
Preventive Oncology International, Inc. Cleveland Heights, USA and
Cleveland Clinic, Womens Health Institute, Cleveland, USA
4
Cleveland Clinic, Department of Anatomic Pathology, Cleveland, USA
2

Corresponding author:
Dr Ruifang Wu, Shenzhen, PR China.
Email: wurf100@126.com

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Journal of Medical Screening 0(0)

assays a signicant dierence (favouring Cervista) in specicity.12 We believed at that time that the Cervista assay
had some characteristics that could be exploited, which
could result in a decrease in the number of women referred
for positive management. We hypothesized that as HPV
types 52/58 are highly prevalent in a Chinese population,
a more targeted screening protocol using the Cervista
Assay A9 pool might result in a more ecient screening
model for cervical cancer in China. To test this hypothesis
we re-analyzed the SHENCCAST II data.

Methods
The study population consisted of the 8,556 women (of
10,000 enrolled) from SHENCCAST II who had all prescribed screening and diagnostic procedures, and had complete data.8 This project and all associated studies have
been approved by the human subject review boards of
the Cleveland Clinic (CCF, 08-457, 7/11/2008) and the
Peking University Shenzhen Hospital (2/10/2009). The
protocol, previously detailed8, referred women for colposcopy based on three direct (physician obtained) HPV
assays, two self-collected HPV assays, and cytology. All
patients seen for colposcopy had a minimum of ve cervical
biopsies, as per the Preventive Oncology International
micro-biopsy protocol of directed and random biopsies.13
All histology slides were interpreted by a gynaecologic
pathologist from Peking University Shenzhen Hospital as
Normal, CIN 1, CIN 2, CIN 3, AIS, or cancer, with
review by a pathologist from the Cleveland Clinic
(Author BY).
The Cervista assay uses proprietary Invader technology
(Hologic, Inc., Madison, WI), a signal amplication
method for the detection of specic nucleic acid
sequences.14 Based on the correlation among 14 types of
high-risk HPV DNA gene sequences, three dierent oligonucleotide mixtures, A5/A6, A7 and A9, are designed for
the assay to test the 14 HPV DNA types in groups. An
A5/A6 oligonucleotide probe mixture (Oligo Mixes) is
used for detecting HPV types 51, 56 and 66 (the A5/A6
group of HPV), an A7 oligonucleotide probe mixture is
used for HPV types 18, 39, 45, 59 and 68 (the A7 group of
HPV), and an A9 oligonucleotide mixture is used for HPV
types of 16, 31, 33, 52 and 58 (the A9 group of HPV). The
Cervista assay and Cervista HPV 16/18 genotyping test
(Hologic, Inc.; Marlborough, MA) were approved by
the US FDA and recommended for clinical use in published guidelines.15
The PCR-based MALDI-TOF genotyping assay is a
mass spectrometry method that uses a multiplex primary
PCR.16 MALDI-TOF can accurately identify 14 HR
HPVs, including HPV types 16, 18, 31, 33, 35, 39, 45,
51, 52, 56, 58, 59, 66, and 68, which include the Cervista
A9 group. Neither the Cervista HPV assay using the A9
group or the MALDI-TOF assay have received approval
by the SFDA (in China) or the FDA in the USA.
The performance characteristics of the screening tests
were evaluated by calculating the sensitivity and specicity

for detecting high-grade lesions (CIN 2 and CIN 3) as

the endpoint. McNemars test was used to compare the
sensitivities and specicities of the tests, and P-values of
less than 0.05 were considered signicant. The expected
values and 95% condence intervals for sensitivity, specicity were calculated. The percentages of the study population referred for colposcopy or cytology were calculated
based on the number of HR-HPV of positive or cytology
of 5ASC-US in the screening population. All condence
intervals are exact binomial condence intervals. Data
analyses were performed using STATA 10.1 (StataCorp
LP, College Station, Tx).
Specically for this analysis we used the data for
Cervista HPV and MALDI-TOF on the direct samples
of the study population, to evaluate the subsets of the
Cervista HPV assay for positive triage. We analyzed the
sensitivity and specicity of each of the Cervista HPV
groups for the detection of CIN 2 and CIN 3. In addition we compared the sensitivity and specicity with
MALDI-TOF by using a MALDI-TOF A9 Group plus
HPV 18 (MALDI-TOF A9 18) and MALDI-TOF A9
Group minus 52/58 (MALDI-TOF A9 -52/58).

Results
The mean age of the 8,556 women was 38.9 years.
Cytological abnormalities of 5ASCUS were found in
12.1% (1031/8556), 5LGSIL in 4.8% (413/8556) and
5HGSIL in 1.4% (120/8556) of the study population.
Pathology results show that CIN 2 and CIN 3
were found in 2.7% (233/8556) and 1.7% (141/8556)
respectively.
The HPV positive rate for endocervical (direct) specimens was 11.1% (950/8556) for the Cervista assay.
Among the Cervista HPV positives, the A5/A6, A7 and
A9 groups represented 23.89% (227/950), 22.95% (218/
950) and 67.79% (644/950), respectively.
Table 1 shows the correlation between Cervista HPV
groups and histology CIN 2 or CIN 3. The CIN 2
odds ratio values of the positive results of the A5/A6, A7,
A9 groups were 2.84, 8.17, and 103.62, respectively. The
CIN 3 odds ratio values of the positive results of the A5/
A6, A7, A9 groups were 3.212, 7.30, and 128.059, respectively. The results show that HPV A9 group is highly
related to these cervical lesions (CIN 2 or CIN 3)
compared with A5/A6, A7 groups (p < . 001)
Table 2 shows that the sensitivity and specicity for
CIN 2 were 6.9% (3.6,10.2) and 97.5% (97.2,97.8)
for group A5/A6, 15.5% (10.9,20.1), 97.8% (97.5,98.1)
for group A7, and 85.4% (80.9,89.9), 94.7% (94.2,95.2)
for group A9, respectively. The sensitivity for CIN 2 for
groups A5/A6 or A7 of HPV was signicantly lower than
group A9 (p 0.000), the sensitivity for CIN 2 for group
A5/A6 (6.9%) was also lower compared with group A7
(16.5%) (p 0.004), and specicity for CIN 2 for
group A5/A6 (97.5%) was similar to group A7 (97.8%)
(p 0.121) and higher than group A9 (94.7%) (p < .001).
The sensitivity and specicity for CIN3 were 7.8% (4.2,

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Zhao et al.

Table 1. Odds ratios of Cervista HPVA5/A6, A7 and A9 group for CIN 2/ CIN 3 (risk estimate).
OR

P value

HPV group

N (%)

CIN 2

CIN 3

CIN 2

CIN 3

A5/A6
A7
A9

227 (23.89)
218 (22.74)
644 (67.79)

2.84(1.68-4.80)
8.17(5.57-12.01)
103.62(71.14-150.92)

3.21(1.71-6.03)
7.30(4.50-11.85)
128.06(74.43-220.34)

<0.001
<0.001


<0.001
<0.001


HPV A9 group shows the highest risk factor for high-grade cervical lesions based on the odds ratio value, McNemars less than 0.05 for the comparison of odds
ratio for Cervista HPVA5/A6 vs. A9, and A7 vs. A9.

Table 2. The sensitivity, specificity of three Cervista HPV groups for CIN 2/ CIN 3.
Sensitivity%

Specificity%

McNemar P

HPV group

CIN 2

CIN 3

CIN 2

CIN 3

CIN 2

CIN 3

A5/6

6.9
(3.6,10.2)
15.5
(10.9,20.1)
85.4
(80.9,89.9)

7.8
(4.2, 13.9)
14.9
(9.7, 22.1)
89.4
(82.8, 93.7)

97.5
(97.2,97.8)
97.8
(97.5,98.1)
94.7
(94.2,95.2)

97.4
(97.1, 97.8)
97.7
(97.3, 98.0)
93.8
(93.3, 94.3)

<0.001

<0.001

<0.001

<0.001

A7
A9

McNemars less than 0.05 for the both comparison of sensitivity and specificity for Cervista HPVA5/A6 vs. A9, and A7 vs. A9 for CIN 2/CIN 3.

13.9) and 97.4% (97.1, 97.8) for group A5/A6, 14.9% (9.7,
22.1) and 97.7% (97.3, 98.0) for group A7, and 89.4%
(82.8, 93.7) and 93.8% (93.3, 94.3) for group A9, respectively. The sensitivity for CIN 3 for groups A5/A6 or A7
of HPV was lower than group A9 (p 0.000), the specicity for CIN 3 for group A5/A6 (97.4%) was similar to
group A7 (97.7%) (p 0.518), and higher than group A9
(93.8%) (p < .001).
In table 3, we show the results of cytology, Cervista
HPV, Cervista A9, Cervista A9 followed cytology,
MALDI-TOF A918 and MALDI-TOF A9 minus
52/58 related to disease endpoints (CIN2/CIN3). The
sensitivity and specicity for CIN2 were respectively
93.1% (89.8,96.4) and 91.2% (90.6,91.8) for Cervista
HPV, 85.4% (80.9,89.9) and 94.7% (94.2,95.2) for
Cervista A9, and 91.5% (87.92,95.08) and 93.5%
(92.97,94.03) for Cervista A9 followed cytology. Those
for Cytology 5ASCUS were 83.7% (79.0,88.4) and
90.0% (89.4,90.6), for MALDI-TOF A9 type 18
88.4% (84.3,92.5) and 93.5(93.0,94.0), and for MALDITOF A9 minus types 52/58 53.2% (46.8,59.6) and 97.5%
(97.2,97.8) respectively. The sensitivity and specicity for
CIN3 were respectively 95.0 % (91.4, 98.6) and 90.3%
(89.7, 90.9) for Cervista HPV, 89.4% (84.3, 94.5) and
93.8% (93.3, 94.3) for Cervista A9, and 94.3%
(90.5,98.1) and 92.6% (92.0,93.2) for Cervista A9 followed
cytology. Those for Cytology 5ASCUS were 88.7%
(83.5,93.9) and 89.2% (88.5,89.9), for MALDI-TOF
A9 type 18 91.5% (86.9,96.1) and 95.7(95.3,96.1), and
for MALDI-TOF A9 minus types 52/58 64.5% (56.6,72.4)
and 97.2% (96.8,97.6) respectively. Using McNemars less
than 0.05 as the point for the comparison, there is no

dierence between Cervista A9 and cytology in sensitivity

(2 0.102, p 0.089), but they dier signicantly in specicity (2 17.23, p 0.000). Sensitivity (2 1.607,
p 0.205) of MALDI-TOF A918 for CIN3 is statistically similar to that of Cervista A9, but the specicity
(2 13.781, p 0.000) is signicantly lower.
According to the above results, the following algorithm
is proposed: If the woman tests positive for the Cervista
group A9 in her primary screen she is directly called back
for colposcopy. If the woman tests negative for A9 but
positive in groups A5/A6 and/or A7 she is triaged by
cytology and then referred for colposcopy if the cytology
5ASCUS. This algorithm produces a sensitivity for the
diagnosis of CIN2 of 91.5%, CIN3 of 91.5%, and a
specicity of 93.5%, 92.6%. The percentage of women
referred to colposcopy would decrease from 11.1% to
8.8%, the percentage requiring cytology would decrease
from 11.1% to 3.6%, and the sensitivity of detecting CIN
2 (91.5%), CIN3 (94.3%) would be similar to the full
Cervista assay for CIN 2 (93.1%), CIN3 (95.0%).

Discussion
Cervical cancer precursors can be eectively detected and
cancer prevented through screening with an HPV test and
cytological examination of the cervix.17 The false negative
rate of an HPV test for high-grade lesions will be less than
5%, with a negative predictive value over 99%.18 However
80-90% of these HPV infections are transient and disappear
without inducing cervical cancer precursors, and therefore
require no treatment.3 As a result, using an HPV test for
primary screening creates a large number of HPV-positives

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Journal of Medical Screening 0(0)

Table 3. The positive rates of cytology, Cervista, Cervista A9, Cervista A9 followed by cytology, MALDI-TOF A9 type 18, MALDI-TOF A9
minus 52/58 and their sensitivity and specificity for CIN 2/ CIN 3.

Screening test

Histology
N (%*)

Cytology
N (%)

Cytology

1031/8556
(12.1%)

8556/8556
(100%)

Cervista positive

950/8556
(11.1%)

950/8556
(11.1%)

Cervista A9 positive

644/8556
(7.5%)

644/8556
(7.5%)

CervistaA9
followed by cytology ***

756/8556
(8.8%)

306/8556
(3.6%)

MALDI-TOF A918 positive

750/8556
(8.8%)

750/8556
(8.8%)

MALDI-TOF A9-52/58

330/8556
(3.9%)

330/8556
(3.9%)

Sensitivity
N (95%CI)

Specificity
N (95%CI)

CIN 2

CIN 3

CIN 2

CIN 3

195/233
83.7%
(79.0, 88.4)
217/233
93.1%
(89.8,96.4)
199/233
85.4%
(80.9,89.9)
213/233
91.5%
(87.92,95.08)
206/233
88.4%
(84.3,92.5)
124/233
53.2%
(46.8,59.6)

125/141
88.7 %
(83.5, 93.9)
134/141
95.0 %
(91.4,98.6)
126/141
89.4%
(84.3,94.5)
133/141
94.3%
(90.5,98.1)
129/141
91.5%
(86.9,96.1)
91/141
64.5%
(56.6,72.4)

7487/8323
90.0%
(89.4, 90.6)
7590/8323
91.2%
(90.6,91.8)
7878/8323
94.7%
(94.2,95.2)
7780/8323
93.5%
(92.97,94.03)
7779/8323
93.5
(93.0,94.0)
8117/8323
97.5%
(97.2,97.8)

7509/8415
89.2 %
(88.5, 89.9)
7599/8415
90.3%
(89.7,90.9)
7897/8415
93.8%
(93.3,94.3)
7792/8415
92.6%
(92.0,93.2)
7794/8145
95.7
(95.3,96.1)
8176/8415
97.2%
(96.8,97.6)

*Rate of return for colposcopy by screening test.

***CervistaA9 followed by cytology: If CervistaA9 positive, refer to colposcopy; if CervistaA9 negative and other subtypes HR-HPV positive, underwent
cytology, only Cyto 5ASCUS, refer to colposcopy.

and a huge burden for the medical system to evaluate those

women who, ultimately, need no intervention.
Management of the high-risk HPV infected woman has
become a major issue of common concern. Many studies
now show that HPV genotyping can serve as an indicator of
risk, and thereby be used for the triage of patients who test
high-risk HPV positive. With some geographic variation in
genotype distribution, the geographically important types
can guide the triage for specic regions of the world.1925
Our data from SHENCCAST II show the prevalence of
the HR-HPV genotypes in the general population of
Shenzhen, China and its surrounding communities as
HPV 52(21.3%) followed by HPV 16(13.4%), HPV
58(12.1%), HPV33 (7.1%), HPV39 (6.8%), HPV51
(6.7%), HPV45 (4.9%), HPV66 (4.8%), HPV31 (4.6%),
and HPV18 (4.1%).26 Furthermore, in our Chinese population, types 16, 58, 18, 31, 33, and 52 had the highest risk
of predicting CIN 2 and CIN3, and the sensitivity
decreased to 53.2% (46.8,59.6) for a diagnosis CIN 2
and 64.5% (56.6,72.4) CIN3 by using the genotyping
assay MALDI-TOF for the A9 types minus 52/58 compared with Cervista A9 positive, 85.4% (80.9,89.9) for
diagnosis CIN 2 and 89.4% (84.3,94.5) CIN3.
Applying MALDI-TOF A9 18 as a triage had less
impact on increasing the sensitivity and specicity for
both CIN 2 and CIN 3 lesions our population
compared with Cervista A9, conrming that for Chinese
women HPV 18 is less important, and HPV52/58 is relatively more important.

These data are similar to the study reported by Zhao et al,

where 1,064 eligible women participating in routine cervical
cancer screening in three hospitals in Beijing, China, were
enrolled in a multi-centre clinical trial.27 The sensitivity of
Cervista HPV HR for CIN 2 in this study population was
98.48%; the clinical sensitivity and specicity of just the
group A9 were 87.97% and 78.3% respectively. The odds
ratio of a positive result with group A5/A6, A7 and A9 was
1.611(0.976, 2.660), 1.819 (1.107,2.988), and 26.390
(15.300,45.520) respectively. Their data provide further evidence that the Cervista group A9 plus cytology triage for the
non-A9 HPV positives is a reasonable screening protocol.
The Cervista group A9 can be used for the triage of a highrisk positive group directly to colposcopy after primary
screening with Cervista HPV.
Identifying the infections most likely to be associated
with high-grade disease or cancer can help to reduce the
high-risk population and make a rational triage of clinically
HPV infected women. Hopefully, new screening and triage
algorithms can reduce the overall economic burden to a
healthcare system, by reducing the number of women
requiring referral for colposcopy. Our analysis shows that
by combining positive Cervista A9 primary screening and
referral, with negative A9, positive A5/A6 and/or A7 cytology triage, some key programmatic advantages are realized. These include: 1) maintaining the desired high
sensitivity and specicity, 2) reducing the number of
women referred for colposcopy, and 3) reducing the
number requiring cytology. This algorithm seems

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Zhao et al.

particularly suited for a Chinese population. This will

clearly have an impact on the healthcare system, by reducing the workload, and hopefully these advantages will also
be realized in the form of decreased costs for the patients.
The strength of our study is that it is from a widely published and well-validated database, with minimal verication bias.
A proper cost analysis of this proposed algorithm is
planned for the future.
Conflict of interest
None of the funding organizations made decisions concerning
the data analysis, the content of this manuscript, or the decision
to publish this report.

Support
This investigator initiated study was funded by Shenzhen
Technical Innovation Committer under the Foundation
Medicine Research Projects: A Study on Function and
Functional Adjustments of the Carcinogens related to
Canceration from HPV Infection to Cervical Cancer,
Preventive Oncology International Inc. (Cleveland
Heights, Ohio), Hologic Inc. (Bedford, Mass.) and the
Shenzhen Female Doctors Assoc. (Shenzhen, P.R.
China)
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