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. Author manuscript; available in PMC: 2016 Jun 15.
Published in final edited form as: Int J Cancer. 2014 Dec 1;136(12):2854–2863. doi: 10.1002/ijc.29337

Human Papillomavirus Testing 2007 – 2012: Co-testing and Triage Utilization and Impact on Subsequent Clinical Management

Jack Cuzick 1, Orrin Myers 2, William C Hunt 3, Debbie Saslow 4, Philip E Castle 5, Walter Kinney 6, Alan Waxman 7, Michael Robertson 3, Cosette M Wheeler 3, on behalf of the New Mexico HPV Pap Registry Steering Committee
PMCID: PMC4737644  NIHMSID: NIHMS752596  PMID: 25447979

Abstract

In the United States high-risk HPV (HPV) testing is recommended for women with ASC-US cytology, and co-testing with cytology and HPV is a recommended option for screening women aged ≥30 years. No population-based data are available to examine utilization of HPV testing in the United States. Using the New Mexico HPV Pap Registry data resource, we describe population trends (2007–2012) in utilization and positivity rates for HPV testing as a routine co-testing screening procedure and for triage of ASC-US and other cytologic outcomes. For women aged 30–65 years co-testing increased from 5.2% in 2007 to 19.1% in 2012 (P< 0.001). Overall 82% of women with ASC-US cytology who did not receive co-testing also had an HPV test. HPV positivity was age and cytology result dependent but did not show time trends. For women with negative cytology, 64% received an additional screening test within 3 years if no co-test was done or if it was positive, but this was reduced to 47% with a negative co-test. Reflex HPV testing for ASC-US cytology is well established and occurs in most women. Evidence for reflex testing is also observed following other abnormal cytology outcomes. Co-testing in women aged 30–65 years has more than tripled from 2007 to 2012, but was still only used in 19.1% of women aged 30–65 years attending for screening in 2012. Women receiving co-testing had longer repeat screening intervals, but rescreening within 3 years is still very common even with co-testing.

Keywords: high risk HPV testing, HPV co-testing, Cervical screening, utilization, outcome, and coverage, New Mexico, New Mexico HPV Pap Registry, United States

INTRODUCTION

High-risk HPV (HPV) testing using the Hybrid Capture 2 (HC2; Digene, Silver Spring, MD) test was first approved for triage testing of atypical squamous cells of unknown significance (ASC-US) cytology in 1999 and for screening in 2004. No population-based data are available to examine utilization of HPV testing in the United States (U.S). Using the New Mexico HPV Pap Registry (NMHPVPR) data resource, we describe population trends (2007–2012) in utilization and positivity rates for HPV testing as a routine co-testing procedure in women attending screening and for triage of ASC-US and other cytologic outcomes.

Since 1999 there have been several changes in U.S. guidelines; (1). In brief in 2001, after the ALTS results were published, the American Society for Colposcopy and Cervical Pathology (ASCCP) recommended HPV testing as the “preferred” reflex option for the triage of woman with atypical squamous cells of unknown significance (ASC-US) cytology (2). In 2002, the American Cancer Society (ACS) made a preliminary recommendation for HPV testing every 3 years for women aged 30 and older (3). In 2004 following the U.S. Food-and-Drug Administration (U.S. FDA) approval of a clinical test for HPV to be used in cervical cancer screening, the ACS, ASCCP, and the National Institutes of Health/National Cancer Institute (NIH/NCI), issued an interim guidance for concurrent HPV and cytology testing (“co-testing”) every 3 years for primary screening in women aged 30 years or older, and reflex HPV testing after ASC-US cytology in all women (4,5,6). The ASCCP reiterated these recommendations in 2006 and suggested that when HPV16 and HPV18 testing was available, women with negative cytology who tested positive for either or both HPV16 and HPV18 could be referred immediately to colposcopy (7,8,9). In 2012 comprehensive new screening guidelines were issued that amongst other things recommended the option of co-testing at 5 year intervals for women aged 30–65 years (10,11,12). Most recently the U.S. FDA approved the use of the Cobas HPV test (Roche) alone for primary screening of women aged 25 to 64 years (13).

While one survey of providers at Federally Qualified Health Centers (14) found that 39% of providers reported using HPV co-testing, very little is known about the actual (documented) uptake and uses of HPV testing in routine clinical practice. Co-testing has been used routinely in women aged 30 years or older in one large managed health care system since 2003 (15), but apart from that, we found only one single institution’s report on utilization from 2004–2007 (16). While ASC-US reflex testing was very high (95%), co-testing in women aged 30 years or more was only about 15%.

METHODS

Population and Methods

All cervical cytology, HPV testing and cervical pathology is reported under state regulations to the New Mexico HPV Pap Registry (NMHPVPR) (http://nmhealth.org/ERD/healthdata/documents/NotifiableDiseasesConditions022912final.pdf). Data were obtained from 9 laboratories in New Mexico from 1 Jan 2006 to 1 Jan 2013, and augmented with reports from 9 out-of-state laboratories. These test results were linked to individual women using probabilistic matching with Registry Plus Link Plus (17), and augmented by manual reviews where linkage was uncertain. Further details are provided in (1). The focus of this report is HPV testing occurring within 28 days of a screening cytology test. Specifically by HPV testing we mean testing for the 13 high risk types contained in the Digene Hybrid Capture 2 test (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68; Qiagen, Germantown, Maryland, USA). A screening cytology test was defined as a cytology test that was not preceded by another cytology test within 300 days. Data from 2006 were only used to determine if tests in 2007 were screening tests. We also analyzed the amount of HPV testing and cytology more than 28 days but less than 3 years after a screening test as a function of initial cytology and HPV test results (when done), and also all biopsies within 3 years of the initial test, to explore the extent to which HPV testing was done as part of surveillance of abnormal results and how the HPV result influenced the decision to refer to colposcopy. As only biopsy results and not colposcopy referrals were available, we used biopsy as a surrogate for colposcopy. Almost all HPV testing before 2012 was done with Hybrid Capture 2.

Statistical methods

Binomial statistics, with a normal approximation where appropriate, were used to compute 95% confidence intervals for proportions and changes in proportions. Log-binomial models were used to examine trends over time and to test for differences among age groups. If Log-binomial models failed to converge, Poisson regression with robust variance estimation was used (18). The first cytology result in any calendar year was used for analyses. The age-specific rates of co-testing were estimated as the proportion of cytology negative screening tests that also had a HPV test within 28 days. These rates were used to estimate the number of women with different cytology outcomes who had a co-test with HPV and these numbers were subtracted from the numerator and denominator to provide an estimate of the proportion of women who had triage testing for different initial cytologic outcomes. For women with a screening test in 2007–9, time to the first or second subsequent cytology, HPV test or biopsy/ECC were also computed for a 3 year interval after the index test. Outcomes were provided for all HPV tests without adjustment for whether an HPV test was due to co-testing or triage.

RESULTS

HPV Utilization and Positivity

In 2007–2012, a total of 147,882 (11.9%) HPV tests within 28 days of a screening test were identified among women aged 15–65 years. Utilization in 2012 is shown in Table 1. Full details by year of test, age and outcome are given in Web Table 1. Trends in HPV utilization by calendar year are shown by age and cytology outcome in Figure 1. HPV utilization among women aged 30–65 years increased during 2007–2012 for all cytology outcomes, but HPV positivity was constant over the period for all but ASC-US screening results (Table 2 and Figure 2). However, both utilization and positivity depended on cytology outcome and are discussed accordingly below.

Table 1.

Screening HPV co-test utilization (within 28d of cytology), HPV triage testing and HPV positivity among women with HPV co-tests by screening cytology result, for age groups 21–29 years, 30–65 years and 21–65 years for 2012. Triage estimates calculated using HPV utilization rates for women with negative cytology to adjust for co-testing.

Cytologya 21–29y 30–65y 21–65y
# Screens HPV test within 28d % Tested HPV Positive (%) Triage (%) # Screens HPV test within 28d % Tested HPV Positive (%) Triage (%) # Screens HPV test within 28d % Tested HPV Positive (%) Triage (%)
Negative 38,208 1,919 5.0 18.6 0.0 114,897 21,962 19.1 6.9 0.0 153,105 23,881 15.6 7.9 0.0
ASC-US 3,187 2,603 81.7 61.2 80.7 5,360 4,626 86.3 29.3 83.1 8,547 7,229 84.6 40.8 81.7
LSIL 2,114 619 29.3 89.7 25.5 1,561 727 46.6 77.6 33.9 3,675 1,346 36.6 83.1 24.9
AGC 76 37 48.7 45.9 46.0 414 201 48.6 16.4 36.4 490 238 48.6 21.0 39.1
ASC-H 270 121 44.8 83.5 41.9 359 202 56.3 58.9 45.9 629 323 51.4 68.1 42.4
HSIL+ 272 72 26.5 93.1 22.6 270 112 41.5 84.8 27.7 542 184 33.9 88.0 21.7
All 44,127 5,371 12.2 50.1 --b 122,861 27,830 22.7 13.3 --b 166,988 33,201 19.9 19.2 --b
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a

ASC-US = atypical squamous cells of undetermined significance

LSIL = low-grade grade squamous intraepithelial lesion

AGC = atypical glandular cells

ASC-H = atypical squamous cells cannot rule out HSIL

HSIL+ = high-grade squamous intraepithelial lesion

b

Not calculated for mix of normal and abnormal cytology results.

Figure 1.

Figure 1

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Trends in HPV utilization by cytology result and age group. For negative cytology this consists of all results and is an estimate of the amount of co-testing. For abnormal cytology, number of HPV tests performed (numerator) and number not receiving co-testing (denominator) are computed by subtracting number of estimated co-tests based on results for negative cytology and is an estimate of the amount of HPV triage in those not receiving co-testing.

Table 2.

HPV utilization and positivity rates, 2007 – 2012, and annual change by cytology result and age.

Cytologya Age, y HPV Utilization HPV Positivity
Overall rate, (%)(95% CI) Annual change(%)(95% CI) P-value Overall positivity, (%)(95% CI) Annual change(%)(95% CI) P-value
Negative 15–20 4.55 (4.35,4.76) 10.6 (7.31,14.0) <.001 23.8 (21.9,25.8) −2.03 (−7.39,3.64) 0.37
21–29 3.69 (3.60,3.79) 7.51 (5.79,9.26)b <.001 20.2 (19.2,21.3) −2.83 (−5.81,0.24) 0.06
30–39 10.6 (10.4,10.7) 34.2 (32.9,35.5)b <.001 9.48 (9.03,9.96) −0.84 (−3.87,2.29) 0.49
40–49 9.17 (9.03,9.33) 32.1 (30.6,33.5)b <.001 6.40 (5.99,6.84) −3.25 (−7.11,0.77) 0.09
50–65 7.99 (7.86,8.11) 32.8 (31.4,34.2)b <.001 4.81 (4.48,5.18) −1.31 (−5.77,3.36) 0.47
30–65 9.15 (9.07,9.23) 33.1 (32.3,33.9)b <.001 6.97 (6.73,7.21) −1.47 (−3.60,0.71) 0.13
ASC-US 15–20 75.0 (73.6,76.4) 1.90 (0.59,3.23) 0.02 71.7 (70.1,73.3) 0.31 (−1.18,1.82) 0.60
21–29 79.2 (78.4,79.9) 0.59 (−0.01,1.19) 0.05 61.2 (60.2,62.2) 0.67 (−0.33,1.68)b 0.14
30–39 80.6 (79.7,81.6) 0.58 (−0.17,1.34) 0.10 38.4 (37.2,39.6) 2.37 (0.35,4.42) 0.03
40–49 80.9 (79.9,82.0) 1.20 (0.41,1.99) 0.01 23.2 (22.0,24.4) 3.93 (0.76,7.19) 0.03
50–65 79.5 (78.3,80.6) 1.77 (0.88,2.66) 0.005 21.8 (20.6,23.1) 2.10 (−1.40,5.72) 0.17
30–65 80.4 (79.8,81.0) 1.14 (0.68,1.61) 0.002 28.6 (27.9,29.4) 2.70 (1.13,4.30)b 0.009
LSIL 15–20 28.0 (26.5,29.5) 9.07 (5.18,13.1) 0.003 92.9 (91.3,94.4) −0.83 (−1.97,0.32) 0.11
21–29 25.0 (24.0,26.0) 2.25 (−0.30,4.86) 0.07 90.1 (88.8,91.5) −0.44 (−1.32,0.45) 0.24
30–39 28.1 (26.4,30.0) 1.23 (−2.75,5.38) 0.44 82.7 (80.4,85.2) −0.15 (−1.89,1.63) 0.83
40–49 28.9 (26.5,31.6) 5.46 (0.00,11.2) 0.05 74.4 (70.6,78.3) −0.64 (−3.66,2.48) 0.60
50–65 33.7 (30.8,36.8) 7.47 (1.54,13.7) 0.02 72.9 (68.7,77.3) −0.32 (−3.85,3.33) 0.81
30–65 29.9 (28.6,31.3) 4.29 (1.46,7.20) 0.01 78.4 (76.5,80.3) −0.38 (−1.81,1.07) 0.50
AGC 15–20 56.9 (43.1,75.1) −6.23 (−23.1,14.4) 0.42 57.5 (40.5,81.6) 10.6 (−6.98,31.5) 0.18
21–29 48.0 (42.4,54.3) −3.32 (−10.8,4.73) 0.31 48.4 (40.8,57.3) 1.44 (−8.22,12.1) 0.71
30–39 41.3 (36.6,46.6) −0.03 (−7.35,7.87) 0.99 34.5 (28.5,41.8) −1.13 (−12.6,11.8) 0.81
40–49 35.9 (32.0,40.3) −1.11 (−7.86,6.13) 0.68 13.1 (9.46,18.2) 1.12 (−17.2,23.5) 0.88
50–65 35.7 (31.7,40.2) 5.31 (−2.18,13.4) 0.12 13.1 (9.28,18.4) −6.62 (−24.2,15.1) 0.41
30–65 37.3 (34.8,39.9) 1.47 (−2.73,5.85) 0.39 19.6 (16.8,22.9) −0.89 (−9.95,9.07) 0.81
ASC-H 15–20 47.5 (41.6,54.2) −0.94 (−10.1,9.11) 0.80 87.7 (82.2,93.6) −0.38 (−5.12,4.59) 0.84
21–29 46.5 (43.4,49.7) −4.53 (−8.51, −0.37) 0.04 79.4 (75.9,83.1) 0.76 (−2.05,3.64) 0.50
30–39 51.1 (47.0,55.5) −6.91 (−11.7, −1.83) 0.02 68.3 (63.5,73.5) 3.86 (−0.80,8.75) 0.08
40–49 55.1 (49.8,61.0) −7.55 (−13.3, −1.40) 0.03 44.3 (37.9,51.8) 2.30 (−6.98,12.5) 0.54
50–65 58.1 (52.8,64.0) −1.77 (−7.16,3.94) 0.43 34.9 (28.9,42.1) −0.35 (−11.4,12.1) 0.94
30–65 54.2 (51.4,57.2) −5.41 (−8.51, −2.21) 0.010 52.7 (49.2,56.4) 3.00 (−1.27,7.45) 0.12
HSIL+ 15–20 22.5 (17.3,29.3) 7.91 (−10.7,30.5) 0.33 95.5 (90.0,100) 0.75 (−1.04,2.57)b 0.31
21–29 21.5 (19.0,24.3) 5.71 (−1.80,13.8) 0.10 95.4 (92.7,98.1) −1.40 (−3.98,1.25) 0.21
30–39 24.3 (20.8,28.4) 13.5 (2.61,25.5) 0.03 90.7 (86.5,95.1) 1.74 (−1.21,4.78) 0.18
40–49 17.8 (13.5,23.3) 7.24 (−9.34,26.8) 0.31 84.5 (76.3,93.6) 0.01 (−5.88,6.27) 0.99
50–65 22.1 (17.3,28.3) 0.27 (−13.7,16.5) 0.96 79.0 (70.0,89.2) −3.81 (−10.1,2.91) 0.19
30–65 22.5 (20.0,25.3) 9.02 (1.27,17.4) 0.03 86.8 (83.1,90.6) 0.24 (−2.34,2.90) 0.81
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a

ASC-US = atypical squamous cells of undetermined significance

LSIL = low-grade grade squamous intraepithelial lesion

AGC = atypical glandular cells

ASC-H = atypical squamous cells cannot rule out HSIL

HSIL+ = high-grade squamous intraepithelial lesion

b

Significant quadratic trend detected, P<0.05.

Figure 2.

Figure 2

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Trends in HPV positivity by screening cytology test result, age and year.

Negative Cytology (co-testing)

For women aged under 30 years, HPV testing in the presence of negative cytology has slightly increased from 3.7% in 2007 to 5.1% in 2012 (Table 2, Web Table 1). However large increases in co-testing have occurred in older women. The increase was largest in women aged 30–39 years, where co-testing increased from 5.9% in 2007 to 22.0% in 2012. It was somewhat less in older women, being 16.4% in 2012 for women aged 50–65 years. Overall for women aged 30–65 years, co-testing utilization increased 33.1% per year (95% CI 32.3 to 33.9), from 5.2% in 2007 to 19.1% in 2012. The increase was accelerating over time with the largest annual increase (55.1%, 95% CI (52.4 to 57.8)) occurring between 2011 and 2012. HPV positivity was age dependent but stable over time (Figures 2 & 3), being 23.8% in women aged 15–20 years, 20.2% in women aged 21–29 years, 9.5% in women aged 30–39 years, 6.4% in women aged 40–49 years, and 4.8% in women aged 50–65 years. In women aged 30–65 years combined HPV positivity was 7.0%.

Figure 3.

Figure 3

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HPV positivity rate (%) and 95% confidence interval by screening cytology outcome and age. 2007 – 2012.

The impact of co-testing on subsequent management is shown in Figure 4 and Web Table 2. It is clear that a negative HPV co-test leads to less repeat cytology in the next three years, but co-testing led to more HPV testing even when an initial HPV test was negative, indicating some women are receiving annual co-testing regardless of their prior HPV test results. For women with negative cytology 64% received an additional screening test within 3 years if no HPV co-test was done or if it was positive (Fig 4A), but this was reduced to 47% if they had a negative HPV co-test. Overall for women aged 21–65 years who had a co-test, 6.3% had a biopsy in the next three years compared to 5.1% for women who were not co-tested (P<0.001). As expected biopsy rates were much higher in those with a positive HPV test: 18.1% of women aged 21–65 years had received a biopsy in the following 3 years compared to 5.1% in those not receiving an HPV test (P <0.001) or who had a negative HPV test result (5.1%, P <0.001).

Figure 4.

Figure 4

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Time to follow up cytology (A), HPV test (B), biopsy (C) or any follow up (D) after normal screening cytology result by HPV co-test status for New Mexico women age 30 – 65 years. Time to second follow up (red-hued lines) is also shown for cytology, HPV tests and biopsies. Sample size and percent of sample by co-test status shown in panel A. Note that different panels have different vertical scales.

ASC-US

HPV testing was performed in 84.5% of women with ASC-US cytology in 2012 and 81.7% were estimated to have received HPV testing as a secondary triage test. Triage testing percentages were similar among age groups and increased only slightly over time (1.1% per year for women aged 30 – 65 year, Figure 1 & Table 2). HPV positivity exhibited a strong age dependence (Figure 3), being 71.7% at ages 15–20 years, 61.2% at ages 21–29 years, 38.4% at ages 30–39 years, 23.2% at ages 40–49 years, and 21.8% at ages 50–65 years. HPV positivity was stable over time in women aged <30 years, but a positive trend was seen in women aged 30–65 years (2.7% per year, P = 0.009, Table 2). However the annual rate of increase is slowing in this age group (significant downward quadratic component (P = 0.04).

It was clear that HPV status influenced subsequent clinical management (Web Figure 1 and Web Table 2). 53.8% of HPV-positive ASC-US women aged 21–65 years had a biopsy within 1 year compared to 6.4% who were HPV negative ASC-US (P <0.001) and 14.4% of women without an HPV test (P <0.001). The comparable figures after 3 years of follow up were 59.4%, 11.7% and 19.9%, respectively. This effect was age dependent. Women with a negative HPV test aged 21–29 years were half as likely to have a biopsy than women without a test (9.7% vs. 21.8%, respectively, RR=0.45, 95%CI (0.38 to 0.53), whereas for women aged 50–65 years there was little difference between proportion with a biopsy in those with a negative test and no test (11.5% vs.14.1%, respectively, RR = 0.82, 95% CI (0.65 to 1.02)).

Early repeat HPV testing was more common in women who did not have an HPV test within the initial 28 days, but after 1 year additional HPV testing was most common in women initially HPV positive and least common in women with a negative test (Web Figure 1). After 3 years similar rates of first repeat cytology were seen for all HPV testing categories, but second cytology percentages were lower in HPV negative women (P < 0.001).

LSIL

Use of HPV testing in women with low-grade squamous intraepithelial lesions (LSIL) cytology was substantially higher at all ages than for women with negative cytology, indicating that HPV triage was being used in some cases. Triage occurred in about 30% of all LSIL among women aged 30–65 years, increased with age (P <0.001), and showed a small increase over time (P=0.01, Table 2). HPV positivity decreased with older ages (Figure 3), but not as strongly as for ASC-US or atypical squamous cells cannot rule out high-grade (ASC-H), ranging from 93% in women aged 15–20 years, to 73% in those aged 50–65 years, but were stable over the calendar periods assessed.

Biopsy rates within three years for women aged 21–65 years were 60.9% for those with no test, 60.3% for those with a positive test, and 48.9% for those with a negative test (P <0.001, Web Figure 2 and Web Table 2). HPV test status did not impact repeat cytology, but had a small impact on repeat HPV testing.

AGC

Triage HPV testing was performed in 37% of women with atypical glandular cells (AGC), which was well above the percentage in women aged 30–65 years with normal cytology. Younger women were more likely to be HPV tested (P<0.001, Table 2) and had higher HPV positivity than older women (P<0.001, Figure 3) but there was no trend over time for testing or positivity. One year biopsy rates for women aged 30–65 years were 77.1% if HPV positive, 57.7% for HPV negative and 60.5% if there was no HPV test (Web Table 2).

ASC-H

HPV testing was also common in women with ASC-H cytology indicating a substantial number were receiving HPV triage testing. Triage rates were age dependent, being highest in women aged 50–65 years (58%, P<0.001, Table 2). Triage testing rates were 54% among women aged 30–65 years, but they were decreasing over time by 5.4%/year, due to more women with ASC-H now being directly referred to colposcopy (trend for increasing biopsy rate within 300 days P = 0.001), in keeping with current guidelines. HPV positivity showed a strong age dependence (P < 0.001, Figure 3) and ranged from 88% in women aged 15–20 years to 35% in those aged 50–65 years.

Biopsy rates within one year for women aged 21–65 years were 49.2% for those with a negative HPV test, compared to 64.9% for those not tested and 66.3% with a positive test. After three-years 53.1% of women with a negative HPV test had had a biopsy, compared to 70.1% for those with no test, and 72.3% for those with a positive test (Web Figure 3 & Web Table 2). Women with a positive test were slightly more likely to have repeat HPV testing within three years (40.1%) than those with a negative (32.0%) or no test (34.2%). HPV test status did not impact repeat cytology utilization.

HSIL

HPV triage testing for women aged 30–65 years with high-grade squamous intraepithelial lesions (HSIL) was 22.5% and increased 9.0% per year (P=0.03, Table 2). Triage testing rate was not age dependent (P=0.21) but HPV positivity was associated with age (P<0.001, Figure 3). HPV positivity was >90% among women aged <40y and 79% among women aged 50–65 years. There was no time trend over the period. The one-year biopsy rate decreased with age from 78.3% among women aged 30–39y to 70.3% among ages 50–65y (P=0.09). For women aged 21–65 years, the few HPV negative women had a lower one-year biopsy rate (48.0%) than women without a HPV test (76.3%) or with a positive HPV co-test (73.2%, P=0.01). This was also true at year 3. (Web Figure 4 and Web Table 2).

DISCUSSION

These results provide the first population-based profile of utilization and outcomes of HPV testing in cervical cancer screening in a U.S. population, both in a co-testing and triage context. Co-testing with HPV and cytology in women aged 30–65 years has increased more than three-fold from 5.2% in 2007 to 19.1% of all screens in 2012, with the largest increase occurring in 2012. Absolute co-testing rates were highest in women aged 30–39 years, but substantial increases were seen in all groups aged over 30 years. HPV testing in women aged less than 30 years with negative cytology remained constant at about 5%. Further work is needed to determine the reasons for HPV co-testing in these younger women, but it could relate to cytologic abnormalities found on previous cytology screening tests. Our records did not indicate the reason for the HPV test; therefore co-testing percentages were inferred from HPV testing percentages in women with negative cytology as there would be no reason for reflex testing in these women. The same co-testing rate would be expected in women with abnormal cytology and we have assumed this to infer the percentage of triage-based HPV testing. In fact the difference between the triage rate and total rate was small except for women over the age of 30 years in recent years when co-testing became more common. This correction also eliminated the artificial increase in HPV testing in women with abnormal cytology which was due to increased co-testing and not increased triage testing.

HPV positivity was similar in different cytology groups as seen in large trials (19,20), and a managed care organization (15), but our percentages were for an entire state population and do not have the inherent selection problems of a trial or a managed care population. Our evaluation is likely more representative of the diversity of U.S. healthcare delivery as it transcends the boundaries of provider practices, payers and a variety of organizational health care structures delivering cervical screening across the entire state of New Mexico. Further population-based studies in other areas are needed to see if there is important geographic variation in these results.

Specifically triage of ASC-US cytology by HPV testing was used in 82% of cases not receiving co-testing and was similar across age groups and calendar time. Subsequent management was dependent on the HPV result with 53.8% of HPV-positive women receiving a biopsy within 1 year compared to 6.4% of HPV-negative women and 14.4% of those for whom HPV testing was not initially performed (Web Figure 1 & Web Table 2) and the difference was maintained for at least 3 years. Of interest was that women having HPV triage for ASC-US had more biopsies overall than those who did not receive a HPV test. This is not surprising, given that most women without a HPV test would be followed by a repeat cytology test and many of these lesions would be expected to regress in this period. More work is needed to see if this might be partially confounded by a clinician effect, whereby clinicians not performing HPV triage for ASC-US also had a higher threshold for biopsy. We used biopsy proportions as a surrogate for colposcopy referrals as very few women attending colposcopy for an abnormal cytology are not subjected to biopsy (A. Waxman, per comm.).

Two important findings were i) the extent to which triage HPV testing was employed when the cytology result was greater than ASCUS (25% of LSIL, 46% of AGC, 42% of ASC-H and 26% of HSIL+) when immediate colposcopy is the recommended management, and ii) the number of women aged 21–65 years who should have been referred to colposcopy following current guidelines, but who did not have a biopsy within 1 year (46% of HPV positive ASCUS, 45% of LSIL, 42% of ASC-H and 21% of HSIL+). Triage of LSIL is not currently recommended in the U.S. (21), however for older women a substantial proportion of LSIL is HPV negative and very little disease has been observed in this group (22, 23) making this an area where it may be appropriate to reconsider current guideline recommendations. It is difficult to understand the need for HPV triage in HSIL except in rare cases where the cytology result might be suspect or there are specific reasons for wanting to be more certain about the likelihood of disease before referral. In any case the HSIL HPV positivity was very often more than 90% (Web Table 1), thus this is of very limited clinical value and likely not cost-effective. Further work is needed to understand the reasons for these HPV testing activities on an individual practice and patient basis and to understand differences in HPV positivity within cytology groups by age.

Triage testing for ASC-H decreased over time, in line with current guidelines that these women should be directly referred to colposcopy. Evidence for HPV triage for other cytologic abnormalities was also apparent but its role in management here is unclear as guidelines indicate these women should be referred directly to colposcopy (21). It is of interest that for normal cytology and ASC-US, use of HPV testing increased biopsies rates overall with this being mostly due to high biopsy rates for HPV positive women. In other abnormal cytology groups, those with positive HPV tests or no HPV test had similar biopsy rates but those with negative HPV test had lower rates. The safety of this practice needs to be examined with longer term follow up of these women.

HPV positivity for all cytologic abnormalities was fairly constant over the five years of this survey. These data provide a solid baseline for assessing current guidelines in relation to co-testing and triage of low-grade cytology.

A key issue regarding the validity of these data is completeness of population ascertainment and recording of screening results. The population was based on the 2010 census and was adjusted for undercounting. For women residing in New Mexico, all laboratories performing tests on these women were required under regulations specified by the New Mexico Notifiable Diseases and Conditions to report all Pap cytology and HPV test results as well as all cervical pathology data to the NMHPVPR. A few women living near the borders with other states might have had tests that were not captured in our database, but as discussed in detail in (1) far less than 1% of cervical cytology and HPV tests might have been missing from the NMHPVPR database. The accuracy of matching records is also an issue. We only linked records where there was strong evidence that this was the same women, so it is possible that some tests for the same women were ascribed to different women because of incomplete identifiers. As reported in (1) extensive efforts indicate that linkage is very complete. For example in other analyses, biopsy reports could be linked to a recent cytology or HPV report in 99% of the cases. However only 1.1% of tests had partial matches that were not taken to be linked, but which had an appreciable probability of linkage to a known record had full information been available.

Further analyses will look at HPV testing utilization and outcome, both as co-testing and for triage of low grade cytology by socioeconomic status, urban-rural and other geographic variables. Of particular interest is to determine if co-testing was based in any way on the identification of increased risk or other factors that could explain the overall higher biopsy rates in these women or whether it is an intrinsic aspect of this policy. Histopathologic outcome in the following 3 years will also be examined according to the use of HPV testing and positivity and this will be important for cost effectiveness analyses.

As HPV vaccination becomes more widespread and more vaccinated individuals reach the age where screening is offered, the impact of vaccination on the cost-effectiveness and accuracy of screening (due to fewer positives) will need to be reevaluated, and population based screening registries such as the New Mexico HPV Pap Registry will be essential for this purpose.

Supplementary Material

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Novelty Impact Statement.

HPV co-testing use in primary cervical cancer screening is a relatively new recommendation but no population-based data exist for the United States. Using the New Mexico HPV Pap Registry (NMHPVPR), we provide insights into the still low but rapidly increasing use of co-testing and document its use for triage of higher grade cytology, where immediate colposcopy is already recommended. The NMHPVPR serves as a model for evaluating cervical screening activity and potentially other cancer screening.

Abbreviations

NM

New Mexico

U.S

United States

NMHPVPR

New Mexico HPV Pap Registry

HPV

human papillomavirus

HSIL

high-grade squamous intraepithelial lesion

LSIL

low-grade grade squamous intraepithelial lesion

ASC-H

atypical squamous cells cannot rule out HSIL

AGC

atypical glandular cells

ASC-US

atypical squamous cells of undetermined significance

HPV

high-risk human papillomavirus infection

Footnotes

Funding Disclosures: Information reported in this publication was funded by the US National Cancer Institute ((U54CA164336; CMW) and the US National Institute of Allergy and Infectious Diseases (U19AI08408; CMW). Ongoing evaluations of cervical screening, diagnosis and treatment by the NMHPVPR have been reviewed and approved under exempt status by the University of New Mexico Human Research Review Committee.

Potential Conflicts of Interest: Dr Cuzick has received research funding and reagents from Qiagen, Roche, GenProbe/Hologic, Abbott, BD, Cepheid, Genera and Trovagene, and has been personally compensated for Advisory Boards or Speakers Bureau activities by GenProbe/Hologic, Abbott, BD, Merck and Cepheid. Dr. Castle has received commercial HPV tests for research at a reduced or no cost from Roche, Qiagen, Norchip, mtm, BD and Arbor Vita Corp., has been compensated financially as a member of a merck Data and Safety Monitoring Board for HPV vaccines, paid as a consultant for BD, Gen-Probe/Hologic, Roche, Cepheid, ClearPath, Guided Therapeutics, Teva Pharmaceuticals, Inovio Pharmaceuticals, Genticel and GE Healthcare and has received honroraria as a speaker for Roche and Cepheid. Dr. Wheeler has received support for equipment and reagents for HPV genotyping from Roche Molecular Systems and contracts from Merck and GSK for HPV vaccine trials through her institution, the University of New Mexico. No other author has reported a conflict of interest.

References

  • 1.Cuzick J, Myers O, Hunt WC, et al. A Population-based Evaluation of Cervical Screening in the United States: 2008–2011. Cancer Epidemiol Biomarkers Prev. 2014;23:765–73. doi: 10.1158/1055-9965.EPI-13-0973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Wright TC, Jr, Cox JT, Massad LS, et al. for the 2001 ASCCP-Sponsored Consensus Conference. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120–2129. doi: 10.1001/jama.287.16.2120. [DOI] [PubMed] [Google Scholar]
  • 3.Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. 2002;52:342–62. doi: 10.3322/canjclin.52.6.342. [DOI] [PubMed] [Google Scholar]
  • 4.ACOG Practice Bulletin: clinical management guidelines for obstetrician-gynecologists. Number 45, August 2003, Cervical cytology screening (replaces committee opinion 152, March 1995) Obstet Gynecol. 2003;102:417–27. doi: 10.1016/s0029-7844(03)00745-2. [DOI] [PubMed] [Google Scholar]
  • 5.Anonymous. Screening for cervical cancer: recommendations and rationale. Am Fam Physician. 2003;67:1759–66. [PubMed] [Google Scholar]
  • 6.FDA. [accessed 4 Nov 2013]; http://www.accessdata.fda.gov/psn/printer-full.cfm?id=20.
  • 7.Wright TC, Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197:346–55. doi: 10.1016/j.ajog.2007.07.047. [DOI] [PubMed] [Google Scholar]
  • 8.Moscicki AB, Cox JT. Practice improvement in cervical screening and management (PICSM): symposium on management of cervical abnormalities in adolescents and young women. J Low Genit Tract Dis. 2010;14:73–80. doi: 10.1097/lgt.0b013e3181cec411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.ACOG Committee on Practice Bulletins--Gynecology. ACOG Practice Bulletin no 109: Cervical cytology screening. Obstet Gynecol. 2009;114:1409–20. doi: 10.1097/AOG.0b013e3181c6f8a4. [DOI] [PubMed] [Google Scholar]
  • 10.Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012;137:516–42. doi: 10.1309/AJCPTGD94EVRSJCG. [DOI] [PubMed] [Google Scholar]
  • 11.Moyer VA; U S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156:880–91. doi: 10.7326/0003-4819-156-12-201206190-00424. [DOI] [PubMed] [Google Scholar]
  • 12.ACOG practice bulletin 131: screening for cervical cancer. Obstet Gynecol. 2012;120(5):1222–38. doi: 10.1097/aog.0b013e318277c92a. [DOI] [PubMed] [Google Scholar]
  • 13. [accessed 25 April 2014]; http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394773.htm.
  • 14.Roland KB, Benard VB, Greek A, Hawkins NA, Manninen D, Saraiya M. Primary care provider practices and beliefs related to cervical cancer screening with the HPV test in Federally Qualified Health Centers. Prev Med. 2013;57:419–25. doi: 10.1016/j.ypmed.2013.04.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Castle PE, Fetterman B, Thomas Cox J, et al. The age-specific relationships of abnormal cytology and human papillomavirus DNA results to the risk of cervical precancer and cancer. Obstet Gynecol. 2010;116:76–84. doi: 10.1097/AOG.0b013e3181e3e719. [DOI] [PubMed] [Google Scholar]
  • 16.Phelan DF1, Boitnott JK, Clark DP, Dubay LC, Gravitt PE. Trends of human papillomavirus testing in cervical cancer screening at a large academic cytology laboratory. Obstet Gynecol. 2011;118:289–95. doi: 10.1097/AOG.0b013e3182253c33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. [accessed on Oct 4, 2014]; http://www.cdc.gov/cancer/npcr/
  • 18.Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159:706–702. doi: 10.1093/aje/kwh090. [DOI] [PubMed] [Google Scholar]
  • 19.Wright TC, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206:46.e1–46.e11. doi: 10.1016/j.ajog.2011.07.024. [DOI] [PubMed] [Google Scholar]
  • 20.Kitchener HC, Almonte M, Wheeler P, et al. ARTISTIC Trial Study Group. HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial. Br J Cancer. 2006;95:56–61. doi: 10.1038/sj.bjc.6603210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17:S1–S27. doi: 10.1097/LGT.0b013e318287d329. [DOI] [PubMed] [Google Scholar]
  • 22.Cuzick J, Cox TJ, Zhang G, et al. Human papillomavirus testing for triage of women with low-grade squamous intraepithelial lesions. Int J Cancer. 2013;132:959–66. doi: 10.1002/ijc.27723. [DOI] [PubMed] [Google Scholar]
  • 23.Ronco G, Cuzick J, Segnan N, et al. NTCC working group. HPV triage for low grade (L-SIL) cytology is appropriate for women over 35 in mass cervical cancer screening using liquid based cytology. Eur J Cancer. 2007;43:476–80. doi: 10.1016/j.ejca.2006.11.013. [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

Supp Fig S1
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Supp Table S1
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NIHMS752596-supplement-Supp_Table_S2.docx (72.3KB, docx)

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