More than 38,000 HPV-associated cancers occur in the United States each year affecting approximately 23,000 women. With cervical cancer being the most common HPV-associated cancer among women, it is important for physicians to understand the underlying data supporting the FDA decision on hrHPV primary testing for cervical cancer screening, and its relationship to current harmonized guidelines.
Adoption Barriers for High-Risk HPV (hrHPV) Primary Testing for Cervical Cancer Screening
Since the introduction of the conventional Pap test by Babes and Papanicolaou in the 1920s and publication of it use in diagnosis of uterine cancer in 1943,1 cytology has become an essential part of cervical cancer screening programs in the U.S. and globally. However, more recently, large prospective cohort and randomized controlled trials have demonstrated that while the Pap is good at reducing cervical cancer, screening with cytology alone has inherent limitations. Cytology interpretations are very subjective and have low reproducibility not only amongst individual cytopathologists, but also between laboratories (see Table 1).
This was shown elegantly in the U.S.-based ATHENA (Addressing THE Need for Advanced HPV Diagnostics) study.2 ATHENA is the largest prospective U.S. screening FDA registration study where over 42,000 women that were >25 years of age and who were undergoing routine screening had a gynecologic exam, a ThinPrep® cytology test and HPV testing with genotyping. All women who were HPV positive or cytology positive, as well as a subset of women who were HPV negative and had a normal Pap, underwent colposcopy. The reason for colposcopy in this group when not normally indicated was for verification bias due to the inherent limitations of a subjective colposcopy. Cytology on the ATHENA trial went to four different high quality regional labs. What was identified on this study was that the ASCUS rate varied widely across of each of these labs (see Table 1).2
ATHENA provided many other findings of which Omnia Education’s learners are well aware. We collectively are also aware of the subsequent emergence of Interim Clinical Guidance on the use of primary high-risk HPV (hrHPV) testing for cervical cancer screening, especially as related to women aged 25 to 29, and the dichotomy between 2012 ACS, ASCCP, ASCP USPSTF and ACOG cervical cancer screening guidelines and the Interim Guidance by the SGO and ASCCP in 2015.3,4
There has been much discussion, often heated, on whether medical practices should adopt the Interim Clinical Guidance on use of primary hrHPV testing in lieu of cytology or cotesting, coupled with a defined screening algorithm should women be found positive for HPV type 16 or 18. Essentially, those women who are HPV 16 and/or 18 positive, which makes up a small percentage of women in the general screening population, should be triaged to immediate colposcopy because their risk of having a high grade CIN (or worse) at the time of screening far exceeds the risk threshold for routine triage to colposcopy. In contrast, those that are HPV negative should undergo routine screening. Women who are hrHPV positive, but do not have HPV 16 or 18, should have a secondary test which is cytology. If the cytology is negative for intraepithelial lesion or malignancy (NILM) then they should have a follow-up testing in 12 months. If the cytology is ASCUS or greater, they should have an immediate colposcopy.3
As all are aware, Physicians, testing laboratories, and patient voices have been heard on both sides of the argument.
The purpose of this eECHO is not to rehash the arguments of each side or to put specific weight on their respective validity, but rather to reach out to some of our learners to assess their view(s) toward adopting primary hrHPV testing into their clinical practice. This was undertaken during the Women’s Health Annual Visit (WHAV) Conference held in Chicago on November 18, 2016.
As part of that conference, learners were provided background cervical cancer screening findings from various trials, including ATHENA. Part of that education reflected that sensitivity for detection of high-grade CIN (or worse) with hrHPV testing far exceeds that of Pap testing. Additionally, cotesting which includes Pap test and hrHPV test is also more sensitive than either Pap or hrHPV test alone; however, the sensitivity difference of cotesting compared to hrHPV testing alone appeared to be minimal. Also provided were data supporting that knowledge of one’s HPV status can help predict a risk of developing cervical disease over the course of a decade, which cannot be done with cytology alone.7
A series of questions was asked of the Chicago WHAV participants. The findings are summated below:
- About three-fourths of learners believe they have a good grasp of the data used by FDA in its decision to approve an “HPV DNA test for women 25 and older that can be used alone to help a health care professional assess the need for a woman to undergo additional diagnostic testing for cervical cancer.”Nearly 70% are most concerned that CIN3+ sensitivity is slightly lower with primary hrHPV testing compared with cotesting
- Nearly 40% are secondarily concerned that their patients will be resistant to not receiving the Pap test to which they have become accustomed
- The main reason learners believe that primary hrHPV testing misses some cancers is that the cancer is associated with an unusual HPV genotype or has an L1 deletion not detected by many PCR assays (52%)
- 63% of learners currently perform cotesting at 3 year intervals, not 5 year intervals, and are happy with this approach, which is counter to currently recommended guidelines
- 34% of learners screen annually with either Pap or cotest, which is counter to currently recommended guidelines
- When asked how likely they are to adopt primary hrHPV cervical cancer screening for at least some women in their practice within the next 2 years:
- 22% responded there was a <5% chance
- 12% responded there was up to a 20% chance
- 27% responded there was up to a 50% chance
- 39% responded there was a better than 50% chance
These findings are significant in that nearly 2 years has passed (at this writing) since release of the Interim Clinical Guidance on use of primary hrHPV testing in lieu of cytology or cotesting in women aged 25 to 29, coupled with a defined screening algorithm should women be found positive for HPV type 16 or 18. Moreover, while these findings demonstrate that there is continuing adoption of primary hrHPV cervical cancer screening into clinical practices, they also illustrate some of the existing barriers faced to achieving more wide-spread adoption of primary hrHPV testing, including the apparent number of physicians who are screening with disregard to the collective guidelines.
- Traut HF, Papanicolaou GN. Diagnosis of uterine cancer by vaginal smear. Cal West Med. 1943;59(2):121-122.
- Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136(2):187-95.
- Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecol Oncol. 2015;136(2):178-82.
- CDC: Cervical Cancer Screening Guidelines for Average-Risk Women. Available online at: https://www.cdc.gov/cancer/cervical/pdf/guidelines.pdf (Last accessed 12/11/16).