<![CDATA[HPV-based cervical cancer screening in US]]>

The evidence supporting HPV screening
The evidence supporting switching from cytology screening to HPV screening is very uniform and clear. Multiple large randomized trials have demonstrated that HPV testing is more sensitive at detecting precancer compared to cervical cytology, leading to longer term protection against cancer.¹ In a pooled analysis of randomized trials, HPV testing provided greater protection against invasive cervical cancer compared to cytology.² European RCTs as well as a large observational study from Kaiser Permanente demonstrated that the benefit of adding cytology to HPV testing is very low at the cost of performing cytology in the entire population, substantially reducing cost-effectiveness compared to primary HPV screening alone. The mistaken notion that HPV alone screening may miss a substantial subset of treatable cervical cancers has been debunked.³ Despite the strong evidence supporting HPV-based cervical cancer screening, its implementation is slow and varies strongly between healthcare settings. Here, we summarize the current status and future directions of HPV-based screening and management in the US, and we describe specifics of the US system and their influence on implementation.

Current primary screening options in the US
Cervical cancer screening is currently undergoing a major transition in the US. The US was the first country to approve and recommend HPV tests for use in cervical screening, initially for triage of ASCUS cytology in 2003, and later for use as an adjunct to cytology in primary screening. Recently, the first HPV-alone screening strategy was approved.⁴ However, new approaches did not supplant existing strategies; instead, they became additional options. Three options are now available (Pap cytology, HPV testing, cotesting with both cytology and HPV), which differ by starting age, screening interval, and management options (Table 1). This abundance of choices is challenging for providers and has led to a lot of confusion, frequently resulting in poor implementation of specific strategies, with a strong tendency to screen much more frequently than needed.

Regulatory approval vs. guidelines recommendations
It is important to differentiate regulatory approval of specific tests from organizational guidelines that recommend screening strategies. Regulatory approval through the Food and Drug Administration (FDA) focuses on safety and clinical efficacy of a specific test based on large, typically industry-sponsored Premarket Approval (PMA) trials. The result of a successful PMA process is regulatory approval of the new test for the pre-specified indication that was evaluated in the trial. Regulatory approval is binding and can be enforced.

In contrast, guidelines recommend a screening strategy, not specific assays. Multiple organizations develop guidelines for cervical cancer screening. In 2012, several professional societies led by the American Cancer Society developed screening guidelines that recommended HPV-cytology co-testing at 5-year screening intervals as the preferred screening option with cytology at 3-year intervals as an alternative. The independent US Preventive Services Task Force (USPSTF) came out with the same recommendations, for the first time providing a unified set of recommendations for providers. The USPSTF guidelines recently underwent a revision, and the previously announced draft recommendations proposed to switch to HPV alone at 5-year in tervals while keeping the recommendation for 3-year cytology. The guidelines attempt to arrive at a cost-effective public health recommendation. Many clinical stakeholders have voiced strong concerns regarding the draft USPSTF recommendation for HPV alone testing with 5-year screening intervals, citing the long interval and slightly reduced protection of this approach compared with the old standard of yearly Pap cytology. The final USPSTF guidelines now still include the option for co-testing.

Importantly, there is no organized screening program in the US, and in most settings, screening recommendations are not binding and are not enforced except in some cases via insurance reimbursement policies. Many providers still screen women annually with cytology or even with HPV-cytology co-testing. Currently, there is little disincentive by reimbursement systems outside of government health services (Medicare and Medicaid) that addresses too-frequent screening. The separation of regulatory approval from guidelines recommendations can create challenges for manufacturers of screening tests and regulatory authorities when transformative changes of practice are considered: Guidelines typically restrict to approve tests for specific indications, and regulatory trials typically focus on applications that are recommended by guidelines. This impasse is eventually solvable by introduction of new data from large independent clinical studies, which, in the case of cervical screening, are now underway.

Screening age and triage
The primary screening approaches have different starting ages: Primary cytology is recommended from age 21 to 65, while use of HPV testing tends to start at older ages (at 25) because of the high prevalence of transient HPV infections in women age 20-24. The starting age for co-testing is 30, while FDA approval and interim guidance for primary HPV screening alone permits a starting age of 25 (Table 1). Importantly, HPV-based screening requires triage tests to decide who among the HPV-positive women needs to go to colposcopically-directed biopsy to decide whether precancer is present that requires treatment.⁵ A specific triage test can counterbalance a higher test positivity of the primary screening test, thereby allowing for an earlier starting age of HPV screening. Currently, cytology and HPV16/18 genotyping are the only approved triage strategies. Novel triage tests now under development will need to undergo regulatory evaluation similar to the trials that were conducted for primary screening tests. Regulatory groups are reluctant to evaluate combinations of tests; however, it is important to evaluate HPV screening and triage strategies jointly, since they are conditional on each other in producing an optimally accurate answer of who needs treatment of precancer to prevent cervical cancer.

Towards risk-based screening and management
Given the number of existing screening and triage options in the US, and several additional options undergoing regulatory approval trials, we do not expect a single screening strategy in the US in the future. To address this, there is an ongoing effort in collaboration between multiple professional societies led by the ASCCP and NCI to develop risk-based cervical cancer screening and management guidelines (Figure 1).^6,7 The goal is to develop risk-based clinical action thresholds that are independent of specific screening and triage tests. Current and future assays can be benchmarked against these thresholds, and permit us to update recommendations more easily when new tests become available. Implementation of these risk-based guidelines will be supported by applications that run on mobile devices or in electronic medical record systems to provide immediate risk-based recom mendations using information from laboratory tests, previous screening results, and results from the clinical evaluation.

Summary and conclusions
Cervical cancer screening and management is undergoing a transition phase in the US. Within the next two years, new screening and management guidelines will be announced by various societies. The goal is to unify the messages about cervical cancer screening as much as possible, and to improve adoption and implementation of new screening approaches, particularly when these affect providers through extended screening intervals and switch from one technology to another (e.g. cytology to HPV testing).⁸

References

1. Arbyn M, Ronco G, Anttila A, et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 2012;30 Suppl 5:F88-99. Review. Erratum in: Vaccine. 2013;31(52):6266.
2. Ronco G, Dillner J, Elfström KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014;383(9916):524-32. Erratum in: Lancet 2015;386(10002):1446.
3. Schiffman M, Kinney WK, Cheung LC, et al. Relative Performance of HPV and Cytology Components of Cotesting in Cervical Screening. J Natl Cancer Inst 2018;110(5):501508.
4. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol 2015;125(2):330-7.
5. Wentzensen N, Schiffman M, Palmer T, et al. Triage of HPV positive women in cervical cancer screening. J Clin Virol 2016;76 Suppl 1:S49-S55.
6. Schiffman M, Wentzensen N, Khan MJ, et al. Preparing for the Next Round of ASCCP-Sponsored Cervical Screening and Management Guidelines. J Low Genit Tract Dis 2017;21(2):87-90.
7. Arbyn M, Xu L, Verdoodt F, et al. Genotyping for Human Papillomavirus Types 16 and 18 in Women With Minor Cervical Lesions: A Systematic Review and Meta-analysis. Ann Intern Med 2017;166(2):118-127.
8. Schiffman M, Wentzensen N. Effective use of human papillomavirus testing for cervical cancer screening requires extended intervals to target persistent infections and precancerous lesions. Prev Med 2017;105:378-380.

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Nicolas Wentzensen
MD, PhD, MS
Head of Clinical Epidemiology
Unit and Deputy Chief
of Clinical Genetics Branch
Division of Cancer,
Epidemiology and Genetics,
National Cancer Institute
Bethesda, US
wentzenn@ mail.nih.gov

Mark Schiffman
MD, MPH
Senior Investigator
Clinical Epidemiology,
Unit and Clinical
Genetics Branch
Division of Cancer,
Epidemiology and Genetics,
National Cancer Institute
Bethesda, US
schiffmm@ exchange.nih.gov

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