Large-scale cervical cancer screening by cytology became common practice in the United States (US) in the 1960s. Since that time, best screen- ing practices have been refined as studies have shed light on the optimal ages to start and cease screening, screening intervals, and the use of concomitant high-risk human papillomavirus (hrHPV) testing. Originally proposed by Wright et al in 2004, concomitant hrHPV testing, also known as co-testing, has become the preferred cervical cancer screening strategy in women >30 years of age.¹ Furthermore, in 2012, the American Society for Colposcopy and Cervical Pathology management guidelines were revised, rec- ognizing the utility of co-testing as a surveillance or follow up test after treatment of cervical precancer. Most recently, hrHPV testing alone has been proposed as a mode of primary screening.²

Of the four HPV assays used for co-testing and triage of equivocal cytology (e.g., atypical squamous cells of undetermined significance) ap- proved by the US Food and Drug Administration (FDA) agency, two have been approved for primary HPV screening. One of them, the Roche Cobas® 4800 HPV Test, is the first test approved by the FDA for primary cervical cancer screening without cytology. Using real-time polymerase chain reactions for amplification of the L1 gene of the HPV genome, the Cobas® 4800 system is able to distinguish HPV type 16 and 18 from the other twelve hrHPV types.

A number of large randomized trials and cohort studies have assessed primary hrHPV tests as a primary screening strategy and corroborate the enhanced sensitivity of primary HPV screening over cytology alone.^3,4 Gage et al analyzed a cohort of 1 million women in Northern California. The study concluded that the 3-year cumulative incidence rate (CIR) of cervical precancerous abnormalities (CIN3+) was lower after a negative hrHPV testing compared to after a nega- tive cytology result (0.07% vs. 0.19%).² The ATHENA trial, a US prospective registration trial that utilized the Roche Cobas® 4800 system, also demonstrated the superior protection of primary hrHPV screening vs. cytology alone (3-year CIR of CIN3+ 0.3% vs. 0.8%).^2,5

It should be noted that a certain percentage of invasive cervical cancers are hrHPV negative.² Furthermore, although a growing body of evidence validates the improved sensitivity of primary hrHPV screening, the practice is not with- out criticism in the US. Initial primary hrHPV screening may lead to unnecessary follow-up tests and biopsies. In women between 25 and 29 years of age, the ATHENA trial noted a baseline hrHPV rate and abnormal cytology rate (≥ ASCUS) of 21.1% and 9.8%, respectively.⁵ Using the FDA-approved primary HPV screening algorithm, which includes genotyping for HPV 16 and 18 and reflex cytology for other hrHPV types as defined in Figure 1, the trial detected almost one third of all CIN2+ cases in this age group. But using the algorithm also doubled the number of colposcopies compared with screening starting at age 30.2 Most importantly, more studies will be required to determine if this early detection of CIN2+ will translate to decreased cervical cancer morbidity and mortality.

References

1. Wright TC, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103(2):304-9.
2. 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.
3. Arbyn M, Ronco G, Anttila A, et al. Evidence regarding HPV testing in secondary prevention of cervical cancer. Vaccine 2012; 30 Suppl 5:F88-99.
4. Ronco G, Dillner J, Elfstrom 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.
5. Wright TC, Stoler MH, Behrens CM, et al. 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):189-97.