In women undergoing cervical cancer screening, the use of primary human papillomavirus (HPV) testing compared with cytology testing results in a significantly lower likelihood of cervical intraepithelial neoplasia (CIN) grade 3 or higher (CIN3+) at 48 months, according to a study published in the Journal of the American Medical Association.

Cervical cancer screening with cytology is one of the most widely used cancer control interventions in high-income settings and has demonstrated decreased cervical cancer morbidity and mortality. Despite this, it was estimated that 12,820 women in the United States would develop cervical cancer in 2017, with death resulting in approximately 4210 of those women, indicating a continued need to improve cervical cancer prevention.

Roughly 99.7% of all cervical cancers are associated with a persistent cervical infection with an oncogenic HPV genotype preceding the invasive tumor. Although HPV vaccination has potential as an effective cancer control strategy, current vaccine uptake rates and costs create a growing need for continued secondary prevention via screening, and advances in improving screening remain a key women’s health priority. This study reports the 48-month findings from the Human Papillomavirus For Cervical Cancer screening trial (HPV FOCAL), a publicly funded Canadian trial ( identifier: ISRCTN79347302) designed to compare the effect of primary HPV testing alone with liquid-based cytology (LBC) screening alone for the prevention of CIN grade 3 or higher in the context of an organized screening program.

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Recruited from 2008 to 2012 through collaborating clinicians, 19,009 women age 25 to 65 were included in the study. Participants had no history of CIN2+ in the 5 years prior to inclusion in the study, no history of invasive cervical cancer, no history of hysterectomy, had not received a Papanicolaou test within the past 12 months, and were not receiving immunosuppressive therapy. Participants were randomly assigned to the intervention (n=9552) or control (n=9457) group. Participants in the intervention group received HPV testing; individuals whose results were negative returned at 48 months. Participants in the control group received LBC testing; individuals whose results were negative returned at 24 months for LBC and again at 48 months if results  remained negative. At the 48-month mark, both groups received HPV and LBC testing. The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome.

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At 48 months, significantly fewer CIN3+ cases were detected overall and across all age groups in the intervention group compared with the control group, with a CIN3+ rate of 2.3/1000; the risk ratio in the intervention group compared with the control group was 0.42 (95% CI,0.25-0.69) . Furthermore, significantly fewer CIN2+ cases were detected overall across all age groups in the intervention group compared with the control group at 48 months:CIN2+ rate 5.0/1000; risk ratio for the intervention group compared with the control group was 0.36 (95%CI,0.24-0.54). In addition, women who were HPV-negative at baseline were significantly less likely to have CIN3+ and CIN2+ at 48 months compared with women who were cytology-negative at baseline. Furthermore, primary HPV testing detected significantly more CIN3+ and CIN2+ cases in the first round and significantly reduced CIN3+ and CIN2+ rates 48 months later.

Overall, the study investigators concluded that, “Previous studies found the benefit of HPV and cytology co-testing was based primarily on the contribution of HPV, which this trial now prospectively validates.”


Ogilvie GS, van Niekerk D,et al; . Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial. JAMA. 2018;320(1):43-52. doi:10.1001/jama.2018.7464