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Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 MonthsThe HPV FOCAL Randomized Clinical Trial

Educational Objective
To learn whether human papillomavirus (HPV) screening is accurate and timely for the detection of cervical cancer.
1 Credit CME
Key Points

Question  Does cervical cancer screening using primary cervical human papillomavirus (HPV) testing compared with cytology result in a lower likelihood of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) at 48 months?

Findings  In this randomized clinical trial that included 19 009 women, screening with primary HPV testing resulted in significantly lower likelihood of CIN3+ at 48 months compared with cytology (2.3/1000 vs 5.5/1000).

Meaning  HPV-based screening resulted in lower likelihood of CIN3+ than cytology after 48 months, but further research is needed to understand long-term clinical outcomes as well as cost-effectiveness.


Importance  There is limited information about the relative effectiveness of cervical cancer screening with primary human papillomavirus (HPV) testing alone compared with cytology in North American populations.

Objective  To evaluate histologically confirmed cumulative incident cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) detected up to and including 48 months by primary HPV testing alone (intervention) or liquid-based cytology (control).

Design, Setting, and Participants  Randomized clinical trial conducted in an organized Cervical Cancer Screening Program in Canada. Participants were recruited through 224 collaborating clinicians from January 2008 to May 2012, with follow-up through December 2016. Women aged 25 to 65 years with no history of CIN2+ in the past 5 years, no history of invasive cervical cancer, or no history of hysterectomy; who have not received a Papanicolaou test within the past 12 months; and who were not receiving immunosuppressive therapy were eligible.

Interventions  A total of 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups. Women in the intervention group received HPV testing; those whose results were negative returned at 48 months. Women in the control group received liquid-based cytology (LBC) testing; those whose results were negative returned at 24 months for LBC. Women in the control group who were negative at 24 months returned at 48 months. At 48-month exit, both groups received HPV and LBC co-testing.

Main Outcomes and Measures  The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome.

Results  Among 19 009 women who were randomized (mean age, 45 years [10th-90th percentile, 30-59]), 16 374 (8296 [86.9%] in the intervention group and 8078 [85.4%] in the control group) completed the study. At 48 months, significantly fewer CIN3+ and CIN2+ were detected in the intervention vs control group. The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2-7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69). The CIN2+ incidence rate at 48 months was 5.0/1000 (95% CI, 3.8-6.7) in the intervention group and 10.6/1000 (95% CI, 8.7-12.9) in the control group. The CIN2+ risk ratio was 0.47 (95% CI, 0.34-0.67). Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology-negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]).

Conclusions and Relevance  Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months. Further research is needed to understand long-term clinical outcomes as well as cost-effectiveness.

Trial Registration  isrctn.org Identifier: ISRCTN79347302

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Article Information

Corresponding Author: Gina Suzanne Ogilvie, MD, FCFP, DrPH, BC Women’s Hospital and Health Centre, 4500 Oak St, Room H203G (Box 42), Vancouver, BC V6H 3N1, Canada (gina.ogilvie@cw.bc.ca).

Accepted for Publication: May 17, 2018.

Correction: This article was corrected on December 4, 2018, to clarify the colposcopy referral rates reported in the Results section.

Author Contributions: Drs Ogilvie and Coldman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ogilvie, van Niekerk, Krajden, Smith, Martin, Peacock, Stuart, Franco, Coldman.

Acquisition, analysis, or interpretation of data: Ogilvie, Krajden, Cook, Gondara, Ceballos, Quinlan, Lee, Martin, Gentile, Peacock, Stuart, Franco, Coldman.

Drafting of the manuscript: Ogilvie, van Niekerk, Krajden, Smith, Gondara.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ogilvie, Gondara, Peacock, Franco, Coldman.

Obtained funding: Ogilvie, van Niekerk, Krajden, Martin, Peacock, Stuart, Franco, Coldman.

Administrative, technical, or material support: Ogilvie, van Niekerk, Krajden, Smith, Ceballos, Quinlan, Lee, Stuart, Coldman.

Supervision: Ogilvie, van Niekerk, Krajden, Quinlan, Peacock, Coldman.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Krajden and Coldman were principal investigators, and Drs Ogilvie, van Niekerk, and Franco and Mr Cook were coinvestigators on investigator-led, industry-funded (Hologic Inc and Roche) adjunct studies to the HPV FOCAL trial, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the operation of the main HPV FOCAL trial results presented here. Funding for industry-funded studies was issued to the investigator institutions to conduct these adjunct studies and investigators did not personally benefit financially. Dr Krajden also reported receiving grants from Siemens. Ms Smith reported receiving personal fees from Roche Molecular Systems outside the submitted work. Dr Quinlan reported receiving personal fees from Merck, Cook Myosite, and Allergan. Dr Lee reports personal fees from Merck outside the submitted work. Dr Franco reported receiving grants, personal fees, and/or nonfinancial support from Merck, GlaxoSmithKline, and Roche outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by grant MCT82072 from the Canadian Institutes of Health Research (CIHR).

Role of the Funder/Sponsor: As part of its review and approval of the funding application, CIHR approved the design, analysis, and conduct of the study. The funder had no role in the collection, management, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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