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

Abstract

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.

Conflict of interest statement

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.

Figures

Figure 1.. Flow Diagram of HPV FOCAL Trial of HPV vs Cytology Screening to Detect Cervical Intraepithelial Neoplasia

ASCUS indicates atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LBC, liquid-based cytology; LSIL, low-grade squamous intraepithelial lesion.

Figure 2.. Cumulative Cervical Intraepithelial Neoplasia Grade 3 or Greater (CIN3+) and Grade 2 or Greater (CIN2+) Incidence for All Intervention and Control Group Participants Attending 48-Month Exit

Incidence at 18, 42, and 72 months is marked by a point and the confidence intervals around it are shown as the point range. Points are jittered with respect to the x-axis to avoid overlays. Groups are artificially divided at 48 months to show the incidence in same participants if they were to be tested using liquid-based cytology alone. Hence, the number at risk is the same across partitions within primary groups. A, Cumulative CIN3+ incidence for intervention and control groups for all participants attending 48-month exit screen. B, Cumulative CIN2+ incidence for intervention and control groups for all participants attending 48-month exit screen. If cases were CIN3+ (in panel A) or CIN2+ (in panel B) at the initial screen but did not attend the exit screen, they contribute as an event at that time point.

Figure 3.. Cumulative Cervical Intraepithelial Neoplasia Grade 3 or Greater (CIN3+) and Grade 2 or Greater (CIN2+) Incidence for Baseline Human Papillomavirus (HPV) and Cytology-Negative Participants Attending 48-Month Exit Screen

Incidence of CIN3+ (A) and CIN2+ (B) for baseline HPV and cytology-negative participants attending 48-month exit screen. Groups are artificially divided at 48 months to show the incidence in the same participants if they were to be tested using liquid-based cytology alone.