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.

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.