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While cervix screening using cytology is recommended at 2‐ to 3‐year intervals, given the increased sensitivity of human papillomavirus (HPV)‐based screening to detect precancer, HPV‐based screening is recommended every 4‐ to 5‐years. As organized cervix screening programs transition from cytology to HPV‐based screening with extended intervals, there is some concern that cancers will be missed between screens. Participants in HPV FOr CervicAL Cancer (HPV FOCAL) trial received cytology (Cytology Arm) at 24‐month intervals or HPV‐based screening (HPV Arm) at 48‐month intervals; both arms received co‐testing (cytology and HPV testing) at exit. We investigated the results of the co‐test to identify participants with cervical intraepithelial neoplasia grade 2 or higher (CIN2+) who would not have had their precancer detected if they had only their arm's respective primary screen. In the Cytology Arm, 25/62 (40.3%) identified CIN2+s were missed by primary screen (ie, normal cytology/positive HPV test) and all 25 had normal cytology at the prior 24‐month screen. In the HPV arm, three CIN2+s (3/49, 6.1%) were missed by primary screen (ie, negative HPV test/abnormal cytology). One of these three misses had low‐grade cytology findings and would also not have been referred to colposcopy outside of the trial. Multiple rounds of cytology did not detect some precancerous lesions detected with one round of HPV‐based screening. In our population, cytology missed more CIN2+, even at shorter screening intervals, than HPV‐based screening. This assuages concerns about missed detection postimplementation of an extended interval HPV‐based screening program. We recommend that policymakers consider a shift from cytology to HPV‐based cervix screening. [ABSTRACT FROM AUTHOR]

The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing the efficacy of primary HPV testing to cytology among women in the population‐based Cervix Screening Program in British Columbia, Canada. We conducted a cost‐effectiveness analysis based on the HPV FOCAL trial to estimate the incremental cost per detected high‐grade cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+). A total of 19,009 women aged 25 to 65 were randomized to one of two study groups. Women in the intervention group received primary HPV testing with reflex liquid‐based cytology (LBC) upon a positive finding with a screening interval of 48 months. Women in the control group received primary LBC testing, and those negative returned at 24 months for LBC and again at 48 months for exit screening. Both groups received HPV and LBC co‐testing at the 48‐month exit. Incremental costs during the course of the trial were comparable between the intervention and control groups. The intervention group had lower overall costs and detected a larger number of CIN2+ lesions, resulting in a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of ‐$773 [all costs in 2018 USD]. Cost per detected lesion was sensitive to the costs of sample collection, HPV testing, and LBC testing. The HPV FOCAL Trial results suggest that primary HPV testing every 4 years produces similar outcomes to LBC‐based testing every 2 years for cervical cancer screening at a lower cost. [ABSTRACT FROM AUTHOR]

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high‐risk human papillomavirus (HPV) and the control arm received liquid‐based cytology (LBC) at baseline and 24 months. Both arms received 48‐month exit HPV and LBC cotesting. Exit results are presented for per‐protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow‐up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25–65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56–1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43–1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14–65) and intervention 43 (95% CI: 25–73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1–0.7). This per‐protocol analysis found that screening with HPV using a 4‐year interval is as safe as LBC with a 2‐year screening interval. LBC screening in HPV negative women at exit identified few additional lesions. What's new? Human papillomavirus (HPV) testing is a sensitive approach for detecting cervical intraepithelial neoplasia grade 2 and higher (CIN2+). However, whether HPV testing alone, with extended intervals between visits, is more effective than HPV testing and liquid‐based cytology (LBC) combined for cervical screening remains uncertain. Here, HPV testing every four years was found to be at least as effective as LBC every two years for CIN2+ identification. Moreover, women were more likely to comply with screening protocol when four‐year intervals were used, compared to two‐year intervals. Women with CIN1 at colposcopy and women initially HPV‐positive may require screening with both methods. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: HPV FOCAL is a randomized trial (ISRCTN79347302, registered 20 Apr 2007) comparing high-risk (hr) HPV testing vs. liquid-based cytology (LBC) for cervical cancer screening of women aged 25-65. We compared the Digene Hybrid Capture® 2 High-Risk HPV DNA Test® (HC2) and the Roche cobas® 4800 HPV Test (COBAS) for primary screening.Methods: Women (n=6,172) were screened at baseline by HC2 and COBAS and by LBC 24 months later. We assessed HPV genotyping and reflex LBC for colposcopy triage of baseline HPV positive women.Results: Overall HC2/COBAS agreement was 96.1% (kappa 0.75) and positive agreement was 77.5%. Baseline CIN2 and CIN3+ rates based on HPV screening were 8.6/1,000 and 6.6/1,000 respectively; 24 month rates were 0.7/1,000 and 0.4/1,000 (LBC screening). HC2 and COBAS were concordant positive for 91% of round 1 CIN2 and 98% of CIN3+. CIN3+ was significantly associated with HPV 16 (Odds Ratio [OR] 5.11; 95% confidence interval [CI] 2.30, 11.37), but not HPV 18 (OR 2.62; 95% CI 0.73, 9.49), vs. non-HPV 16/18 HPV at baseline. There was no significant association between HPV genotype and CIN2. CIN3+ was significantly more likely for high-grade (OR 5.99; 95% CI 2.53, 14.18), but not low-grade (OR 0.54; 95% CI 0.20, 1.49), vs. negative LBC. No significant association was observed between LBC grade and CIN2. HPV 16 and 18 were associated with 33% of CIN2 and 68% of CIN3+ identified at baseline.Conclusions: For hrHPV positive women, abnormal reflex LBC is appropriate for colposcopy triage. In addition, immediate referral of women with HPV 16/18 and normal cytology may allow for earlier detection of CIN2+ lesions which would not be detected until after follow-up testing. [ABSTRACT FROM AUTHOR]

Background: In the HPV FOCAL trial, we will establish the efficacy of hr-HPV DNA testing as a stand-alone screening test followed by liquid based cytology (LBC) triage of hr-HPV-positive women compared to LBC followed by hr-HPV triage with ⩾ CIN3 as the outcome. Methods/Design: HPV-FOCAL is a randomized, controlled, three-armed study over a four year period conducted in British Columbia. It will recruit 33,000 women aged 25-65 through the province's population based cervical cancer screening program. Control arm: LBC at entry and two years, and combined LBC and hr-HPV at four years among those with initial negative results and hr-HPV triage of ASCUS cases; Two Year Safety Check arm: hr-HPV at entry and LBC at two years in those with initial negative results with LBC triage of hr-HPV positives; Four Year Intervention Arm: hr-HPV at entry and combined hr-HPV and LBC at four years among those with initial negative results with LBC triage of hr-HPV positive cases Discussion: To date, 6150 participants have a completed sample and epidemiologic questionnaire. Of the 2019 women enrolled in the control arm, 1908 (94.5%) were cytology negative. Women aged 25-29 had the highest rates of HSIL (1.4%). In the safety arm 92.2% of women were hr-HPV negative, with the highest rate of hr-HPV positivity found in 25-29 year old women (23.5%). Similar results were obtained in the intervention arm HPV FOCAL is the first randomized trial in North America to examine hr-HPV testing as the primary screen for cervical cancer within a population-based cervical cancer screening program. Trial Registration: International Standard Randomised Controlled Trial Number Register, ISRCTN79347302. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer, a preventable disease associated with the human papillomavirus, is responsible for significant morbidity and mortality globally. Primary human papillomavirus testing is more sensitive in detecting precancerous cervical lesions than cytologic screening and can be conducted using either DNA- or RNA-based assays. Screening programs must select the most appropriate assay from several available assays for their population. It is not yet known whether these assays perform equivalently in the long term, particularly among women with a negative human papillomavirus test result. This study aims to compare long-term safety after a negative human papillomavirus test result across both DNA- and RNA-based testing assays.Objective: This study aimed to compare long-term high-grade cervical intraepithelial neoplasia (grade 2 or higher and grade 3 or higher) outcomes of 2 DNA-based assays (Digene Hybrid Capture 2 High-Risk HPV DNA Test and cobas 4800 HPV Test) and 1 messenger RNA-based assay (Aptima HPV Assay) using data from the Human Papillomavirus For Cervical Cancer Trial-DECADEl (FOCAL-DECADE) cohort, by first comparing the positive and negative rates between the assays and then investigating the cumulative incidence of cervical intraepithelial neoplasia grade 2 and higher and grade 3 or higher detection among participants in the FOCAL DECADE cohort over follow-up according to human papillomavirus testing assays.Study Design: The FOCAL Trial was a randomized controlled trial that evaluated human papillomavirus testing for primary cervical cancer screening. The FOCAL-DECADE cohort subsequently followed FOCAL Trial participants passively through the British Columbia Cervix Screening Program Database for approximately 10 years after the FOCAL Trial study exit to examine the rates of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher. For this study, eligible participants had baseline human papillomavirus-negative results from at least 1 assay and had 1 or more cytologic screens after baseline (9509 participants for DNA-based and 3473 participants for DNA- vs RNA-based assay comparisons). We constructed cumulative incidence curves and compared the hazard ratios for cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher detection according to the assays.Results: Over 10 years of follow-up, the cumulative incidence of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher did not significantly differ between the DNA-based assays (hazard ratio, 0.95; 95% confidence interval, 0.84-1.06; P=.35 and hazard ratio, 0.82; 95% confidence interval, 0.66-1.01; P=.06 for cervical intraepithelial neoplasia grade 2 or higher and cervical intraepithelial neoplasia grade 3 or higher, respectively) or between the DNA- and RNA-based assays (hazard ratio, 0.97; 95% confidence interval, 0.87-1.06; P=.48 and hazard ratio, 0.94; 95% confidence interval, 0.79-1.13; P=.52 for cervical intraepithelial neoplasia grade 2 or higher and cervical intraepithelial neoplasia grade 3 or higher, respectively).Conclusion: Among participants who tested negative for human papillomavirus at baseline, the long-term risk of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher did not significantly differ regardless of whether DNA- or RNA-based human papillomavirus testing assays were used. Screening program decision makers can be confident that for women who test negative for human papillomavirus, DNA- and RNA-based assays exhibit similar cervical intraepithelial neoplasia grade 2 or higher outcomes over several years. [ABSTRACT FROM AUTHOR]

• First estimates of HPV prevalence 10 years post school-based vaccination in BC. • Non-statistically significant decline in prevalence of HPV16/18 post-vaccination. • Changes in screening guidelines may underestimate the vaccination program impact. British Columbia (BC) introduced a publicly funded, school-based human papillomavirus (HPV) immunization program in 2008 with the quadrivalent vaccine. In 2010/2011, a baseline evaluation of HPV prevalence was conducted among women undergoing cervical cancer screening. After 10 years of publicly funded HPV vaccination, HPV-type prevalence was re-evaluated. From August 2017 to March 2018, 1107 physicians were invited to return cytobrushes used during routine Pap screening to the Cervical Cancer Screening Laboratory for HPV testing. Only age or year of birth was collected. Specimens were screened for high-risk HPV (hrHPV) and positive samples were genotyped. HPV type prevalence was compared for females 15–22 yrs (those eligible for the school-based vaccination) and 23+ yrs (ineligible for school-based vaccination) for the 2010/2011 and the 2017/2018 data. There were 3309 valid samples received for testing; of these, 3107 were included in the analysis. The overall hrHPV prevalence was 12.2% (95% CI 11.3–13.3) in 2010/11, and 12.0% (95% CI 10.9–13.2) in 2017/18. For the 15–22 age group, the prevalence for any hrHPV was 26.8% (95% CI 23.1–30.8) in 2010/11 and 25.4% (95% CI 15.3–37.9) in 2017/18. For those aged 15–22, HPV16 prevalence in 2010/11 was 8.8% (95% CI 6.5–11.5) and in 2017/18 was 6.3% (95% CI 1.8–15.5), with corresponding figures for HPV18 3.7% (95% CI 2.3–5.7) and 0% (95% CI 0.0–5.7), respectively. For all hrHPV types, there were no statistically significant differences between the 2010/11 and 2017/18 periods. This study illustrates the prevalence of hrHPV in BC over time in women undergoing cervical cancer screening, where an indication of a decline in HPV16/18 is seen in vaccine eligible women. [ABSTRACT FROM AUTHOR]