Strategies to accelerate the elimination of cervical cancer in British Columbia, Canada: a modelling study.

BACKGROUND: To eliminate cervical cancer in Canada by 2040, defined as an annual age-standardized incidence rate (ASIR) lower than 4.0 per 100 000 women, the Canadian Partnership Against Cancer (CPAC) identified 3 priorities for action: increasing human papillomavirus (HPV) vaccine coverage, implementing HPV-based screening and increasing screening participation, and improving follow-up after abnormal screen results. Our objective was to explore the impact of these priorities on the projected time to elimination of cervical cancer in British Columbia. METHODS: We used OncoSim-Cervical, a microsimulation model led and supported by CPAC and developed by Statistics Canada that simulates HPV transmission and the natural history of cervical cancer for the Canadian population. We updated model parameters to reflect BC's historical participation rates and program design. We simulated the transition to HPV-based screening and developed scenarios to explore the additional impact of achieving 90% vaccination coverage, 95% screening recruitment, 90% ontime screening, and 95% follow-up compliance. We projected cervical cancer incidence, ASIR, and year of elimination for the population of BC for 2023-2050. RESULTS: HPV-based screening at current vaccination, participation, and follow-up rates can eliminate cervical cancer by 2034. Increasing on-time screening and follow-up compliance could achieve this target by 2031. Increasing vaccination coverage has a small impact over this time horizon. INTERPRETATION: With the implementation of HPV-based screening, cervical cancer can be eliminated in BC before 2040. Efforts to increase screening participation and follow-up through this transition could potentially accelerate this timeline, but the transition from cytology- to HPV-based screening is fundamental to achieving this goal.

Experiences with thermal ablation for cervical precancer treatment after self-collection HPV-based screening in the ASPIRE Mayuge randomized trial.

Cervical cancer remains a significant public health burden in low-resourced countries. Thus, the WHO prioritized cervix screening, and recently recommended thermal ablation treatment for cervical precancer. However, there is limited information on side effects during treatment and recovery, and acceptability among those treated. The ASPIRE Mayuge trial recruited women to participate in self-collection cervix screening between 2019 and 2020 (N = 2019). Screen-positive women (N = 531, 26.3%) were referred for visual inspection with acetic acid and thermal ablation treatment, per Uganda Ministry of Health recommendations; 71.2% of those referred attended follow-up. Six months post-screening, a subset of trial participants were recontacted. Those who received thermal ablation completed a survey assessing side effects during and after the procedure, and willingness to recommend the treatment to others. We summarized the results to describe the side effects and acceptability of thermal ablation treatment. Of 2019 participants, 349 (17%) received thermal ablation. A subset of 135 completed the follow-up survey, where 90% reported pain during treatment; however, intensity and duration were low. Over a third of women reported problems with recovery for reasons including pain, discharge and bleeding. Regardless, 98% reported they would recommend the treatment to others. The use of thermal ablation to treat cervical precancer appears to be highly acceptable in this population. While many women reported side effects during the procedure and recovery, the majority said they would recommend the treatment to others. However, given the substantial proportion who reported problems with recovery, efforts should be made to provide additional resources to women after receiving thermal ablation treatment for cervical precancer.

Human papillomavirus-based screening at extended intervals missed fewer cervical precancers than cytology in the HPV For Cervical Cancer (HPV FOCAL) trial.

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.

Attitudes and Preferences Regarding Non-Clinic-Based Self-Collection for Sexually Transmitted Infection Testing Among Clinic Attendees in British Columbia, Canada.

BACKGROUND: Sexually transmitted infections (STIs) are a global epidemic; although screening programs reduce transmission, barriers, including access and stigma, hinder success. The World Health Organization highlights the ability to maintain health without the direct support of a health care provider as one form of self-care, which can be applied to STI testing. Self-care through non-clinic-based self-collection for STI testing can address barriers while providing comprehensive care. Before implementation of innovative changes to screening approaches, it is important to understand if communities who rely on in-person care will self-collect outside of the clinic setting. This study investigated willingness to use non-clinic-based self-collection for STI testing among STI clinic attendees in British Columbia, Canada. METHODS: Participants (n = 446) were recruited from STI clinics offering clinic-based self-collection for STI testing and completed a survey assessing self-care attitudes, including willingness to self-collect urine samples, throat swabs, and anogenital swabs outside of the clinic setting. Descriptive statistics, bivariable analyses, and multivariable models were conducted to investigate willingness to use non-clinic-based STI self-collection methods and associated correlates. RESULTS: This population reported high willingness to use non-clinic-based self-collection methods for STI testing (urine samples, 73%; throat swabs, 67%; anogenital swabs, 65%). Those aged 35 to 54 years compared with 15 to 34 years were more likely to be willing (adjusted odds ratio, 1.87; 95% confidence interval, 1.03-3.50); those identifying as straight/mostly straight compared with gay/lesbian were less likely to be willing (adjusted odds ratio, 0.39; 95% confidence interval, 0.23-0.65). CONCLUSIONS: Non-clinic-based self-collection for STI testing can address barriers to testing while maintaining quality care. Those currently receiving in-person care find these methods highly acceptable. These findings reinforce that self-collection for STI testing used in British Columbia clinics is acceptable to clients and may be extended to collection performed outside of the clinical setting.

Intention to Receive a COVID-19 Vaccine by HIV Status Among a Population-Based Sample of Women and Gender Diverse Individuals in British Columbia, Canada.

COVID-19 vaccination is recommended for people living with HIV (PLWH), among whom social inequities and co-morbidities may drive risks of COVID-19 infection and outcome severity. Among a provincial (British Columbia) sample, we determined the prevalence of COVID-19 vaccine intention by HIV status and assessed socio-demographic, vaccine hesitancy, and psychological predictors of vaccine intention. Individuals (25-69 years) recruited from province-wide research cohorts and the general public completed an online survey examining COVID-19 impacts (August/2020-March/2021). In an analysis restricted to women and gender diverse participants (n = 5588), we compared intention to receive a recommended COVID-19 vaccine (Very likely/Likely vs Neutral/Unlikely/Very Unlikely) by self-reported HIV status. Logistic regression models assessed the independent effect of HIV status and other factors on COVID-19 vaccine intention. Of 5588 participants, 69 (1.2%) were living with HIV, of whom 79.7% were on antiretroviral therapy. In bivariate analyses, intention to vaccinate was significantly lower among PLWH compared to participants not living with HIV (65.2% vs 79.6%; OR 0.44; 95%CI 0.32-0.60). However, this association was not statistically significant after adjustment for ethnicity, income, education, and essential worker status (aOR 0.85; 95%CI 0.48-1.55). Among PLWH, those with greater vaccine confidence, positive attitudes towards the COVID-19 vaccine, and more strongly influenced by direct and indirect social norms to vaccinate had significantly higher odds of vaccine intention. Tailored messaging is needed to build vaccine confidence, address questions about vaccine benefits, and support informed vaccination decision-making to promote COVID-19 vaccine uptake among women and gender diverse people living with HIV.

Long-term cervical precancer outcomes after a negative DNA- or RNA-based human papillomavirus test result.

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.

Intention to receive a COVID-19 vaccine: results from a population-based survey in Canada.

BACKGROUND: The success of any COVID-19 vaccine program ultimately depends on high vaccine uptake. This study determined overall intention to receive a COVID-19 vaccine and identified factors that predict intentions to be vaccinated against COVID-19 in Canada, specifically in key priority groups identified by the American Committee on Immunization Practice (ACIP) and the National Advisory Committee on Immunization (NACI) for early immunization. METHODS: Individuals from research cohorts from the general population of British Columbia aged 25-69 were invited complete an online survey based on validated scales and theoretical frameworks to explore intention to receive a COVID-19 vaccine. Two multivariable logistic regression models were conducted to determine factors associated with intention to receive the COVID-19 vaccine. RESULTS: Of 4948 respondents, 79.8% intended to receive a COVID-19 vaccine. In multivariable modeling, respondents who intended to receive the vaccine had higher vaccine attitudinal scores (p <  0.001), reported greater influence of direct social norms (p = 0.001), and indirect social norms, including their family physician (p = 0.024), and Provincial Health Officer (p = 0.011). Older individuals (> 60 years) were more likely to intend to receive the vaccine, while females (95%CI 0.57,0.93), those with less than high school education (95%CI 0.5,0.76), those who self-identified as non-white (95%CI 0.60,0.92), self-identified as Indigenous (95%CI 0.36,0.84) and essential non-health care workers (95%CI 0.59,0.86) had lower adjusted odds of intending to receive a COVID-19 vaccine. CONCLUSIONS: To optimize vaccine coverage, public health should focus on key messages around vaccine safety and benefit, and leverage trusted practitioners for messaging. As certain key populations identified by NACI and ACIP for early immunization report a lower intention to vaccinate, there is a need for in-depth education and support for these communities to ensure optimal uptake.

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening.

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.

Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial.

Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case-control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25-65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50

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.

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.

HPV for cervical cancer screening (HPV FOCAL): Complete Round 1 results of a randomized trial comparing HPV-based primary screening to liquid-based cytology for cervical cancer.

Complete Round 1 data (baseline and 12-month follow-up) for HPV FOCAL, a randomized trial establishing the efficacy of HPV DNA testing with cytology triage as a primary screen for cervical cancer are presented. Women were randomized to one of three arms: Control arm - Baseline liquid-based cytology (LBC) with ASCUS results triaged with HPV testing; Intervention and Safety arms - Baseline HPV with LBC triage for HPV positives. Results are presented for 15,744 women allocated to the HPV (intervention and safety combined) and 9,408 to the control arms. For all age cohorts, the CIN3+ detection rate was higher in the HPV (7.5/1,000; 95%CI: 6.2, 8.9) compared to the control arm (4.6/1,000; 95%CI: 3.4, 6.2). The CIN2+ detection rates were also significantly higher in the HPV (16.5/1,000; 95%CI: 14.6, 18.6) vs. the control arm (10.1/1,000; 95%CI: 8.3, 12.4). In women ≥35 years, the overall detection rates for CIN2+ and CIN3+ were higher in the HPV vs. the control arm (CIN2+:10.0/1,000 vs. 5.2/1,000; CIN3+: 4.2/1,000 vs. 2.2/1,000 respectively, with a statistically significant difference for CIN2+). HPV testing detected significantly more CIN2+ in women 25-29 compared to LBC (63.7/1,000; 95%CI: 51.9, 78.0 vs. 32.4/1,000; 95%CI: 22.3, 46.8). HPV testing resulted in significantly higher colposcopy referral rates for all age cohorts (HPV: 58.9/1,000; 95%CI: 55.4, 62.7 vs. CONTROL: 30.9/1,000; 95%CI: 27.6, 34.6). At completion of Round 1 HPV-based cervical cancer screening in a population-based program resulted in greater CIN2+ detection of across all age cohorts compared to LBC screening.

Post-Loop Electrosurgical Excision Procedure High-Risk Human Papillomavirus Testing as a Test of Cure: The British Columbia Experience.

OBJECTIVES: To determine whether Hybrid Capture 2 High-Risk HPV DNA Test (HC2) can be used as a test of cure in women treated for cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and allow discharge from colposcopy follow-up with a return to a cytology-based screening program for HC2-negative women. MATERIALS AND METHODS: Data were analyzed for all women who underwent a loop electrosurgical excision procedure between August 1, 2008, and June 30, 2011, and had a valid HC2 result after loop electrosurgical excision procedure and follow-up histopathology result, to determine risk of persistent or recurrent CIN 2+ in HC2-positive and HC2-negative women. RESULTS: Two thousand three hundred forty women had adequate biopsies and valid HC2 results. Of 460 HC2-positive women, 118 (25.7%) were diagnosed with CIN 2+, whereas of 1,880 HC2-negative women, 35 (1.9%) had a subsequent diagnosis of CIN 2+ (p < .0002) yielding a HC2-negative predictive value of 98.1% (95% confidence interval = 97.4-98.7). Of 460 HC2-positive women, 306 initially had negative biopsies. In the subsequent 36 months, 38 of the 306 were diagnosed with CIN 2+. CONCLUSIONS: We conclude that women with a negative HC2 test can safely return to routine annual cytology screening by primary care providers while women who test HC2 positive are at higher risk and should continue to be followed by colposcopy, even if their initial biopsy is negative.

Disease detection and resource use in the safety and control arms of the HPV FOCAL cervical cancer screening trial.

BACKGROUND: The HPV FOCAL Trial is a RCT comparing human papilloma virus (HPV) with Liquid Based Cytology (LBC) screening for cervical cancer. Results are presented for the comparison of the Safety and Control arms after two rounds. METHODS: HPV FOCAL included randomisation of women aged 25-65 into the Safety arm, where they were initially screened with HPV and the Control arm, where they received entry screening with LBC, with both arms screened again with LBC at 24 months. RESULTS: There are 6203 (Safety) and 6075 (Control) women included in this analysis. For the Safety vs Control arms, Round 1 screening resulted in increased detection of cervical intraepithelial neoplasia 2 or worse (CIN2+),15.3 vs 10.4 per 1000, RR=1.48 (95%CI=1.08-2.03) and higher colposcopy referral rates, 5.6% vs 3.2%. LBC screening at 24 months resulted in similar colposcopy referral rates, 1.5% vs 1.9%, and decreased CIN2+ detection, 2.0 vs 4.7 per 1000, RR=0.43 (95%CI=0.21-0.88) in the Safety vs Control arms. CIN2+ detection and colposcopy referral rates declined with increasing age in both arms. One round of HPV screening detected similar levels of CIN2+ as two rounds of LBC screening. INTERPRETATION: CIN2+ detection at 2 years was lower in those screened by HPV, indicating an improved 2-year negative predictive value of the HPV test.

Correlates of women's intentions to be screened for human papillomavirus for cervical cancer screening with an extended interval.

BACKGROUND: High-risk HPV DNA testing has been proposed as a primary tool for cervical cancer screening (HPV-CCS) as an alternative to the Papanicolaou cytology- method. This study describes factors associated with women's intentions to attend cervical cancer screening if high-risk HPV DNA testing (HPV-CCS) was implemented as a primary screening tool, and if screening were conducted every 4 years starting after age 25. METHODS: This online survey was designed using the Theory of Planned Behaviour to assess factors that impact women's intentions to attend HPV-CCS among women aged 25-69 upon exit of the HPV FOCAL trial. Univariate and regression analyses were performed to compare the demographic, sexual history, and smoking characteristics between women willing and unwilling to screen, and scales for intention to attend HPV-CCS. A qualitative analysis was performed by compiling and coding the comments section of the survey. RESULTS: Of the 981 women who completed the survey in full, only 51.4 % responded that they intended to attend HPV-CCS with a delayed start age and extended screening interval. Women who intended to screen were more likely to have higher education (AOR 0.59, 95 % CI [0.37, 0.93]), while both positive attitudes (AOR 1.26, 95 % CI [1.23, 1.30]) and perceived behavior control (AOR 1.06, 95 % CI [1.02, 1.10]) were significant predictors of intention to screen. Among women who provided comments in the survey, a large number of women expressed fears about not being checked more than every 4 years, but 12 % stated that these fears may be alleviated by having more information. CONCLUSIONS: Acceptability of increased screening intervals and starting age could be improved through enhanced education of benefits. Program planners should consider measures to assess and improve women's knowledge, attitudes and beliefs prior to the implementation of new screening programs to avoid unintended consequences.

Comparison of the Roche cobas® 4800 and Digene Hybrid Capture® 2 HPV tests for primary cervical cancer screening in the HPV FOCAL trial.

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.

Women's intentions to self-collect samples for human papillomavirus testing in an organized cervical cancer screening program.

BACKGROUND: Mounting evidence affirms HPV testing as an effective cervical cancer screening tool, and many organized screening programs are considering adopting it as primary testing. HPV self-collection has comparable sensitivity to clinician collected specimens and is considered a feasible option in hard-to-reach women. We explored women's intentions to HPV self-collect for cervical cancer screening from a cohort participating in a Canadian randomized controlled cervical cancer screening trial. METHODS: Women aged 25-65 were invited to complete an online survey assessing intentions to be screened with HPV testing instead of the Pap smear. The survey was based in the Theory of Planned Behaviour and questions were included to assess women's intentions to self-collect for HPV. Demographic characteristics of women who intended to self-collect were compared with those who did not. Demographic and scale variables achieving a p-value <0.1 in the univariate and bivariate analyses were included in the stepwise logistic regression model. The final model was created to predict factors associated with women's intentions to self-collect an HPV specimen for cervical cancer. Odds ratios were calculated with 95% confidence intervals to identify variables associated with a woman's intention to self-collect for cervical cancer screening. RESULTS: The overall survey response rate was 63.8% (981/1538) with 447 (45.6%) reporting they intended to self-collect, versus 534 (54.4%) reporting they did not. In the univariate analysis, women with more than high school education were more likely to self-collect. Women who intended to receive HPV testing versus the Pap smear were 1.94 times as likely to be in favour of self-collection and those who intended to self-collect had significantly higher attitudinal scores towards HPV self-collection. The adjusted odds ratio and 95% confidence interval from the multivariate analysis demonstrated attitude towards self-collection was the only significant variable predicting a woman's intention to self-collect (OR 1.25; 95% CI: 1.22, 1.29). CONCLUSIONS: The primary predictor of a woman's intention to HPV self-collect for cervical cancer screening was her attitude towards the procedure. From a program planning perspective, these results indicate that education and awareness may be significant contributing factors to improving acceptance of self-collection and subsequently, improving screening attendance rates.

HPV Extended Genotyping to Triage Abnormal Cervical Cancer Screens-Balancing the Harms and Benefits of an Additional Triage Test before Direct Colposcopy Referral.

The Netherlands' cervical cancer screening program transitioned to primary human papillomavirus (HPV) screening in 2017. After the introduction of HPV-based screening, the country saw increases in colposcopy referral rates and detections of low-grade lesions. In July 2022, genotyping was introduced, and those with borderline or mild dyskaryotic (BMD) cytologic abnormalities were only referred to colposcopy if positive for HPV type 16 or 18, and repeat screening otherwise. In this article, various strategies using extended genotyping (HPV16/18/31/33/45/52/58) as a triage test after an abnormal screen were explored using data from HPV-positive participants with normal or BMD cytology in the Population-Based Screening Study Amsterdam (POBASCAM) trial. The authors assessed positive and negative predictive values and colposcopy referral rates for each strategy using extended genotyping to triage women to either direct referral to colposcopy or repeat screening. Direct referral did not meet positive and negative predictive value thresholds for efficiency for any strategies. However, the authors note that direct referral may nonetheless be useful among those with BMD due to minimal increases in colposcopy referrals and concerns of loss to follow-up at repeat screening. These findings demonstrate the potential utility of extended genotyping as a triage test in primary HPV screening programs. The results should be considered alongside the fact that referral to repeat screening may result in loss of engagement of women who need treatment to prevent invasive cancer. See related article by Kroon et al., p. 1037.

Evidence of Decreased Long-term Risk of Cervical Precancer after Negative Primary HPV Screens Compared with Negative Cytology Screens in a Longitudinal Cohort Study.

BACKGROUND: The growing use of primary human papillomavirus (HPV) cervical cancer screening requires determining appropriate screening intervals to avoid overtreatment of transient disease. This study examined the long-term risk of cervical precancer after HPV screening to inform screening interval recommendations. METHODS: This longitudinal cohort study (British Columbia, Canada, 2008 to 2022) recruited women and individuals with a cervix who received 1 to 2 negative HPV screens (HPV1 cohort, N = 5,546; HPV2 cohort, N = 6,624) during a randomized trial and women and individuals with a cervix with 1 to 2 normal cytology results (BCS1 cohort, N = 782,297; BCS2 cohort, N = 673,778) extracted from the provincial screening registry. All participants were followed through the registry for 14 years. Long-term risk of cervical precancer or worse [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)] was compared between HPV and cytology cohorts. RESULTS: Cumulative risks of CIN2+ were 3.2/1,000 [95% confidence interval (CI), 1.6-4.7] in HPV1 and 2.7/1,000 (95% CI, 1.2-4.2) in HPV2 after 8 years. This was comparable with the risk in the cytology cohorts after 3 years [BCS1: 3.3/1,000 (95% CI, 3.1-3.4); BCS2: 2.5/1,000 (95% CI, 2.4-2.6)]. The cumulative risk of CIN2+ after 10 years was low in the HPV cohorts [HPV1: 4.7/1,000 (95% CI, 2.6-6.7); HPV2: 3.9 (95% CI, 1.1-6.6)]. CONCLUSIONS: Risk of CIN2+ 8 years after a negative screen in the HPV cohorts was comparable with risk after 3 years in the cytology cohorts (the benchmark for acceptable risk). IMPACT: These findings suggest that primary HPV screening intervals could be extended beyond the current 5-year recommendation, potentially reducing barriers to screening.

Women's intentions to receive cervical cancer screening with primary human papillomavirus testing.

We explored the potential impact of human papillomavirus (HPV) testing on women's intentions to be screened for cervical cancer in a cohort of Canadian women. Participants aged 25-65 years from an ongoing trial were sent a questionnaire to assess women's intentions to be screened for cervical cancer with HPV testing instead of Pap smears and to be screened every 4 years or after 25 years of age. We created scales for attitudes about HPV testing, perceived behavioral control, and direct and indirect subjective norms. Demographic data and scales that were significantly different (p < 0.1) between women who intended to be screened with HPV and those who did not intend were included in a stepwise logistic regression model. Of the 2,016 invitations emailed, 1,538 were received, and 981 completed surveys for a response rate of 63% (981/1,538). Eighty-four percent of women (826/981) responded that they intended to attend for HPV-based cervical cancer screening, which decreased to 54.2% when the screening interval was extended, and decreased further to 51.4% when screening start was delayed to age of 25. Predictors of intentions to undergo screening were attitudes (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.15, 1.30), indirect subjective norms (OR: 1.02; 95% CI: 1.01, 1.03) and perceived behavioral control (OR: 1.16; 95% CI: 1.10; 1.22). Intentions to be screened for cervical cancer with HPV testing decreased substantially when the screening interval was extended and screening started at age of 25. Use of primary HPV testing may optimize the screening paradigm, but programs should ensure robust planning and education to mitigate any negative impact on screening attendance rates.

Colposcopy referral rates post-introduction of primary screening with human papillomavirus testing: evidence from a large British Columbia cohort study.

Background: Shifting from cytology to human papillomavirus (HPV)-based cervical cancer screening will initially increase colposcopy referrals. The anticipated impact on health systems has been raised as a concern for implementation. It is unclear if the higher rate of colposcopy referrals is sustained after initial HPV-based screens or reverts to new lower baselines due to earlier detection and treatment of precancer. This study aimed to investigate long-term rates of colposcopy referrals after participation in HPV-based screening. Methods: Participants of HPV for Cervical Cancer Screening trial (HPV FOCAL) received one (HPV1, N = 6204) or two (HPV2, N = 9540) HPV-based screens. After exit, they returned to British Columbia's (BC) cytology screening program. A comparison cohort from the BC screening population (BCS, N = 1,140,745) was identified, mirroring trial inclusion criteria. All participants were followed for 10-14 years through the provincial screening registry. Colposcopy referral rates per 1000 screens were calculated for each group. Trial colposcopy referrals for HPV1 and HPV2 were calculated under two referral scenarios: (1) all HPV positive referred to colposcopy; (2) cytology triage with ASCUS or greater referred to colposcopy. Colposcopy referrals from post-trial screens in HPV1 an HPV2 and all screens in BCS were based on actual recommendations from the screening program. A multivariable flexible survival regression model compared hazard ratios (HR) throughout follow-up. Findings: Scenario 2 referral rates were higher during initial HPV screen(s) vs cytology screen (HPV1: 28 per 1000 screens (95% CI: 24, 33), HPV2: 32 per 1000 screens (95% CI: 29, 36), BCS: 8 per 1000 screens (95% CI: 8.9)). However, post-trial rates in HPV1 and HPV2 were significantly lower than in BCS. Cumulative rates in HPV1 and HPV2 approached the cumulative rate in BCS 11-12 years after HPV-based screening (HPV1: 11 per 1000 screens (95% CI: 10, 12), HPV2: 16 per 1000 screens (95% CI: 15-17), BCS: 11 per 1000 screens (95% CI: 10, 11)). Adjusted models demonstrated reductions in referral rates in HPV1 (HR = 0.6, 95% CI: 0.5, 0.7) and HPV2 (HR = 0.7, 95% CI: 0.6, 0.8) relative to BCS by 54 and 72 months post-final HPV screen respectively. Interpretation: Reduced colposcopy referral rates were observed after initial rounds of HPV-based screening. After initial HPV screening, referral rates to colposcopy after cytology triage were below the current rates seen in a centralized cytology program after approximately four years. Any expected increase in referrals at initiation of HPV-based screening could be countered by staged program implementation. Funding: This work was supported by the National Institutes of Health (R01 CA221918), Michael Smith Health Research BC (RT-2021-1595), and the Canadian Institutes of Health Research (MCT82072).