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.

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

Comparative performance of human papillomavirus messenger RNA versus DNA screening tests at baseline and 48 months in the HPV FOCAL trial.

BACKGROUND: HPV FOCAL is a randomized trial comparing high-risk HPV [Hybrid Capture 2 (HC2)] vs. liquid-based cytology (LBC) for primary cervical screening. OBJECTIVE: The present study objective was to compare Aptima HPV (AHPV) and HC2 assay performance at the intervention arm baseline and 48 mo. screens in relation to the rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+). STUDY DESIGN: Women enrolled after December 2010 (n = 3475) were screened at baseline with both AHPV and HC2 (AHPV was blinded). Women with CIN2+ exited the trial; HC2 negative (-) women and those HC2 positive (+) with

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.

Aptima HPV Assay versus Hybrid Capture® 2 HPV test for primary cervical cancer screening in the HPV FOCAL trial.

BACKGROUND: Cervical cancer screening programs are switching from Pap screening to high-risk HPV testing. OBJECTIVES: To compare the Aptima HPV Assay (AHPV) with the Hybrid Capture® 2 High-Risk HPV DNA Test® (HC2) for primary cervical screening. STUDY DESIGN: HPV FOCAL is a randomized trial comparing HC2 to liquid-based cytology (LBC) for screening women aged 25-65. AHPV and HC2 were compared at the baseline screen (n=3473). Genotyping was by the Aptima HPV 16 18/45 Genotype Assay. We assessed HPV genotyping and reflex LBC for colposcopy triage. RESULTS: AHPV/HC2 agreement was 96.5% (kappa 0.76); positive agreement was 77.4%. The AHPV positive rate was 7.2% vs. 8.4% for HC2 (p=0.06). Based on HC2 screening, round 1 CIN2 and CIN3+ rates were 9.2/1000 and 5.2/1000 respectively. Using HC2 as the comparator test, AHPV CIN2+ and CIN3+ relative sensitivities were 0.96 and 1.00 (p=1.00) respectively. High-grade reflex LBC and HPV 16 infection were significantly associated with CIN3+. AHPV specificity was 0.94 vs. 0.93 (p=0.05) for HC2. Compared with triage of HC2+ with abnormal cytology or HPV persistence for 12 months, colposcopy referral would be significantly reduced (38.3/1000 vs. 60.8/1000; p<0.001) if AHPV+ women with abnormal LBC and HPV 16/18/45 were referred at baseline. CIN2+ and CIN3+ detection rates were not significantly different for the two strategies. CONCLUSIONS: AHPV vs. HC2 screening had equivalent CIN2+ and CIN3+ detection. Triage of AHPV+ by abnormal reflex LBC and the presence of HPV 16/18/45 would result in a significantly lower colposcopy referral rate with similar CIN2+ and CIN3+ detection rates as the overall HC2+ referral algorithm.

Fluorescence confocal endomicroscopy of the cervix: pilot study on the potential and limitations for clinical implementation.

Current diagnostic capabilities and limitations of fluorescence endomicroscopy in the cervix are assessed by qualitative and quantitative image analysis. Four cervical tissue types are investigated: normal columnar epithelium, normal and precancerous squamous epithelium, and stromal tissue. This study focuses on the perceived variability within and the subtle differences between the four tissue groups in the context of endomicroscopic in vivo pathology. Conclusions are drawn on the general ability to distinguish and diagnose tissue types, on the need for imaging depth control to enhance differentiation, and on the possible risks for diagnostic misinterpretations.

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.

Reduction in cervical intraepithelial neoplasia in young women in British Columbia after introduction of the HPV vaccine: An ecological analysis.

We report on the rates of cervical intraepithelial neoplasia (CIN) in young women aged 15-22 years of age in British Columbia before and after the introduction of an HPV vaccine program. Rates of cervical intraepithelial neoplasia (CIN) 2+ for each age stratum (15-22) in the calendar years 2004-2012 for the province of British Columbia were obtained from the BC Cancer Agency's population-based cervical cancer program. Incidence rate ratios (IRR) of CIN2+ were described and compared before and after HPV vaccine program introduction in cohorts born in vaccine eligible years, and in non-vaccine eligible years using piece-wise Poisson regression analysis, and adjusted for age. Between 2004 and 2012, rates of CIN2 and CIN2+ in young women aged 15-22 years in the province of British Columbia have decreased overall. After the introduction of the HPV vaccine program, the age adjusted IRR for CIN2+ for young women aged 15-17 years decreased significantly from 0.91 (95% CI: 0.86-0.98 p < 0.01) to 0.36 (95% CI: 0.18-0.73 p < 0.01). During the same time period, no similar reduction was found in young women 18-22 years. After introduction of HPV vaccine program, IRR for CIN2+ in young women 15-17 was significantly reduced for CIN2+ (0.14; 95% CI: 0.04- 0.47; p < 0.01) and CIN2 (0.1; 95% CI: 0.02-0.54; p < 0.01). This ecological analysis shows a significant reduction in CIN2+ lesions in young women aged 15-17 years in British Columbia after the introduction of the HPV vaccine in young women despite vaccine uptake levels below 70%.

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.

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.

A randomized controlled trial of Human Papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL Trial).

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 > or = 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.

Simplifying the implant treatment for an unrestorable premolar with a one-piece implant: a clinical report.

The routine and frequent use of dental implants to replace missing teeth is accompanied by high expectations from patients. These expectations are not limited to function and esthetics but extend to patient comfort and time spent receiving treatment. Replacement of an unrestorable maxillary premolar can be challenging when considering the concerns of patients. This clinical report describes a short, simple, and cost-effective treatment option for replacing an unrestorable premolar tooth with a 1-piece implant.