Risk of cervical precancer among HPV-negative women in the Netherlands and its association with previous HPV and cytology results: A follow-up analysis of a randomized screening study.

BACKGROUND: Human papillomavirus (HPV)-based screening programs still use one-size-fits-all protocols but efficiency and efficacy of programs may be improved by stratifying women based on previous screening results. METHODS AND FINDINGS: We studied the association between cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and previous screening results in the Population-Based Screening Study Amsterdam (POBASCAM) trial, performed in the Netherlands in the setting of regular screening, where women aged from 29 to 61 years old were invited to cytology and HPV co-testing at enrolment in year 1999/2002 and at the next round in 2003/2007. We selected 18,448 women (9,293 from the intervention group and 9,155 from the control group) who tested HPV-negative in 2003/2007 and did not have cervical intraepithelial neoplasia grade 2 or worse (CIN2+) or hysterectomy after enrolment. Follow-up was collected until 14 years after the 2003/2007 screen, covering 4 rounds of screening. Risk of CIN3+ and CIN2+ among women with an HPV-negative test, irrespective of previous round results and stratified according to previous round HPV and cytology results, were calculated by the Kaplan-Meier method. During 14 years of follow-up, 62 CIN3+ cases (24 in the intervention group and 38 in the control group) were detected. HPV-negative women had a 14-year CIN3+ risk of 0.48% (95% confidence interval 0.37 to 0.62) and CIN2+ risk of 1.17% (0.99 to 1.38). The CIN3+ risk among HPV-negative women was increased in women with a previous positive HPV test (2.36%, 1.20 to 4.63; p < 0.001) or co-test (1.68%, 0.87 to 3.20; p < 0.001) and, equivalently, decreased in women with a previous negative HPV test (0.43%, 0.33 to 0.57) or a negative co-test (0.43%, 0.33 to 0.57). The CIN3+ risk was not influenced by the previous cytology result. The CIN3+ risk among HPV-negative women was increased after both a previous HPV16-positive test (3.90%, 1.47 to 10.12; p < 0.001) and a previous HPV16-negative/HPVother-positive test (1.91%, 0.76 to 4.74; p = 0.002). For endpoint CIN2+ (147 cases), findings were similar except that the CIN2+ risk was increased after previous abnormal cytology (4.06%, 2.30 to 7.12; p < 0.001). The presented risk estimates were calculated by tracking histological results through the Dutch nationwide pathology archive (PALGA) and were not adjusted for non-compliance with the colposcopy referral advice. CONCLUSIONS: HPV-negative women had an increased long-term risk of CIN3+ when the HPV test in the previous screening round was positive. This supports the implementation of risk-based intervals that depend on HPV results in the current and previous screening round. TRIAL REGISTRATION: POBASCAM trial, trial registration number ISRCTN20781131.

Estimating the direct effect of human papillomavirus vaccination on the lifetime risk of screen-detected cervical precancer.

Birth cohorts vaccinated against human papillomavirus (HPV) are now entering cervical cancer screening. Assessment of (pre)cancer (CIN3+) risk is needed to assess the residual screening need in vaccinated women. We estimated the lifetime (screen-detected) CIN3+ risk under five-yearly primary HPV screening between age 30 and 60, using HPV genotyping and histology data of 21,287 women participating in a screening trial with two HPV-based screening rounds, 5 years apart. The maximum follow-up after an HPV-positive test was 9 years. We re-estimated the CIN3+ risk after projecting direct vaccine efficacy for the bivalent and the nonavalent HPV vaccines, assuming life-long protection. The lifetime CIN3+ risk was 4.1% (95% confidence interval 3.5-4.9) and declined by 53.5% and 70.5% after bivalent vaccination without and with cross-protection, respectively, translating into a residual lifetime CIN3+ risk of 1.9% (1.4-2.4) and 1.2% (0.9-1.5). The CIN3+ risk declined by 88.5% after nonavalent vaccination, translating into a residual lifetime CIN3+ risk of 0.5% (0.2-0.7). The latter risk increased to 1.6% when vaccine protection only lasted until the first screening round at age 30. Among HPV-positive women with abnormal adjunct cytology, the nine-year CIN3+ risk was 16.9% (8.7-32.4) after nonavalent vaccination. In conclusion, HPV vaccination will lead to a strong decline in the lifetime CIN3+ risk and the remaining absolute CIN3+ risk will be very low. Primary HPV testing combined with adjunct cytology at five-year intervals still seems feasible even after nonavalent vaccination, although unlikely to be cost-effective. Our results support a de-intensification of screening programs in settings with high vaccination coverage.

Hospitalization rates and outcome of invasive bacterial vaccine-preventable diseases in Tuscany: a historical cohort study of the 2000-2016 period.

BACKGROUND: Invasive bacterial diseases (IBD) are a serious cause of hospitalization, sequelae and mortality. Albeit a low incidence, an increase in cases due to H. influenzae was registered in the past 4 years and, in the Tuscany region, an excess of cases due to N. meningitidis since 2015 is alarming. The purpose of this study is to deepen the knowledge of IBD epidemiology in Tuscany with particular attention to temporal trends. METHODS: Tuscan residents hospitalized for IBD from January 1st 2000 to March 18th 2016 were selected from the regional hospital discharge database based on ICD-9-CM codes. Age-specific and standardized hospitalization rates were calculated together with case-fatality rates (CFRs). A time-trend analysis was performed; whereas, prognostic factors of death were investigated through univariable and multivariable analyses. RESULTS: The average standardized hospitalization rates for invasive meningococcal diseases (IMD), invasive pneumococcal diseases and invasive diseases due to H. influenzae from 2000 to 2016 were 0.6, 1.8, and 0.2 per 100,000, respectively. The average CFRs were 10.5%, 14.5% and 11.5% respectively with higher values in the elderly. Older age was significantly associated with higher risk of death from all IBD. A significant reduction in hospitalization rates for IMD was observed after meningococcal C conjugate vaccine introduction. The Annual Percentage Change (APC) was -13.5 (95% confidence interval (CI) -22.3; -3.5) in 2005-2013 but has risen since that period. Furthermore, a significant increasing trend of invasive diseases due to H. influenzae was observed from 2005 onwards in children 1-4 years old (APC 13.3; 95% CI 0; 28.3). CONCLUSIONS: This study confirms changes in the epidemiology of invasive diseases due to H. influenzae and IMD. Furthermore, attention is called to the prevention of IBD in the elderly because of the age group's significantly higher rate of hospitalizations and deaths for all types of IBD.

Comparison of the ScreenFire and Xpert HPV assays for the detection of human papillomavirus and cervical precancer among women living with HIV in Malawi.

BACKGROUND: The World Health Organization recommends human papillomavirus (HPV) testing for primary cervical cancer screening, including among women living with HIV (WLWH). Low-and-middle-income countries account for 85% of the cervical cancer burden globally, yet have limited access to HPV-based screening, largely due to cost. This study aims to compare the performance of a rapid, isothermal amplification HPV assay (ScreenFire) to that of the Xpert HPV assay for the detection of HPV and cervical precancer among WLWH in Malawi. METHODS: We utilized stored self- and provider-collected specimens from a prospective cohort study of WLWH in Malawi from July 2020 to February 2022. Specimens were tested with both Xpert and ScreenFire HPV assays. The overall and within-channel non-hierarchical agreement between ScreenFire and Xpert was determined for both self- and provider-collected specimens. Hierarchical ScreenFire HPV positivity by channel was compared to Xpert for each histological diagnosis-cervical intraepithelial neoplasia grade 2 or worse (CIN2+) compared to

Comparison of the ScreenFire and Xpert HPV assays for the detection of human papillomavirus and cervical precancer among women living with HIV in Malawi.

Background: The World Health Organization (WHO) recommends human papillomavirus (HPV) testing for primary cervical cancer screening, including among women living with HIV (WLWH). Low-and-middle-income countries (LMICs) account for 85% of the cervical cancer burden globally, yet have limited access to HPV-based screening, largely due to cost. This study aims to compare the performance of a rapid, isothermal amplification HPV assay (ScreenFire) to that of the Xpert HPV assay for the detection of HPV and cervical precancer among WLWH in Malawi. Methods: We utilized stored self- and provider-collected specimens from a prospective cohort study of WLWH in Malawi from July 2020 to February 2022. Specimens were tested with both Xpert and ScreenFire HPV assays. The overall and within-channel non-hierarchical agreement between ScreenFire and Xpert was determined for both self- and provider-collected specimens. Hierarchical ScreenFire HPV positivity by channel was compared to Xpert for each histological diagnosis - cervical intraepithelial neoplasia grade 2 or worse (CIN2+) compared to

Design of the HPV-automated visual evaluation (PAVE) study: Validating a novel cervical screening strategy.

Background: The HPV-automated visual evaluation (PAVE) Study is an extensive, multinational initiative designed to advance cervical cancer prevention in resource-constrained regions. Cervical cancer disproportionally affects regions with limited access to preventive measures. PAVE aims to assess a novel screening-triage-treatment strategy integrating self-sampled HPV testing, deep-learning-based automated visual evaluation (AVE), and targeted therapies. Methods: Phase 1 efficacy involves screening up to 100,000 women aged 25-49 across nine countries, using self-collected vaginal samples for hierarchical HPV evaluation: HPV16, else HPV18/45, else HPV31/33/35/52/58, else HPV39/51/56/59/68 else negative. HPV-positive individuals undergo further evaluation, including pelvic exams, cervical imaging, and biopsies. AVE algorithms analyze images, assigning risk scores for precancer, validated against histologic high-grade precancer. Phase 1, however, does not integrate AVE results into patient management, contrasting them with local standard care.Phase 2 effectiveness focuses on deploying AVE software and HPV genotype data in real-time clinical decision-making, evaluating feasibility, acceptability, cost-effectiveness, and health communication of the PAVE strategy in practice. Results: Currently, sites have commenced fieldwork, and conclusive results are pending. Conclusions: The study aspires to validate a screen-triage-treat protocol utilizing innovative biomarkers to deliver an accurate, feasible, and cost-effective strategy for cervical cancer prevention in resource-limited areas. Should the study validate PAVE, its broader implementation could be recommended, potentially expanding cervical cancer prevention worldwide. Funding: The consortial sites are responsible for their own study costs. Research equipment and supplies, and the NCI-affiliated staff are funded by the National Cancer Institute Intramural Research Program including supplemental funding from the Cancer Cures Moonshot Initiative. No commercial support was obtained. Brian Befano was supported by NCI/ NIH under Grant T32CA09168.

Design of the HPV-Automated Visual Evaluation (PAVE) Study: Validating a Novel Cervical Screening Strategy.

Objective: To describe the HPV-Automated Visual Evaluation (PAVE) Study, an international, multi-centric study designed to evaluate a novel cervical screen-triage-treat strategy for resource-limited settings as part of a global strategy to reduce cervical cancer burden. The PAVE strategy involves: 1) screening with self-sampled HPV testing; 2) triage of HPV-positive participants with a combination of extended genotyping and visual evaluation of the cervix assisted by deep-learning-based automated visual evaluation (AVE); and 3) treatment with thermal ablation or excision (Large Loop Excision of the Transformation Zone). The PAVE study has two phases: efficacy (2023-2024) and effectiveness (planned to begin in 2024-2025). The efficacy phase aims to refine and validate the screen-triage portion of the protocol. The effectiveness phase will examine acceptability and feasibility of the PAVE strategy into clinical practice, cost-effectiveness, and health communication within the PAVE sites. Study design: Phase 1 Efficacy: Around 100,000 nonpregnant women, aged 25-49 years, without prior hysterectomy, and irrespective of HIV status, are being screened at nine study sites in resource-limited settings. Eligible and consenting participants perform self-collection of vaginal specimens for HPV testing using a FLOQSwab (Copan). Swabs are transported dry and undergo testing for HPV using a newly-redesigned isothermal DNA amplification HPV test (ScreenFire HPV RS), which has been designed to provide HPV genotyping by hierarchical risk groups: HPV16, else HPV18/45, else HPV31/33/35/52/58, else HPV39/51/56/59/68. HPV-negative individuals are considered negative for precancer/cancer and do not undergo further testing. HPV-positive individuals undergo pelvic examination with collection of cervical images and targeted biopsies of all acetowhite areas or endocervical sampling in the absence of visible lesions. Accuracy of histology diagnosis is evaluated across all sites. Cervical images are used to refine a deep learning AVE algorithm that classifies images as normal, indeterminate, or precancer+. AVE classifications are validated against the histologic endpoint of high-grade precancer determined by biopsy. The combination of HPV genotype and AVE classification is used to generate a risk score that corresponds to the risk of precancer (lower, medium, high, highest). During the efficacy phase, clinicians and patients within the PAVE sites will receive HPV testing results but not AVE results or risk scores. Treatment during the efficacy phase will be performed per local standard of care: positive Visual Inspection with Acetic Acid impression, high-grade colposcopic impression or CIN2+ on colposcopic biopsy, HPV positivity, or HPV 16,18/45 positivity. Follow up of triage negative patients and post treatment will follow standard of care protocols. The sensitivity of the PAVE strategy for detection of precancer will be compared to current SOC at a given level of specificity.Phase 2 Effectiveness: The AVE software will be downloaded to the new dedicated image analysis and thermal ablation devices (Liger Iris) into which the HPV genotype information can be entered to provide risk HPV-AVE risk scores for precancer to clinicians in real time. The effectiveness phase will examine clinician use of the PAVE strategy in practice, including feasibility and acceptability for clinicians and patients, cost-effectiveness, and health communication within the PAVE sites. Conclusion: The goal of the PAVE study is to validate a screen-triage-treat protocol using novel biomarkers to provide an accurate, feasible, cost-effective strategy for cervical cancer prevention in resource-limited settings. If validated, implementation of PAVE at larger scale can be encouraged. Funding: The consortial sites are responsible for their own study costs. Research equipment and supplies, and the NCI-affiliated staff are funded by the National Cancer Institute Intramural Research Program including supplemental funding from the Cancer Cures Moonshot Initiative. No commercial support was obtained. Brian Befano was supported by NCI/NIH under Grant T32CA09168. Date of protocol latest review: September 24 th 2023.

REPRODUCIBLE AND CLINICALLY TRANSLATABLE DEEP NEURAL NETWORKS FOR CANCER SCREENING.

Cervical cancer is a leading cause of cancer mortality, with approximately 90% of the 250,000 deaths per year occurring in low- and middle-income countries (LMIC). Secondary prevention with cervical screening involves detecting and treating precursor lesions; however, scaling screening efforts in LMIC has been hampered by infrastructure and cost constraints. Recent work has supported the development of an artificial intelligence (AI) pipeline on digital images of the cervix to achieve an accurate and reliable diagnosis of treatable precancerous lesions. In particular, WHO guidelines emphasize visual triage of women testing positive for human papillomavirus (HPV) as the primary screen, and AI could assist in this triage task. Published AI reports have exhibited overfitting, lack of portability, and unrealistic, near-perfect performance estimates. To surmount recognized issues, we implemented a comprehensive deep-learning model selection and optimization study on a large, collated, multi-institutional dataset of 9,462 women (17,013 images). We evaluated relative portability, repeatability, and classification performance. The top performing model, when combined with HPV type, achieved an area under the Receiver Operating Characteristics (ROC) curve (AUC) of 0.89 within our study population of interest, and a limited total extreme misclassification rate of 3.4%, on held-aside test sets. Our work is among the first efforts at designing a robust, repeatable, accurate and clinically translatable deep-learning model for cervical screening.

Use of risk-based cervical screening programs in resource-limited settings.

Cervical cancer screening and management in the U.S. has adopted a risk-based approach. However, the majority of cervical cancer cases and deaths occur in resource-limited settings, where screening and management are not widely available. We describe a conceptual model that optimizes cervical cancer screening and management in resource-limited settings by utilizing a risk-based approach. The principles of risk-based screening and management in resource limited settings include (1) ensure that the screening method effectively separates low-risk from high-risk patients; (2) directing resources to populations at the highest cancer risk; (3) screen using HPV testing via self-sampling; (4) utilize HPV genotyping to improve risk stratification and better determine who will benefit from treatment, and (5) automated visual evaluation with artificial intelligence may further improve risk stratification. Risk-based screening and management in resource limited settings can optimize prevention by focusing triage and treatment resources on the highest risk patients while minimizing interventions in lower risk patients.

Reproducible and clinically translatable deep neural networks for cervical screening.

Cervical cancer is a leading cause of cancer mortality, with approximately 90% of the 250,000 deaths per year occurring in low- and middle-income countries (LMIC). Secondary prevention with cervical screening involves detecting and treating precursor lesions; however, scaling screening efforts in LMIC has been hampered by infrastructure and cost constraints. Recent work has supported the development of an artificial intelligence (AI) pipeline on digital images of the cervix to achieve an accurate and reliable diagnosis of treatable precancerous lesions. In particular, WHO guidelines emphasize visual triage of women testing positive for human papillomavirus (HPV) as the primary screen, and AI could assist in this triage task. In this work, we implemented a comprehensive deep-learning model selection and optimization study on a large, collated, multi-geography, multi-institution, and multi-device dataset of 9462 women (17,013 images). We evaluated relative portability, repeatability, and classification performance. The top performing model, when combined with HPV type, achieved an area under the Receiver Operating Characteristics (ROC) curve (AUC) of 0.89 within our study population of interest, and a limited total extreme misclassification rate of 3.4%, on held-aside test sets. Our model also produced reliable and consistent predictions, achieving a strong quadratic weighted kappa (QWK) of 0.86 and a minimal %2-class disagreement (% 2-Cl. D.) of 0.69%, between image pairs across women. Our work is among the first efforts at designing a robust, repeatable, accurate and clinically translatable deep-learning model for cervical screening.

Sociodemographic Characteristics and Screening Outcomes of Women Preferring Self-Sampling in the Dutch Cervical Cancer Screening Programme: A Population-Based Study.

BACKGROUND: In the Netherlands, lower high-risk human papillomavirus (hrHPV) positivity but higher cervical intraepithelial neoplasia (CIN) 2+ detection were found in self-collected compared with clinician-collected samples. To investigate the possible reason for these differences, we compared sociodemographic and screening characteristics of women and related these to screening outcomes. METHODS: We extracted data from PALGA on all primary hrHPV screens and associated follow-up tests for 857,866 screened women, invited in 2017 and 2018. We linked these data with sociodemographic data from Statistics Netherlands. Logistic regression was performed for hrHPV positivity and CIN 2+/3+ detection. RESULTS: Out of the 857,866 women, 6.8% chose to use a self-sampling device. A higher proportion of self-sampling users was ages 30 to 35 years, was not previously screened, was living in a one-person household, or was the breadwinner in the household. After adjustment for these factors self-sampling had lower hrHPV positivity (aOR, 0.65; 95% CI, 0.63-0.68)) as compared with clinician-collected sampling, as well as lower odds of CIN 2+ (aOR, 0.76; 95% CI, 0.70-0.82) and CIN 3+ (aOR, 0.86; 95% CI, 0.78-0.95) detection. CONCLUSIONS: It is likely that the observed differences between the two sampling methods are not only related to sociodemographic differences, but related to differences in screening test accuracy and/or background risk. IMPACT: Self-sampling can be used for targeting underscreened women, as a more convenient screening tool. Further investigation is required to evaluate how to implement self-sampling, when it is used as a primary instrument in routine screening. See related commentary by Arbyn et al., p. 159.

Pricing of HPV tests in Italian tender-based settings.

BACKGROUND AND AIM: Human papillomavirus (HPV) testing has been recommended by the WHO as the first choice method in cervical cancer screening. So far, only a limited number of countries have implemented primary HPV testing, partly because of the assumed high costs of HPV testing. We assessed tender-based prices of HPV testing in Italy, where programmatic HPV-based screening has been implemented at the regional level. MATERIALS AND METHODS: Procurement notices and awards, published between 2014 and December 2021, were retrieved from the European online platform for public procurement. The unit price per HPV test was calculated as the ratio of the contract award price and contract volume. The association between the unit price and contract volume, calendar year, number of offers, region's per capita gross domestic product and population density was assessed by linear regression. Fractional polynomials were used to describe the association between the unit price and contract volume. RESULTS: We retrieved data from 29 procurement procedures. The median unit price per HPV test was €10.75, ranging from €4.30 to €204.80. The unit price was not higher than €5 for 6 out of 11 contract awards with a volume of at least 100,000 tests. After discarding two low-volume contracts with very high contract prices (€182.40 and €204.80), volume explained 86.5% of the variation in unit price. The unit price was not associated with other variables. CONCLUSIONS: The Italian experience showed that the tender-based unit price of an HPV test is very low when procured at high volume, indicating that there is no reason for countries to further delay the implementation of HPV-based screening because of prohibitively high HPV testing costs.

Health authorities purchase healthcare goods and services in bulk through a procedure called tendering that drives the price down as a result of price competition. A contract is made between the health authority and the supplier for a fixed price (i.e. tender-based price) for a certain amount of goods (i.e. contract volume) and a certain period. HPV testing for cervical cancer screening is subject to tendering and tender-based prices are important to inform about the costs associated with cervical screening. We collected public tender documents for HPV testing in Italian regions and calculated tender-based unit prices per HPV test. We found tender-based unit prices ranging from €4.30 and €204.80, with low prices for contracts with large volumes. In particular, the unit price per HPV test was not higher than €5 for the majority of contracts with a volume of at least 100,000 tests. This shows that the implementation of HPV-based screening does not lead to prohibitively high costs and may even lead to cost savings. Health authorities might collaborate in order to contract large volumes of HPV tests. Transparency around the prices of HPV testing as provided by this study is important to support health authorities when organizing a tender for the purchase of HPV tests.

Women with a positive high-risk human papillomavirus (HPV) test remain at increased risk of HPV infection and cervical precancer ≥15 years later.

Little is known about the long-term association between high-risk human papillomavirus (hrHPV) test results in women participating in a hrHPV-based cervical cancer screening program. To address this question, we collected data of 2217 women who participated in the POBASCAM hrHPV-based screening trial (enrolment 1999/2002) and also attended the Dutch hrHPV-based screening program between January 2017 and March 2018. Among 143 women who tested hrHPV-positive in 1999/2002, 45 (31.5%) had ≥ CIN2 or hysterectomy before 2017 and 17 (11.9%) tested hrHPV-positive at the 2017/2018 screen. In comparison, among 2074 women who tested hrHPV-negative in 1999/2002, 10 (0.5%) had ≥ CIN2 or hysterectomy before 2017 and 119 (5.7%) tested hrHPV-positive at the 2017/2018 screen. It follows that in the group of women who were not treated for ≥ CIN2 or had a hysterectomy in between the two screens 15 years apart (N = 2162), women who were hrHPV-positive in 1999/2002 had a higher risk of being hrHPV-positive in 2017/2018 than those who were hrHPV-negative in 1999/2002 (OR 3.4, 95% CI 1.8-6.1). A similar association was found at the genotype level for genotype-concordant results (5.1, 1.0-11.3) and for genotype non-concordant results (3.7, 1.6-6.7). Women who were hrHPV-positive in 2017/2018 had a higher risk of CIN3 after a hrHPV-positive result in 1999/2002 than after a hrHPV-negative result (5.8, 1.0-27.8). In conclusion, a positive hrHPV result in screening gives a long-term increased risk of a hrHPV-positive result, also for different genotypes, and a long-term increased risk of CIN3. This supports the concept of risk-stratification in hrHPV-based cervical cancer screening where previous hrHPV results are included in screening recommendations.

Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse in HPV-Positive Women with Normal Cytology and Five-Year Type Concordance: A Randomized Comparison.

BACKGROUND: In human papillomavirus (HPV)-based cervical screening programs, management of HPV-positive women with normal cytology is debated. Longitudinal information on HPV type persistence may be employed for risk stratification. METHODS: We assessed the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) after repeatedly testing positive for the same HPV type(s) in the randomized population-based screening study Amsterdam (POBASCAM). We compared 18-month CIN3+ risks in HPV-positive women (intervention, n = 1,066) to those in HPV-positive/cytology-negative women who tested HPV-positive in the next screening round (control, n = 111) five years later, stratified for HPV type concordance. RESULTS: The 18-month CIN3+ risk was 15% in HPV-positive women in the intervention group, 40% in the control group after two-round type concordance (relative risk 2.6, 95% confidence interval 1.9-3.4), and 20% in the control group after a type switch (1.3, 0.5-3.2). The relative increase in CIN3+ risk after two-round type concordance was similar in <35-year-old (3.0, 2.0-4.4) and older women (2.2, 1.4-3.5), and was high in high-risk HPV-positive women who were HPV16/18/31/33/45-negative in both rounds (9.9, 4.4-21.9). CONCLUSIONS: Five-year HPV type concordance signals high CIN3+ risk and warrants referral for colposcopy without additional cytology triage. IMPACT: HPV screening programs become highly efficient when HPV-positive women with negative triage testing at baseline are offered repeat HPV genotyping after five years.

Clinical performance of high-risk HPV testing on self-samples versus clinician samples in routine primary HPV screening in the Netherlands: An observational study.

BACKGROUND: High-risk human papillomavirus (hrHPV) testing on self-collected samples has potential as a primary screening tool in cervical screening, but real-world evidence on its accuracy in hrHPV-based screening programmes is lacking. METHODS: In the Netherlands, women aged 30-60 years invited for cervical screening can choose between sampling at the clinician's office (Cervex Brush) or self-sampling at home (Evalyn Brush). HrHPV testing is performed using Roche Cobas 4800. We collected screening test results between January 2017 and March 2018 and histological follow-up until August 2019. The main outcome measures were mean cycle threshold (Ct) value, cervical intraepithelial neoplasia (CIN) grade 3 or cancer (CIN3+) and CIN grade 2 or worse (CIN2+). FINDINGS: 30,808 women had a self-collected and 456,207 had a clinician-collected sample. In hrHPV-positive women with adequate cytology, Ct values were higher for self-collection than clinician-collection with a mean Ct difference of 1·25 (95% CI 0·98-1·52) in women without CIN2+, 2·73 (1·75-3·72) in CIN2 and 3·59 (3·03-4·15) in CIN3+. The relative sensitivity for detecting CIN3+ was 0·94 (0·90-0·97) for self-collection versus clinician-collection and the relative specificity was 1·02 (1·02-1·02). INTERPRETATION: The clinical accuracy of hrHPV testing on a self-collected sample for detection of CIN3+ is high and supports its use as a primary screening test for all invited women. Because of the slightly lower sensitivity of hrHPV testing on a self-collected compared to a clinician-collected sample, an evaluation of the workflow procedure to optimise clinical performance seems warranted. FUNDING: National Institute for Public Health and the Environment (the Netherlands) and the European Commission.

Antibodies Against Chlamydia trachomatis and Ovarian Cancer Risk in Two Independent Populations.

BACKGROUND: Pelvic inflammatory disease (PID) has been associated with ovarian cancer risk. To clarify the role of Chlamydia trachomatis and other infectious agents in the development of ovarian cancer, we evaluated the association of serologic markers with incident ovarian cancer using a staged approach in two independent populations. METHODS: Studies included: 1) a case-control study in Poland (244 ovarian cancers/556 control subjects) and 2) a prospective nested case-control study in the PLCO Cancer Screening Trial (160 ovarian cancers/159 control subjects). Associations of serologic marker levels with ovarian cancer risk at diagnostic as well as higher thresholds, identified in Poland and independently evaluated in PLCO, were estimated using multivariable adjusted logistic regression. RESULTS: In the Polish study, antibodies (based on laboratory cut-point) against the chlamydia plasmid-encoded Pgp3 protein (serological gold standard) were associated with increased ovarian cancer risk (adjusted odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.20 to 2.22); when a positive result was redefined at higher levels, ovarian cancer risk was increased (cut-point 2: OR = 2.00, 95% CI = 1.38 to 2.89; cut-point 3 [max OR]: OR = 2.19, 95% CI = 1.29 to 3.73). In the prospective PLCO study, Pgp3 antibodies were associated with elevated risk at the laboratory cut-point (OR = 1.43, 95% CI = 0.78 to 2.63) and more stringent cut-points (cut-point 2: OR = 2.25, 95% CI = 1.07 to 4.71); cut-point 3: OR = 2.53, 95% CI = 0.63 to 10.08). In both studies, antibodies against other infectious agents measured were not associated with risk. CONCLUSIONS: In two independent populations, antibodies against prior/current C. trachomatis (Pgp3) were associated with a doubling in ovarian cancer risk, whereas markers of other infectious agents were unrelated. These findings lend support for an association between PID and ovarian cancer.