Assessment of the clinical and analytical performance of three Seegene Allplex SARS-CoV-2 assays within the VALCOR framework.

The coronavirus disease 2019 (COVID-19) pandemic demonstrated the need for accurate diagnostic testing for the early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the pandemic has ended, accurate assays are still needed to monitor viral spread at national levels and beyond through population and wastewater surveillance. To enhance early detection, SARS-CoV-2 assays should have high diagnostic accuracy and should be validated to assure accurate results. Three distinct SARS-CoV-2 assays were evaluated with clinical samples using the VALCOR (VALidation of SARS-CORona Virus-2 assays) framework, with the TaqPath COVID-19 assay (ThermoFisher Scientific, USA) as a comparator. We evaluated clinical sensitivity, specificity, limit of detection (LOD), and overall concordance between comparator and three index Allplex SARS-CoV-2 assays (Seegene, South Korea): Allplex-SC2, Allplex-SC2Fast (Fast PCR), and Allplex-SC2FabR (SARS-CoV-2/FluA/FluB/respiratory syncytial virus). Analytical performance and LOD of index assays were assessed using a dilution series of three synthetic SARS-CoV-2 sequence reference materials (RMs). Ninety SARS-CoV-2 positives and 90 SARS-CoV-2 negatives were tested. All Allplex assays had 100.0% sensitivity (95%CI = 95.9%-100.0%). Allplex-SC2 and Allplex-SC2Fast assays had 97.8% specificity (95%CI = 92.3%-99.7%) and 98.9% overall concordance [κ = 0.978 (95%CI = 0.947-1.000)]. Allplex-SC2FabR assay showed 100.0% specificity (95%CI = 95.9%-100.0%) and 100.0% overall concordance [κ = 1.000 (95%CI = 1.000-1.000)]. LOD assessment of index assays revealed detection down to 2.61 × 102 copies/mL in clinical samples, while the analytical LOD was 9.00 × 102 copies/mL. In conclusion, the evaluation of the three Seegene Allplex SARS-CoV-2 assays showed high sensitivity and specificity and an overall good assay concordance with the comparator. The assays showed low analytical LOD using RM and even a slightly lower LOD in clinical samples. Non-overlapping target gene sequences between SARS-CoV-2 assays and RMs emphasize the need for aligning targeted sequences of diagnostic assays and RMs.IMPORTANCEThe coronavirus disease 2019 pandemic has a significant impact on global public health, economies, and societies. As shown through the first phases of the pandemic, accurate and timely diagnosis is crucial for disease control, prevention, and monitoring. Though the pandemic phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has concluded, diagnostic assays remain in demand to monitor SARS-CoV-2 at the individual patient level, regionally, and nationally, as well as to remain an infectious disease preparedness instrument to monitor any new SARS-CoV-2 dissemination across borders using population and wastewater surveillance. The anticipation by WHO and central health care policy entities such as the Center for Disease Control, EMA, and multiple national health authorities is that SARS-CoV-2 will reside as an endemic respiratory disease for years to come. The key strategic consideration is hence shifting from combating a pandemic situation with a high number of patients to instead allowing precise diagnostics of suspected patients with the intention of correct management in a low-prevalence setting.

Benefits, harms and cost-effectiveness of cervical screening, triage and treatment strategies for women in the general population.

In 2020, the World Health Organization (WHO) launched a strategy to eliminate cervical cancer as a public health problem. To support the strategy, the WHO published updated cervical screening guidelines in 2021. To inform this update, we used an established modeling platform, Policy1-Cervix, to evaluate the impact of seven primary screening scenarios across 78 low- and lower-middle-income countries (LMICs) for the general population of women. Assuming 70% coverage, we found that primary human papillomavirus (HPV) screening approaches were the most effective and cost-effective, reducing cervical cancer age-standardized mortality rates by 63-67% when offered every 5 years. Strategies involving triaging women before treatment (with 16/18 genotyping, cytology, visual inspection with acetic acid (VIA) or colposcopy) had close-to-similar effectiveness to HPV screening without triage and fewer pre-cancer treatments. Screening with VIA or cytology every 3 years was less effective and less cost-effective than HPV screening every 5 years. Furthermore, VIA generated more than double the number of pre-cancer treatments compared to HPV. In conclusion, primary HPV screening is the most effective, cost-effective and efficient cervical screening option in LMICs. These findings have directly informed WHO's updated cervical screening guidelines for the general population of women, which recommend primary HPV screening in a screen-and-treat or screen-triage-and-treat approach, starting from age 30 years with screening every 5 years or 10 years.

Assessment of the clinical and analytical performance of the Aptima SARS-CoV-2 assay using the VALCOR protocol.

BACKGROUND: The COVID-19 pandemic highlighted the importance of diagnostic testing against curbing the spread of SARS-CoV-2. The urgent need and scale for diagnostic tools resulted in manufacturers of SARS-CoV-2 assays receiving emergency authorization that lacked robust analytical or clinical evaluation. As it is highly likely that testing for SARS-CoV-2 will continue to play a central role in public health, the performance characteristics of assays should be evaluated to ensure reliable diagnostic outcomes are achieved. METHODS: VALCOR or "VALidation of SARS-CORona Virus-2 assays" is a study protocol designed to set up a framework for test validation of SARS-CoV-2 virus assays. Using clinical samples collated from VALCOR, the performance of Aptima SARS-CoV-2 assay was assessed against a standard comparator assay. Diagnostic test parameters such as sensitivity, specificity and overall per cent agreement were calculated for the clinical performance of Aptima SARS-CoV-2 assay. RESULTS: A total of 180 clinical samples were tested with an addition of 40 diluted clinical specimens to determine the limit of detection. When compared to the standard comparator assay Aptima had a sensitivity of 100.0% [95% CI 95.9-100.0] and specificity of 96.7% [95% CI 90.8-99.3]. The overall percent agreement was 98.3% with an excellent Cohen's coefficient of κ = 0.967 [95% CI 0.929-1.000]. For the limit of detection, Aptima was able to detect all of the diluted clinical samples. CONCLUSION: In conclusion. validation of Aptima SARS-CoV-2 assay using clinical samples collated through the VALCOR protocol showed excellent test performance. Additionally, Aptima demonstrated high analytical sensitivity by detecting all diluted clinical samples corresponding to a low limit of detection.

Papilloplex HR-HPV test has non-inferior clinical performance for detection of human papillomavirus infection: assessment using the VALGENT framework.

AIM: The Papilloplex high-risk human papillomavirus (hrHPV) test (Genefirst, Oxford, UK) is a single tube real-time HPV test which provides multiplex detection and separate identification of 14 hrHPV types. Here, we present the clinical validation of the test in SurePath samples in comparison to a clinically validated reference test, the GP5+/6+Enzyme ImmunoAssay (GP5+/6+EIA) using the VALGENT (VALidation of HPV GENotyping Tests) framework. METHODS: Clinical performance was assessed using 998 unselected, cervical screening samples enriched with 297 cytologically abnormal specimens (100 atypical squamous cells of unspecified significance, 100 low-grade squamous intraepithelial lesions, 97 high-grade squamous intraepithelial lesions). Cases were defined as women diagnosed with histologically confirmed cervical intraepithelial neoplasia two or more (≥CIN2, N=119) and controls defined as women with two subsequent negative cytology results (N=834). RESULTS: The Papilloplex HR-HPV test has non-inferior sensitivity for detection of cervical precancer (p=0.0001 for ≥CIN2 and p=0.0005 for ≥CIN3) and non-inferior specificity, compared with GP5+/6+EIA (pni=0.0167)). The assay also showed excellent or good agreement for overall hrHPV and nearly all individual HPV types as compared with GP5+/6+EIA/Luminex. CONCLUSION: The Papilloplex HR-HPV applied on cervical specimens stored in SurePath medium fulfils the international clinical accuracy criteria for use in cervical cancer screening.

The non-fatal burden of cancer in Belgium, 2004-2019: a nationwide registry-based study.

BACKGROUND: The importance of assessing and monitoring the health status of a population has grown in the last decades. Consistent and high quality data on the morbidity and mortality impact of a disease represent the key element for this assessment. Being increasingly used in global and national burden of diseases (BoD) studies, the Disability-Adjusted Life Year (DALY) is an indicator that combines healthy life years lost due to living with disease (Years Lived with Disability; YLD) and due to dying prematurely (Years of Life Lost; YLL). As a step towards a comprehensive national burden of disease study, this study aims to estimate the non-fatal burden of cancer in Belgium using national data. METHODS: We estimated the Belgian cancer burden from 2004 to 2019 in terms of YLD, using national population-based cancer registry data and international disease models. We developed a microsimulation model to translate incidence- into prevalence-based estimates, and used expert elicitation to integrate the long-term impact of increased disability due to surgical treatment. RESULTS: The age-standardized non-fatal burden of cancer increased from 2004 to 2019 by 6 and 3% respectively for incidence- and prevalence-based YLDs. In 2019, in Belgium, breast cancer had the highest morbidity impact among women, followed by colorectal and non-melanoma skin cancer. Among men, prostate cancer had the highest morbidity impact, followed by colorectal and non-melanoma skin cancer. Between 2004 and 2019, non-melanoma skin cancer significantly increased for both sexes in terms of age-standardized incidence-based YLD per 100,000, from 49 to 111 for men and from 15 to 44 for women. Important decreases were seen for colorectal cancer for both sexes in terms of age-standardized incidence-based YLD per 100,000, from 105 to 84 for men and from 66 to 58 for women. CONCLUSIONS: Breast and prostate cancers represent the greatest proportion of cancer morbidity, while for both sexes the morbidity burden of skin cancer has shown an important increase from 2004 onwards. Integrating the current study in the Belgian national burden of disease study will allow monitoring of the burden of cancer over time, highlighting new trends and assessing the impact of public health policies.

Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis.

BACKGROUND: The knowledge that persistent human papillomavirus (HPV) infection is the main cause of cervical cancer has resulted in the development of prophylactic vaccines to prevent HPV infection and HPV assays that detect nucleic acids of the virus. WHO has launched a Global Initiative to scale up preventive, screening, and treatment interventions to eliminate cervical cancer as a public health problem during the 21st century. Therefore, our study aimed to assess the existing burden of cervical cancer as a baseline from which to assess the effect of this initiative. METHODS: For this worldwide analysis, we used data of cancer estimates from 185 countries from the Global Cancer Observatory 2018 database. We used a hierarchy of methods dependent on the availability and quality of the source information from population-based cancer registries to estimate incidence of cervical cancer. For estimation of cervical cancer mortality, we used the WHO mortality database. Countries were grouped in 21 subcontinents and were also categorised as high-resource or lower-resource countries, on the basis of their Human Development Index. We calculated the number of cervical cancer cases and deaths in a given country, directly age-standardised incidence and mortality rate of cervical cancer, indirectly standardised incidence ratio and mortality ratio, cumulative incidence and mortality rate, and average age at diagnosis. FINDINGS: Approximately 570 000 cases of cervical cancer and 311 000 deaths from the disease occurred in 2018. Cervical cancer was the fourth most common cancer in women, ranking after breast cancer (2·1 million cases), colorectal cancer (0·8 million) and lung cancer (0·7 million). The estimated age-standardised incidence of cervical cancer was 13·1 per 100 000 women globally and varied widely among countries, with rates ranging from less than 2 to 75 per 100 000 women. Cervical cancer was the leading cause of cancer-related death in women in eastern, western, middle, and southern Africa. The highest incidence was estimated in Eswatini, with approximately 6·5% of women developing cervical cancer before age 75 years. China and India together contributed more than a third of the global cervical burden, with 106 000 cases in China and 97 000 cases in India, and 48 000 deaths in China and 60 000 deaths in India. Globally, the average age at diagnosis of cervical cancer was 53 years, ranging from 44 years (Vanuatu) to 68 years (Singapore). The global average age at death from cervical cancer was 59 years, ranging from 45 years (Vanuatu) to 76 years (Martinique). Cervical cancer ranked in the top three cancers affecting women younger than 45 years in 146 (79%) of 185 countries assessed. INTERPRETATION: Cervical cancer continues to be a major public health problem affecting middle-aged women, particularly in less-resourced countries. The global scale-up of HPV vaccination and HPV-based screening-including self-sampling-has potential to make cervical cancer a rare disease in the decades to come. Our study could help shape and monitor the initiative to eliminate cervical cancer as a major public health problem. FUNDING: Belgian Foundation Against Cancer, DG Research and Innovation of the European Commission, and The Bill & Melinda Gates Foundation.

A roadmap for a comprehensive control of cervical cancer in Poland: integration of available solutions into current practice in primary and secondary prevention.

In Poland, cervical cancer incidence and mortality still remain considerably higher than in Western European countries or North America. Recent data indicate decreasing trends in women younger than 60 years and stable trends in older women. In this article, we identified obstacles in primary and secondary prevention of cervical cancer in Poland. We analysed local legislation, management structure and organization of cervical cancer prevention in Poland and reviewed solutions available and implemented in other European countries. The main weaknesses include: (i) very low coverage of organized screening; concurrent unregistered opportunistic screening with unknown coverage and high test consumption (ii) suboptimal quality assurance in organized screening and no external quality assurance in opportunistic screening (iii) very low coverage of human papillomavirus vaccination that is not centrally reimbursed (iv) absence of pilot evaluation of (a) interventions that may improve population coverage and (b) performance of new preventive strategies. The proposed solutions are multifaceted and involve: (i) legislative and organizational regulation of cervical cancer screening aimed at comprehensive registration of procedures, data access and quality assurance (ii) pilot testing and implementation of new ways to increase coverage of cervical cancer screening, in particular among older women (iii) pilot evaluation with possible introduction of human papillomavirus-based screening and (iv) inclusion of human papillomavirus vaccination into the reimbursed national immunization program.

Effectiveness of bivalent and quadrivalent human papillomavirus vaccination in Luxembourg.

BACKGROUND: In Luxembourg, the human papillomavirus (HPV) vaccination program introduced in 2008, provided either bivalent (BV) or quadrivalent (QV) vaccines to girls aged 12-17 years. Here, we estimate the effectiveness of BV and QV vaccines combined and separately in reducing type-specific HPV prevalence eight years after the introduction of the vaccination program. METHODS: A cross-sectional prevalence study was conducted among women aged 18-29 years in 2015-2017. Seven hundred sixteen participants were recruited at family planning centres or private gynaecology practices in Luxembourg. Vaccination records were verified in the social security database. Cervical samples were tested using the Anyplex II HPV28 assay. Vaccine effectiveness was estimated using logistic regression. RESULTS: In total, 363/716 (50.7%) participants were HPV positive with any HPV and 209/716 (29.2%) with carcinogenic HPV genotypes. HPV vaccination offered high protection against HPV16/18 (adjusted odds ratio (AOR) = 0.13; 95% CI 0.03-0.63), HPV6/11 (AOR = 0.16; 95% CI 0.05-0.48) and cross-protection against HPV31/33/45 (AOR = 0.41; 95% CI 0.18-0.94). The AORs were generally enhanced when only considering vaccination before sexual debut corresponding to AORs: 0.05 (95% CI 0.00-0.88), 0.08 (95% CI 0.02-0.36) and 0.20 (0.06-0.65) against HPV16/18, HPV6/11 and HPV31/33/45, respectively. We observed significant protection against carcinogenic genotypes included in nonavalent vaccine for BV (AOR = 0.29; 95% CI 0.13-0.67), but not for QV (AOR = 0.81; 95% CI 0.47-1.40) (heterogeneity Chi2 P = 0.04). CONCLUSIONS: Our study suggests high effectiveness of HPV vaccination against HPV6/11, HPV16/18 and a cross-protection against HPV31/33/45. Vaccination effectiveness was slightly higher for women vaccinated before sexual debut.

The legal framework for European cervical cancer screening programmes.

BACKGROUND: A comprehensive legal framework needs to be developed to run the health services and to regulate the information systems required to manage and to ensure the quality of cancer screening programmes. The aim of our study was to document and to compare the status of legal basis for cervical screening registration in European countries. METHODS: An electronic questionnaire including questions on governance, decision-making structures and legal framework was developed. The primary responses were collected by September 2016. RESULTS: We sent the questionnaire to representatives of 35 European countries (28 countries of the EU, with the United Kingdom included as 4 countries; 4 EFTA member countries: Iceland, Liechtenstein, Norway, and Switzerland); responses were collected from 33 countries. The legal framework makes it possible to personally invite individuals in 29 countries (88%). Systematic screening registration in an electronic registry is legally enshrined in 23 countries (70%). Individual linkage of records between screening and cancer registries is allowed in 19 of those countries. Linkage studies involving cancer and screening registries have been conducted in 15 countries. CONCLUSION: Although the majority of EU/EFTA countries have implemented population-based screening, only half of them have successfully performed record linkage studies, which are nevertheless a key recommendation for quality assurance of the entire screening process. The European legislation is open to the possibility of using health data for these purposes; however, member states themselves must recognize the public interest to create a legal basis, which would enable all the necessary functions for high-quality cancer screening programmes.

Human papillomavirus vaccination coverage in Luxembourg - Implications of lowering and restricting target age groups.

BACKGROUND: In Luxembourg, a national Human Papillomavirus (HPV) vaccination programme was introduced in 2008, targeting 12-17 year old girls offering a choice of bivalent or quadrivalent vaccine free of charge. In 2015, the programme was changed offering the bivalent vaccine only to 11-13 year old girls. The aim of this study was to evaluate the HPV vaccination coverage, to assess the impact of age target changes and compare vaccination coverage to other European countries. METHODS: Anonymous HPV vaccination records consisting of individual vaccine doses obtained free of charge in pharmacies between 2008 and 2016 were extracted from the Luxembourgish Social Security database. Additional aggregate tables by nationality and municipality were analysed. RESULTS: Of the target cohort of 39,610 girls born between 1991 and 2003 residing in Luxembourg, 24,550 (62.0%) subjects obtained at least one dose, 22,082 (55.7%) obtained at least two doses, and 17,197 (43.4%) obtained three doses of HPV vaccine. The mean age at first dose was 13.7 years during 2008-14 and 12.7 years in 2016 after the age target change. Coverage varied significantly by nationality (p < 0.0001): Portuguese (80%), former Yugoslavs (74%), Luxembourgish (54%), Belgian (52%), German (47%), French (39%) and other nationalities (51%). Coverage varied also by geographical region, with lower rates (<50%) noted in some Northern and Central areas of Luxembourg (range: 38% to 78%). CONCLUSION: Overall HPV vaccination coverage in Luxembourg is moderate and varied by nationality and region. The policy changes in 2015 did not have a substantial impact except lowering age at initiating vaccination. Options to improve coverage deserve further investigation.

Assessing factors associated with long-term work disability after cancer in Belgium: a population-based cohort study using competing risks analysis with a 7-year follow-up.

OBJECTIVES: The number of workers with cancer has dramatically increasing worldwide. One of the main priorities is to preserve their quality of life and the sustainability of social security systems. We have carried out this study to assess factors associated with the ability to work after cancer. Such insight should help with the planning of rehabilitation needs and tailored programmes. PARTICIPANTS: We conducted this register-based cohort study using individual data from the Belgian Disability Insurance. Data on 15 543 socially insured Belgian people who entered into the long-term work disability between 2007 and 2011 due to cancer were used. PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated the duration of work disability using Kaplan-Meier and the cause-specific cumulative incidence of ability to work stratified by age, gender, occupational class and year of entering the work disability system for 11 cancer sites using the Fine and Gray model allowing for competing risks. RESULTS: The overall median time of work disability was 1.59 years (95% CI 1.52 to 1.66), ranging from 0.75 to 4.98 years. By the end of follow-up, more than one-third of the disabled cancer survivors were able to work (35%). While a large proportion of the women were able to work at the end of follow-up, the men who were able to work could do so sooner. Being women, white collar, young and having haematological, male genital or breast cancers were factors with the bestlikelihood to be able to return to work. CONCLUSION: Good prognostic factors for the ability to work were youth, woman, white collar and having breast, male genital or haematological cancers. Reviewing our results together with the cancer incidence predictions up to 2025 offers a high value for social security and rehabilitation planning and for ascertaining patients' perspectives.

Assessment of the Roche Linear Array HPV Genotyping Test within the VALGENT framework.

BACKGROUND: Cervical cancer screening programs are switching from cytology-based screening to high-risk (hr) HPV testing. Only clinically validated tests should be used in clinical practice. OBJECTIVES: To assess the clinical performance of the Roche Linear Array HPV genotyping test (Linear Array) within the VALGENT-3 framework. STUDY DESIGN: The VALGENT framework is designed for comprehensive comparison and clinical validation of HPV tests that have limited to extended genotyping capacity. The Linear Array enables type-specific detection of 37 HPV types. For the purpose of this study, Linear Array results were designated as positive only if one of the 13 hrHPV types also included in the Hybrid Capture 2 (HC2) was detected. The VALGENT-3 framework comprised 1600 samples obtained from Slovenian women (1300 sequential cases from routine cervical cancer screening enriched with 300 cytological abnormal samples). Sensitivity for cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) (n=127) and specificity for

Barriers and opportunities for return-to-work of cancer survivors: time for action--rapid review and expert consultation.

BACKGROUND: The spread of early detection and the improvement of cancer treatment have led to an increased prevalence of cancer survivors, including in the working age population. Return-to-work (RTW) of cancer survivors has become a key issue for national cancer control plans. This study aims (1) to identify the factors that have an impact on RTW of cancer survivors and to draw a risk profile supporting health professionals in the screening of those at risk for barriers of RTW and (2) to sharpen these results with input from health, social security and academic Belgian experts and to provide evidence-based recommendations that facilitate RTW of cancer survivors. METHODS: A rapid review was conducted, based on the methodology elaborated by The Knowledge to Action Research Programme and researchers from the University of York, including a quality assessment of retained studies. Next, the Delphi method was used to organize a consultation with experts in order to discuss, validate and complement the results. RESULTS: Forty-three out of 1860 studies were included. We identified nine risk factors grouped into four categories: socio-demographic, disease and treatment-related, work-related, and personal and subjective factors. Experts suggested dividing them into two even groups: factors which are modifiable and those which are not. The awareness of health professionals regarding the identified factors, a better assessment of work capacities, clarity on the rights and obligations of employers and workers alike, and the setup of a positive discrimination employment policy for cancer survivors were acknowledged as factors facilitating RTW of cancer survivors. CONCLUSIONS: The awareness of health professionals regarding barriers of RTW may improve the early identification of cancer survivors at risk for prolonged time to RTW and may allow early supportive intervention. Social and employment policies should be better tailored to support both employers and cancer survivors in the RTW process, providing incentives to positively discriminate cancer survivors on prolonged sick leave.

Barriers to and facilitators of compliance with clinic-based cervical cancer screening: population-based cohort study of women aged 23-60 years.

OBJECTIVE: This study aims to identify possible barriers to and facilitators of cervical cancer screening by (a) estimating time and travel costs and other direct non-medical costs incurred in attending clinic-based cervical cancer screening, (b) investigating screening compliance and reasons for noncompliance, (c) determining women's knowledge of human papillomavirus (HPV), its relationship to cervical cancer, and HPV and cervical cancer prevention, and (d) investigating correlates of HPV knowledge and screening compliance. MATERIALS AND METHODS: 1510 women attending the clinic-based cervical cancer screening program in Stockholm, Sweden were included. Data on sociodemographic characteristics, time and travel costs and other direct non-medical costs incurred in attending (e.g., indirect cost of time needed for the screening visit, transportation costs, child care costs, etc.), mode(s) of travel, time, distance, companion's attendance, HPV knowledge, and screening compliance were obtained via self-administered questionnaire. RESULTS: Few respondents had low socioeconomic status. Mean total time and travel costs and direct non-medical cost per attendance, including companion (if any) were €55.6. Over half (53%) of the respondents took time off work to attend screening (mean time 147 minutes). A large portion (44%) of the respondents were noncompliant (i.e., did not attend screening within 1 year of the initial invitation), 51% of whom stated difficulties in taking time off work. 64% of all respondents knew that HPV vaccination was available; only 34% knew it was important to continue to attend screening following vaccination. Age, education, and income were the most important correlates of HPV knowledge and compliance; and additional factors associated with compliance were time off work, accompanying companion and HPV knowledge. CONCLUSION: Time and travel costs and other direct non-medical costs for clinic-based screening can be considerable, may affect the cost-effectiveness of a screening program, and may constitute barriers to screening while HPV knowledge may facilitate compliance with screening.

Attendance at cervical cancer screening and use of diagnostic and therapeutic procedures on the uterine cervix assessed from individual health insurance data (Belgium, 2002-2006).

OBJECTIVE: To assess the coverage for cervical cancer screening as well as the use of cervical cytology, colposcopy and other diagnostic and therapeutic interventions on the uterine cervix in Belgium, using individual health insurance data. METHODS: The Intermutualistic Agency compiled a database containing 14 million records from reimbursement claims for Pap smears, colposcopies, cervical biopsies and surgery, performed between 2002 and 2006. Cervical cancer screening coverage was defined as the proportion of women aged 25-64 that had a Pap smear within the last 3 years. RESULTS: Cervical cancer screening coverage was 61% at national level, for the target population of women between 25 and 64 years old, in the period 2004-2006. Differences between the 3 regions were small, but varied more substantially between provinces. Coverage was 70% for 25-34 year old women, 67% for those aged 35-39 years, and decreased to 44% in the age group of 60-64 years. The median screening interval was 13 months. The screening coverage varied substantially by social category: 40% and 64%, in women categorised as beneficiary or not-beneficiary of increased reimbursement from social insurance, respectively. In the 3-year period 2004-2006, 3.2 million screen tests were done in the target group consisting of 2.8 million women. However, only 1.7 million women got one or more smears and 1.1 million women had no smears, corresponding to an average of 1.88 smears per woman in three years of time. Colposcopy was excessively used (number of Pap smears over colposcopies = 3.2). The proportion of women with a history of conisation or hysterectomy, before the age of 65, was 7% and 19%, respectively. CONCLUSION: The screening coverage increased slightly from 59% in 2000 to 61% in 2006. The screening intensity remained at a high level, and the number of cytological examinations was theoretically sufficient to cover more than the whole target population.

A framework provided an outline toward the proper evaluation of potential screening strategies.

OBJECTIVES: Screening tests are often introduced into clinical practice without proper evaluation, despite the increasing awareness that screening is a double-edged sword that can lead to either net benefits or harms. Our objective was to develop a comprehensive framework for the evaluation of new screening strategies. STUDY DESIGN AND SETTING: Elaborating on the existing concepts proposed by experts, a stepwise framework is proposed to evaluate whether a potential screening test can be introduced as a screening strategy into clinical practice. The principle of screening strategy evaluation is illustrated for cervical cancer, which is a template for screening because of the existence of an easily detectable and treatable precursor lesion. RESULTS: The evaluation procedure consists of six consecutive steps. In steps 1-4, the technical accuracy, place of the test in the screening pathway, diagnostic accuracy, and longitudinal sensitivity and specificity of the screening test are assessed. In steps 5 and 6, the impact of the screening strategy on the patient and population levels, respectively, is evaluated. The framework incorporates a harm and benefit trade-off and cost-effectiveness analysis. CONCLUSION: Our framework provides an outline toward the proper evaluation of potential screening strategies before considering implementation.

[Health technology assessment report: HPV DNA based primary screening for cervical cancer precursors]. / Health technology assessment report: ricerca del DNA di papillomavirus umano (HPV) come test primario per lo screening dei precursori del cancro del collo dell'utero.

UNLABELLED: OBJECTIVE OF THE PROJECT: The introduction of the HPV test as a primary screening test will cause important changes in the screening system based on cytology. The purposes of this report are: to define the best screening policies with HPV-based screening on the basis of the resulting efficacy and of undesired effects; comparing them to cytology-based screening; to identify their best conditions of application; to evaluate economic cost, feasibility and impact on the organisation of services of such policy in the Italian situation. CONTENTS: This report contains a section on efficacy and undesired effects based on a systematic review of literature conducted in strict coordination with the preparation of a supplement to the European Guidelines for quality assurance in cervical cancer screening. This chapter corresponds to a preliminary version of the chapter of the European Guidelines on primary screening with HPV. The sections on costs, impact on organisation, and social, ethical and legal impact reflect the Italian situation; they are based on a review of the available Italian data (including unpublished data, mainly from on-going pilot projects) and on a structured analysis of what will result if the proposed protocol is applied to the Italian situation. RESULTS: Efficacy and undesired effects. There is clear scientific evidence that a screening based on validated tests for the DNA of oncogenic HPV as primary test and applying an appropriate protocol is more effective than screening based on cytology in preventing invasive cancers of the uterine cervix. In addition, it entails a limited--if any--increase of the undesired effects both in terms of unneeded referral to diagnostic work-up and in terms of over-diagnosis and consequent overtreatment of spontaneously regressive lesions. The crucial elements of such protocol are the followings: HPV-positive women are not to be directly referred to colposcopy, but the use of triage systems is essential. The currently recommendable method is based on performing cytology in HPV positive women. If the result of this test is abnormal, the woman is immediately referred to colposcopy; if cytology is normal, the woman is invited to repeat a new HPV test after one year. In case such a test is still positive, the woman is referred to colposcopy; in case of negative result, the woman will be re-invited for a new screening round at the regular interval. In organised population-based screening programmes the interval after a negative primary HPV test should be at least 5 years. There is evidence that the 5-year cumulative risk of high-grade CIN after a negative HPV test is lower than the 3-year risk after a normal cytology. On the other hand, the probability of unneeded colposcopies and treatments would plausibly be relevant with 3-year intervals after a negative HPV test. HPV-based screening should not start before 30-35 years. There is evidence that below 30 years HPV-based screening leads to an increased overdiagnosis of CIN2 that would regress spontaneously, with consequent overtreatment. Some increase in overdiagnosis is plausible also between 30 and 34 years. Below such ages, cytological screening is the recommended test. Only tests for the DNA of oncogenic HPV, validated according to the European guidelines as for sensitivity and specificity for high-grade lesions, should be applied. There is no evidence that double testing with cytology and HPV is more protective than stand-alone HPV as primary test, although it entails a small and not relevant increase in sensitivity vs stand-alone HPV. On the contrary, there is evidence that double testing causes a substantial increase in referral to colposcopy and a decrease in its PPV. For this reason, if HPV is used as primary screening test, it is recommended not to add cytology in parallel. Cost and economic evaluation. It is estimated that, if the protocol described is applied, in the current Italian situation the overall costs of HPV-based screening are lower than those of conventional cytological screening applied at the current 3-year intervals, although the cost of each screening round is higher. Impact on organization. For reasons of quality and cost, both the interpretation of cytology and HPV testing require a centralisation. This need is particularly strong, in terms of costs, for HPV test execution. It is therefore recommended to perform the HPV test in a limited number of reference laboratories of large size. This also makes monitoring and evaluating the spontaneous activity easier. HPV-based screening entails problems of organisation related to the need of triage, to complex protocols and to reconversion of the activities of cytological interpretation. Social, ethical and legal impact. The communication of the result of the HPV test to women, particularly if positive, is a further crucial aspect in order to reduce not only the emotional impact, but also the possible risks that women are inappropriately managed or lost to follow-up. Great efforts must be put in the education of healthcare professionals, both directly involved in organised programmes or not, particularly private gynaecologists and general practitioners. RECOMMENDATIONS: In conclusion, the crucial requirement to introduce HPV-based screening programmes is the capacity to guarantee the application of appropriate screening protocols. If protocols do not respect the criteria described above they can cause relevant increase of undesired effects and costs compared to cytology-based screening. Therefore they should be avoided, except in studies able to provide clear evidence about human and economic costs. For this purpose, correct education and information both to healthcare professionals and to the population is needed. In the Italian situation, where organised screening and a relevant spontaneous activity coexist, their interaction is crucial. Actions directed to integrate them and to guarantee as more uniformity of interventions as possible are needed, in particular through the integration of registries and thorough monitoring and a progressive homogenization of protocols. In order to grant the safety of transition, it is needed that the HPV-based organised screening activities are strictly monitored and that the National Centre for Screening Monitoring (ONS) ensures coordination. Knowledge about HPV based screening is still rapidly evolving. It is possible that currently on-going researches suggest changes to the optimal protocols in the next few years, particularly as for the management of HPV positive women. In addition, studies on the validation of new assays were recently published and others are expected. It is suggested to exploit the organised screening activity to produce scientific evidence, in order to clarify the still uncertain aspects of optimal protocols. Different protocols in terms of screening intervals, age of application and management of HPV positive women should be studied in the frame of controlled implementation, through multicentre projects coordinated by ONS. Finally, it is suggested the creation of a National working group to promptly update the recommendations for screening and the list of assays to be considered as validated. On the bases of the results obtained in the first vaccinated cohorts reaching the screening age, for the future, it will be crucial to deliver specific recommendations to the population vaccinated against HPV during adolescence.

Liquid-based cervical cytology using ThinPrep technology: weighing the pros and cons in a cost-effectiveness analysis.

PURPOSE: Cervical cancer screening with liquid-based cytology (LBC) has been developed as an alternative to the conventional Papanicolaou (CP) smear. Cost-effectiveness is one of the issues when evaluating LBC. Based on the results of a Dutch randomised controlled trial, we conducted cost-effectiveness threshold analyses to investigate under what circumstances manually screened ThinPrep LBC is cost-effective for screening. METHODS: The MISCAN-Cervix microsimulation model and data from the Dutch NETHCON trial (including 89,784 women) were used to estimate the costs and (quality-adjusted) life years ((QA)LYs) gained for EU screening schedules, varying cost-effectiveness threshold values. Screening strategies were primary cytological screening with LBC or CP, and triage with human papillomavirus (HPV) testing. RESULTS: Threshold analyses showed that screening with LBC as a primary test can be cost-effective if LBC is less than 3.2 more costly per test than CP, if the sensitivity of LBC is at least 3-5 % points higher than CP, if the quality of life for women in triage follow-up is only 0.39, or if the rate of inadequate CP smears is at least 16.2 %. CONCLUSIONS: Regarding test characteristics and costs of LBC and CP, only under certain conditions will a change from CP to manually screened ThinPrep LBC be cost-effective. If none of these conditions are met, implementation of manually screened ThinPrep LBC seems warranted only if there are advantages other than cost-effectiveness. Further research is needed to establish whether other LBC systems will be more favorable with regard to cost-effectiveness.

Primary screening for human papillomavirus compared with cytology screening for cervical cancer in European settings: cost effectiveness analysis based on a Dutch microsimulation model.

OBJECTIVES: To investigate, using a Dutch model, whether and under what variables framed for other European countries screening for human papillomavirus (HPV) is preferred over cytology screening for cervical cancer, and to calculate the preferred number of examinations over a woman's lifetime. DESIGN: Cost effectiveness analysis based on a Dutch simulation model. Base case analyses investigated the cost effectiveness of more than 1500 different screening policies using the microsimulation model. Subsequently, the policies were compared for five different scenarios that represent different possible scenarios (risk of cervical cancer, previous screening, quality associated test characteristics, costs of testing, and prevalence of HPV). SETTING: Various European countries. POPULATION: Unvaccinated women born between 1939 and 1992. MAIN OUTCOME MEASURES: Optimal screening strategy in terms of incremental cost effectiveness ratios (costs per quality adjusted life years gained) compared with different cost effectiveness thresholds, for two levels of sensitivity and costs of the HPV test. RESULTS: Primary HPV screening was the preferred primary test over the age of 30 in many considered scenarios. Primary cytology screening was preferred only in scenarios with low costs of cytology and in scenarios with a high prevalence of HPV in combination with high costs of HPV testing. CONCLUSIONS: Most European countries should consider switching from primary cytology to HPV screening for cervical cancer. HPV screening must, however, only be implemented in situations where screening is well controlled.