Scientific approaches toward improving cervical cancer elimination strategies.

At the 2023 EUROGIN workshop scientific basis for strategies to accelerate the elimination of cervical cancer and its causative agent, human papillomavirus (HPV) were reviewed. Although some countries have reached key performance indicators toward elimination (>90% of girls HPV vaccinated and >70% of women HPV screened), most are yet to reach these targets, implying a need for improved strategies. Gender-neutral vaccination, even with moderate vaccination coverage was highlighted as a strategy to achieve elimination more rapidly. It is more resilient against major disturbances in vaccination delivery, such as what happened during the coronavirus pandemic. Further, an analysis of ethical/legal issues indicated that female-restricted vaccination is problematic. Extended catch-up of vaccination with concomitant screening, and outreach to vulnerable groups were highlighted. Although birth cohorts with high coverage of HPV vaccination at school are protected against HPV, and HPVs have a very low reproductive rate in women above age 35, adult women below age 30 have inadequate direct protection. In addition to herd protection from gender-neutral vaccination, this group can be protected by offering concomitant catch-up HPV vaccination and HPV screening. Furthermore, hepatitis B vaccination experiences indicate that elimination cannot be achieved without prioritizing vulnerable/migrant populations. The long-lasting durability of vaccination-induced antibody responses suggests prolonged protection with HPV vaccines when adequately administrated. Finally, cost-effectiveness modelling suggests that high-coverage HPV vaccination in multiple population segments will be resource-saving due to reduced need for screening. In summary, the workshop found that strategically optimal deployment of vaccination will accelerate elimination of HPV and cervical cancer.

Cervical cancer screening improvements with self-sampling during the COVID-19 pandemic.

Background: At the onset of the COVID-19 pandemic cervical screening in the capital region of Sweden was canceled for several months. A series of measures to preserve and improve the cervical screening under the circumstances were instituted, including a switch to screening with HPV self-sampling to enable screening in compliance with social distancing recommendations. Methods: We describe the major changes implemented, which were (1) nationwide implementation of HPV screening, (2) switch to primary self-sampling instead of clinician sampling, (3) implementation of HPV screening in all screening ages, and (4) combined HPV vaccination and HPV screening in the cervical screening program. Results: A temporary government regulation allowed primary self-sampling with HPV screening in all ages. In the Stockholm region, 330,000 self-sampling kits were sent to the home address of screening-eligible women, instead of an invitation to clinician sampling. An increase in organized population test coverage was seen (from 54% to 60% in just 1 year). In addition, a national campaign for faster elimination of cervical cancer with concomitant screening and vaccination for women in ages 23-28 was launched. Conclusions: The COVID-19 pandemic necessitated major changes in the cervical cancer preventive strategies, where it can already be concluded that the strategy with organized primary self-sampling for HPV has resulted in a major improvement of population test coverage. Funding: Funded by the Swedish Association of Local Authorities and Regions, the Swedish Cancer Society, the European Union's Horizon 2020 Research and Innovation Program, the Swedish government, and the Stockholm county.

First international proficiency study on human papillomavirus testing in cervical cancer screening.

BACKGROUND: Although cervical screening using Human Papillomavirus (HPV) testing is globally recommended public health policy, there has been no international proficiency studies specifically targeting HPV testing for cervical screening. OBJECTIVE: To obtain the first global overview of the current proficiency of HPV testing services for cervical cancer screening. STUDY DESIGN: A coded proficiency panel of 12 samples containing HPV types 16, 18, 31, 33, 45, 52, 58 or 35/39/51/56/59/68 in human DNA in varying amounts as well as control. Datasets detecting at least a) 10 International Units (IU) of HPV16 and 18, b) 1000 IU of HPV types 31, 33, 45, 52, 58 and c) having no false positives were considered proficient. RESULTS: In total, 84 laboratories worldwide submitted 158 datasets (some laboratories used >1 HPV testing platform). Of those, 122 (77%) were 100% proficient. Only 14/158 datasets (9%) contained false positive results. Comparison of results with assays approved by the Food and Drug Administration (FDA) suggest that future proficiency requirements should also accommodate assays detecting only 100 IU of HPV16/18. A pool of low oncogenicity HPV types that contributed very little to sensitivity, but adversely affected specificity, was detectable by most datasets. CONCLUSION: Internationally recognized proficiency studies of HPV screening, traceable to international standards, provided an overview of current testing performance. There was a high level of proficiency in terms of sensitivity and few false positives, but specificity was not optimal and further research on optimal specificity of HPV screening tests may be warranted.

Value of a catch-up HPV test in women aged 65 and above: A Danish population-based nonrandomized intervention study.

BACKGROUND: High-risk human papillomavirus (HPV) test is replacing cytology as the primary cervical cancer screening test due to superior sensitivity, but in most countries women ≥65 years have never had an HPV test despite they account for around 50% of cervical cancer deaths. We explored the effect of a catch-up HPV test among 65- to 69-year-old women without previous record of HPV-based screening. METHODS AND FINDINGS: This population-based nonrandomized intervention study (quasi-experimental design) included Danish women aged 65 to 69 with no record of cervical cancer screening in the last ≥5.5 years and no HPV-exit test at age 60 to 64 at the time of study inclusion. Eligible women residing in the Central Denmark Region were invited for HPV screening either by attending clinician-based sampling or requesting a vaginal self-sampling kit (intervention group, n = 11,192). Women residing in the remaining four Danish regions received standard care which was the opportunity to have a cervical cytology collected for whatever reason (reference group, n = 33,387). Main outcome measures were detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) per 1,000 women eligible for the screening offer and the benefit-harm ratio of the intervention and standard practice measured as the number of colposcopies needed to detect one CIN2+ case. The minimum follow-up time was 13 months for all tested women (range: 13 to 25 months). In the intervention group, 6,965 (62.2%) were screened within 12 months from the date of study inclusion and 743 (2.2%) women had a cervical cytology collected in the reference group. The CIN2+ detection was significantly higher in the intervention group (3.9, 95% confidence interval (CI): [2.9, 5.3]; p < 0.001; n = 44/11,192) as compared to the reference group (0.3, 95% CI: [0.2, 0.6]; n = 11/33,387). For the benefit-harm ratio, 11.6 (95% CI: [8.5, 15.8]; p = 0.69; n = 511/44) colposcopies were performed to detect one CIN2+ in the intervention group as compared to 10.1 (95% CI: [5.4, 18.8]; n = 111/11) colposcopies in the reference group. The study design entails a risk of confounding due to the lack of randomization. CONCLUSIONS: The higher CIN2+ detection per 1,000 eligible women in the intervention group supports that a catch-up HPV test could potentially improve cervical cancer prevention in older women. This study informs the current scientific debate as to whether women aged 65 and above should be offered a catch-up HPV test if they never had an HPV test. TRIAL REGISTRATION: ClinicalTrials.gov NCT04114968.

Predicting past and future SARS-CoV-2-related sick leave using discrete time Markov modelling.

BACKGROUND: Prediction of SARS-CoV-2-induced sick leave among healthcare workers (HCWs) is essential for being able to plan the healthcare response to the epidemic. METHODS: During first wave of the SARS-Cov-2 epidemic (April 23rd to June 24th, 2020), the HCWs in the greater Stockholm region in Sweden were invited to a study of past or present SARS-CoV-2 infection. We develop a discrete time Markov model using a cohort of 9449 healthcare workers (HCWs) who had complete data on SARS-CoV-2 RNA and antibodies as well as sick leave data for the calendar year 2020. The one-week and standardized longer term transition probabilities of sick leave and the ratios of the standardized probabilities for the baseline covariate distribution were compared with the referent period (an independent period when there were no SARS-CoV-2 infections) in relation to PCR results, serology results and gender. RESULTS: The one-week probabilities of transitioning from healthy to partial sick leave or full sick leave during the outbreak as compared to after the outbreak were highest for healthy HCWs testing positive for large amounts of virus (ratio: 3.69, (95% confidence interval, CI: 2.44-5.59) and 6.67 (95% CI: 1.58-28.13), respectively). The proportion of all sick leaves attributed to COVID-19 during outbreak was at most 55% (95% CI: 50%-59%). CONCLUSIONS: A robust Markov model enabled use of simple SARS-CoV-2 testing data for quantifying past and future COVID-related sick leave among HCWs, which can serve as a basis for planning of healthcare during outbreaks.

Human Papillomavirus Infection Determines Prognosis in Cervical Cancer.

PURPOSE: Detection of human papillomavirus (HPV) by polymerase chain reaction in invasive cervical cancer is strongly associated with prognosis but previous studies have not considered sequencing efforts. We aimed to assess the association when also including comprehensive analysis of HPV infection by deep sequencing and a longer follow-up period. MATERIALS AND METHODS: We subjected all 392 of 2,845 invasive cervical cancer cases that were polymerase chain reaction-negative for HPV to RNA sequencing on the NovaSeq 6000 platform (Illumina) and identified an additional 169 cases as HPV-positive. We followed all women from date of diagnosis to December 31, 2016, emigration, or death, whichever occurred first. The main outcome was all-cause mortality by December 31, 2016. We calculated 5-year cumulative relative survival ratios compared with the female general population and used Poisson regression to estimate excess hazard ratios of all-cause mortality by infection with any of the 13 most oncogenic (high-risk [hr]) HPV types in the tumor. All models were adjusted for age, time since diagnosis, stage, histology, and education level. RESULTS: The 5-year cumulative relative survival ratio was 0.45 (95% CI, 0.39 to 0.51) in the hrHPV-negative group, and 0.74 (95% CI, 0.72 to 0.75) in the hrHPV-positive group. This translated to a statistically significantly 43% lower excess mortality in the hrHPV-positive group compared with the hrHPV-negative (corresponding to an excess hazard ratio 0.57; 95% CI, 0.48 to 0.69). There was no association between HPV risk group, clade, or number of HPV infections and prognosis. CONCLUSION: hrHPV status is a strong determinant of cervical cancer prognosis over 15 years after diagnosis, above and beyond other established factors.

Colposcopic performance in a birth cohort previously eligible for human papillomavirus vaccination.

BACKGROUND: Sweden started subsidized quadrivalent human papillomavirus vaccination for girls aged 13 to 17 in 2007. Since 2012, vaccination has been offered to all girls aged 10 to 12 within a school-based vaccination program, with a coverage of 80% or more. In addition, the vaccine has been offered on-demand as catch-up vaccination for girls aged 13 to 18, with a cumulative coverage of 55% to 60%. Since the first women in Sweden eligible for human papillomavirus vaccination entered the cervical screening program, questions on how to evaluate colposcopic findings among vaccinated women have arisen. Evidence is inconsistent on whether colposcopic features for the detection of cervical lesions are influenced by specific human papillomavirus genotypes and what role they can play in the prevention of invasive cervical cancer in vaccinated women. OBJECTIVE: The primary objective of the study was to compare colposcopic evaluation in vaccinated and unvaccinated women entering the organized cervical screening program. STUDY DESIGN: Women in the 1994 and 1995 birth cohorts who entered the cervical screening program at age 23 in 1 region in Sweden were identified. Colposcopy was performed within 2 to 4 months after a positive screening result in accordance with national guidelines. Colposcopic performance was evaluated according to national guidelines with the Swede score and colposcopic impression. Punch biopsies were taken from colposcopic lesions and as "random biopsies" in the absence of lesions. These biopsies were used as the gold standard for the analysis. An endocervical sample was analyzed for cytologic findings and detection of 14 high-risk human papillomavirus genotypes. All colposcopic imaging was saved digitally for re-review. Vaccination status was obtained through linkage to national vaccination registries. Results were compared between vaccinated and unvaccinated women. RESULTS: In 2018 and 2019, 160 out of 165 (98%) women with a positive screening result attended colposcopy, of which 90 (56%) were vaccinated and 70 (44%) were unvaccinated. Only 7 out of 90 (5%) women in the vaccinated group were human papillomavirus 16/18-positive, compared with 23 out of 70 (33%) in the unvaccinated group (P<.001). There was a total of 61 out of 160 (38%) women with high-grade lesions-33 out of 90 (37%) in the vaccinated group and 28 out of 70 (40%) in the unvaccinated group (P=.697). There was 64% (21/33) of vaccinated women and 75% (21/28) of unvaccinated women with high-grade squamous intraepithelial lesions who had a Swede score of 6 to 10 (indicating high-grade squamous intraepithelial lesions) (P=.124). The sensitivity was slightly higher for the detection of high-grade squamous intraepithelial lesions in unvaccinated women using both colposcopic tests (Swede score, 0.67 vs 0.75; colposcopic impression, 0.67 vs 0.68), but the difference was not statistically significant. CONCLUSION: We found no statistically significant difference between the colposcopic evaluation of vaccinated and unvaccinated women, although human papillomavirus vaccination reduced the prevalence of human papillomavirus 16/18 infection in human papillomavirus-vaccinated women. Our results indicate that colposcopic examination is still a useful tool in vaccinated women entering the organized cervical screening program.

Potential SARS-CoV-2 infectiousness among asymptomatic healthcare workers.

A majority of SARS-CoV-2 infections are transmitted from a minority of infected subjects, some of which may be symptomatic or pre-symptomatic. We aimed to quantify potential infectiousness among asymptomatic healthcare workers (HCWs) in relation to prior or later symptomatic disease. We previously (at the onset of the SARS-CoV-2 epidemic) performed a cohort study of SARS-CoV-2 infections among 27,000 healthcare workers (HCWs) at work in the capital region of Sweden. We performed both SARS-CoV-2 RT-PCR and serology. Furthermore, the cohort was comprehensively followed for sick leave, both before and after sampling. In the present report, we used the cohort database to quantify potential infectiousness among HCWs at work. Those who had sick leave either before or after sampling were classified as post-symptomatic or pre-symptomatic, whereas the virus-positive subjects with no sick leave were considered asymptomatic. About 0.2% (19/9449) of HCW at work were potentially infectious and pre-symptomatic (later had disease) and 0.17% (16/9449) were potentially infectious and asymptomatic (never had sick leave either before nor after sampling). Thus, 33% and 28% of all the 57 potentially infectious subjects were pre-symptomatic or asymptomatic, respectively. When a questionnaire was administered to HCWs with past infection, only 10,5% of HCWs had had no indication at all of having had SARS-CoV-2 infection ("truly asymptomatic"). Our findings provide a unique quantification of the different groups of asymptomatic, potentially infectious HCWs.

Interruption of cancer screening services due to COVID-19 pandemic: lessons from previous disasters.

PURPOSE: To review the scientific literature seeking lessons for the COVID-19 era that could be learned from previous health services interruptions that affected the delivery of cancer screening services. METHODS: A systematic search was conducted up to April 17, 2020, with no restrictions on language or dates and resulted in 385 articles. Two researchers independently assessed the list and discussed any disagreements. Once a consensus was achieved for each paper, those selected were included in the review. RESULTS: Eleven articles were included. Three studies were based in Japan, two in the United States, one in South Korea, one in Denmark, and the remaining four offered a global perspective on interruptions in health services due to natural or human-caused disasters. No articles covered an interruption due to a pandemic. The main themes identified in the reviewed studies were coordination, communication, resource availability and patient follow-up. CONCLUSION: Lessons learned applied to the context of COVID-19 are that coordination involving partners across the health sector is essential to optimize resources and resume services, making them more resilient while preparing for future interruptions. Communication with the general population about how COVID-19 has affected cancer screening, measures taken to mitigate it and safely re-establish screening services is recommended. Use of mobile health systems to reach patients who are not accessing services and the application of resource-stratified guidelines are important considerations. More research is needed to explore best strategies for suspending, resuming and sustaining cancer screening programs, and preparedness for future disruptions, adapted to diverse health care systems.

Estimating Total Excess Mortality During a Coronavirus Disease 2019 Outbreak in Stockholm, Sweden.

Total excess mortality peaked during a coronavirus disease 2019 (COVID-19) outbreak in Stockholm, but 25% of these deaths were not recognized as COVID-19 related nor occurred in hospitals. Estimate of total excess mortality may give a more comprehensive picture of the total disease burden during a COVID-19 outbreak, and may facilitate managing future outbreaks.

Surveillance systems for monitoring cervical cancer elimination efforts: Focus on HPV infection, cervical dysplasia, cervical screening and treatment.

In order to achieve the global elimination of cervical cancer as a public health problem, close surveillance of progress in public health and clinical activities and outcomes across the three pillars of vaccination, screening and treatment will be required. Surveillance should ideally occur within an integrated system that is planned, funded, and regularly evaluated to ensure it is providing timely, accurate and relevant feedback for action. In this paper, we conceptualise the main public health surveillance objectives as process and outcome measures in each of the three pillars. Process measures include coverage/participation measures for vaccination, screening and treatment alongside the ongoing assessment of the quality and reach of these programs and activities. Outcome measures related to the natural history of human papillomavirus (HPV) infection include HPV infection prevalence, precursor cervical lesions and cervical cancers (including stage at diagnosis, cancer incidence and mortality). These outcome measures can be used for monitoring the effectiveness of the three core activities in the short, medium and long term to assess whether these interventions are effectively reducing their occurrence. We discuss possible methods for the surveillance of these measures in the context of country capacity, drawing from examples in Australia, the USA and in low and middle income countries.

Performance indicators in breast cancer screening in the European Union: A comparison across countries of screen positivity and detection rates.

Comparable performance indicators for breast cancer screening in the European Union (EU) have not been previously reported. We estimated adjusted breast cancer screening positivity rate (PR) and detection rates (DR) to investigate variation across EU countries. For the age 50-69 years, the adjusted EU-pooled PR for initial screening was 8.9% (cross-programme variation range 3.2-19.5%) while DR of invasive cancers was 5.3/1,000 (range 3.8-7.4/1,000) and DR of ductal carcinoma in situ (DCIS) was 1.3/1,000 (range 0.7-2.7/1,000). For subsequent screening, the adjusted EU-pooled PR was 3.6% (range 1.4-8.4%), the DR was 4.0/1,000 (range 2.2-5.8/1,000) and 0.8/1,000 (range 0.5-1.3/1,000) for invasive and DCIS, respectively. Adjusted performance indicators showed remarkable heterogeneity, likely due to different background breast cancer risk and awareness between target populations, and also different screening protocols and organisation. Periodic reporting of the screening indicators permits comparison and evaluation of the screening activities between and within countries aiming to improve the quality and the outcomes of screening programmes. Cancer Screening Registries would be a milestone in this direction and EU Screening Reports provide a fundamental contribution to building them.

Key issues that need to be considered while revising the current annex of the European Council Recommendation (2003) on cancer screening.

The 2003 European Council recommendation urging the Member States to introduce or scale up breast, cervical and colorectal cancer screening through an organized population-based approach has had a remarkable impact. We argue that the recommendation needs to be updated for at least two sets of reasons. First, some of the current clinical guidelines include new tests or protocols that were not available at the time of the Council document. Some have already been adopted by organized screening programs, such as newly defined age ranges for mammography screening, Human Papillomavirus (HPV)-based cervical cancer screening, fecal immunochemical test (FIT) and sigmoidoscopy for colorectal cancer screening. Second, the outcomes of randomized trials evaluating screening for lung and prostate cancer have been published recently and the balance between harms and benefits needs to be pragmatically assessed. In the European Union, research collaboration and networking to exchange and develop best practices should be regularly supported by the European Commission. Integration between primary and secondary preventive strategies through comprehensive approaches is necessary not only to maximize the reduction in cancer burden but also to control the rising trend of other noncommunicable diseases sharing the same risk factors.

Performance of colorectal cancer screening in the European Union Member States: data from the second European screening report.

OBJECTIVE: To present comparative data about the performance of colorectal cancer (CRC) screening programmes in the European Union Member States (EU MSs). DESIGN: Cross-sectional study. We analysed key performance indicators-participation rate, positivity rate (PR), detection rate (DR) and positive predictive value for adenomas and CRC-based on the aggregated quantitative data collected for the second EU screening report. We derived crude and pooled (through a random effects model) estimates to describe and compare trends across different MSs/regions and screening protocols. RESULTS: Participation rate was higher in countries adopting faecal immunochemical test (FIT) (range: 22.8%-71.3%) than in those using guaiac faecal occult blood test (gFOBT) (range 4.5%-66.6%), and it showed a positive correlation (ρ=0.842, p<0.001) with participation in breast cancer screening in the same areas. Screening performance showed a large variability. Compliance with referral for colonoscopy (total colonoscopy (TC)) assessment ranged between 64% and 92%; TC completion rate ranged between 92% and 99%. PR and DR of advanced adenomas and CRC were higher in FIT, as compared with gFOBT programmes, and independent of the protocol among men, older subjects and those performing their first screening. CONCLUSIONS: The variability in the results of quality indicators across population-based screening programmes highlights the importance of continuous monitoring, as well as the need to promote quality improvement efforts, as recommended in the EU guidelines. The implementation of monitoring systems, ensuring availability of data for the entire process, together with initiatives aimed to enhance reproducibility of histology and quality of endoscopy, represent a priority in screening programmes management.

Community environments shaping transactional sex among sexually active men in Malawi, Nigeria, and Tanzania.

Transactional sex, or the exchange of sex for material goods or money, is a risky sexual behavior that has been linked to HIV/AIDS and gender-based violence. Throughout sub-Saharan Africa, transactional sex remains a common practice, putting men and women at risk of HIV. However, little is known of how community environments shape men's participation in risky transactional sex. This analysis examines community-level influences on participation in risky transactional sex among sexually active men in three African countries (Malawi, Tanzania, and Nigeria). The analysis uses Demographic and Health Survey (DHS) data to examine the association between men's report of risky transactional sex and community characteristics including economic, gender norms, HIV behavior and knowledge, and demographic factors. The results show that men residing in communities with more female education and later age of first birth are less likely to report risky transactional sex, while men who live in communities where men report higher number of sexual partners are more likely to report risky transactional sex. While programmatic interventions should continue to improve women's status individually and relative to men, such efforts should be extended to recognize that many community and cultural influences also affect men's sexual behavior. Programs that understand, discuss, and challenge community factors that influence men's sexual behavior may be able to provide a more effective intervention resulting in opportunities for communities to initiate behavioral change.