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COHEAHR Report Summary

Project ID: 603019
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 2 - COHEAHR (Comparing health services interventions for the prevention of HPV-related cancer)

Project Context and Objectives:
CoheaHr stands for "comparing health services interventions for the prevention of HPV-related cancer" and is an European Commission-funded multidisciplinary consortium of key researchers in the field of HPV screening and vaccination. CoheaHr aims to provide a strong evidence base which will enable policy makers and other stakeholders to make informed decisions on HPV prevention strategies, thereby contributing to strengthening health systems and health services interventions in Europe. HPV-related cancers include cancers of the anogenital tract and the oropharynx. The consortium focuses explicitly on cervical cancer – for which both primary prevention (HPV vaccination) and secondary prevention methods (screening) are available.

The project is organized in 7 different work packages (WP) – as depicted in the figure below.
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The CoheaHr consortium is conducting a number of studies in organised screening settings to determine i) the efficacy and feasibility of self-collection of specimens for HPV testing as an alternative to physician-based sampling (WP2), ii) the safety and quality of life of less frequent screening in women vaccinated at young age (WP3a), and iii) the effectiveness of HPV screening in women vaccinated two years before entering the screening programme (WP3b). In addition, a multi-country study is ongoing to assess the acceptability and feasibility of HPV vaccination in screen-eligible women (WP4). In WP5 transmission and Markov models are being (further) developed, validated and used to provide long-term projections of vaccination and screening on cancer incidence and mortality. The trials will provide (some of) the input parameters for these models. Finally the data will feed a previously established standardised joint European data warehouse and pooled analyses and meta-analyses will be performed (WP6).

Project Results:
Since its initiation in November 2013, two randomized controlled clinical trials (RCT, WP2 and WP3a) and the feasibility study (WP4) have started enrolment. The methodology of the third RCT (WP3b) was changed because in the current framework of the health care services and infrastructure a randomized comparative effectiveness trial was no longer feasible. A summary of the progress in the different work packages is provided here below.

The first trial (WP2; IMPROVE) is an RCT comparing hrHPV self-sampling as first screening test versus physician-collected sample. The trial is conducted in the Netherlands and coordinated by the VU University Medical Center ( Women who accept to participate in the study are randomly assigned to self-collection at home, or physician-collection at the general practitioners office. After approval was obtained from the Dutch Health Council / Ministry of Health and the first invitations were sent out in April 2015. In autumn 2015, sample sizes were recalculated based on response rate and HPV prevalence observed in the first 30,000 women invited for the study. In the period from April 2015 up to August 2016 a total of 187,000 women were invited to participate in the IMPROVE-study, of these 15,401 (8.2%) women have given written informed consent and were randomized. Of the women randomized, 5,423 baseline HPV tests were obtained in the intervention arm and 4,032 in the control arm. Cross-tests results are available for approximately 80% of HPV-positive women. A total of 12,000 women with a valid HPV test results are needed in order to achieve 80% power to establish non-inferiority of self-sampling. When all the specimens have been processed - this number will be reached.

The second trial (WP3a) is an RCT evaluating different screening policies in vaccinated women and is conducted in Finland (University of Tampere). HPV-vaccinated women (birth cohorts 1992-1995) are randomized to three different arms to receive PAP smear at the age of 22, 25 and 30; at age 25 and 30; or at age 30 only. Arm 1 and 3 will include at least 7,000 women each. In November 2016, enrolment of the 1992 and 1993 birth cohorts was completed. The enrolment of the 1994 birth cohort is on-track and invitations are being send to the 1995 birth cohort.

In the third trial (WP3b), a randomized comparative effectiveness trial was planned to evaluate the influence of vaccination at age 22-23 on the performance of cervical HPV-based screening. According to the original description of work, 15,000 aged 22/23 years old, would be randomized to be vaccinated or not, and screened by HPV 2 years later in the framework of national screening programs in Sweden and Italy. However, in the current framework of the health care services and infrastructure a randomized comparative effectiveness trial was no longer feasible, and the research methodologies were adapted accordingly. In Sweden a registry-based study will be conducted, linking screening and vaccination registries. The new protocol is nearly finalized. In Italy, HPV-based screening outcomes (type specific prevalence, cytological abnormalities, histological diagnosis) will be compared between vaccinated and unvaccinated women by linking screening and vaccination registries. In addition, vaccinated women testing HPV-negative at age 25 will provide the basis for evaluating the extension of screening intervals in HPV-negative women. If, at age 30, the detection rate of CIN3+ in these women will be lower than a pre-defined value the screening interval will be extended by one year. This will be repeated in subsequent birth cohorts for further extension. In 2017, the first cohort of unvaccinated women will be screened by HPV and in 2018 the first cohort that was offered catch-up vaccination.

The fourth study (WP4) aims to assess the acceptability and feasibility of HPV vaccination in screen-eligible 25 to 45-year-old women. Eight of the 11 countries have obtained regulatory/ethical approval and seven countries have initiated enrolment. In total 915 women were enrolled, 693 women completed the acceptability questionnaire and 451 women accepted vaccination. One research site had to withdraw from the fieldwork due to changes in the running of the nationwide screening program. Strategies to mitigate the impact of the withdrawal are being discussed.

With respect to the modelling work (WP5) in the first 36 months of the project: the HPV transmission model was used to assess the impact of selected vaccination strategies in different populations. Moreover, the model was used to replicate observed herd effects and quantify the contribution of herd effects to the control and elimination of different HPV types. The cancer progression model was calibrated. A separate model is used to assess the impact and cost-effectiveness of girls-only vaccination or gender-neutral vaccination on the health outcomes for both females and males.

Furthermore, a web-based survey for EU countries was performed, collecting information on cervical cancer prevention strategies, quality assurance and associated costs. The results will be analysed during the coming months.

In WP6 – multiple meta-analyses have been conducted and published and as well as publications using data of the pooled data-set have been published. In addition, assistance was given to public health authorities updating guidelines for cervical cancer prevention.

Potential Impact:
HPV research and development has delivered to the promise by introducing proprietary technologies and methods such as new HPV vaccines and HPV DNA screening to clinical practice. CoheaHr is taking the next crucial step in optimising the delivery of health services by providing a comprehensive evidence base regarding the comparative effectiveness and cost-effectiveness of nation-wide screening and vaccination programmes for HPV related disease. First results of CoheaHr have been disseminated at international conferences and a special session on CoheaHr has been held at Eurogin 2015 (Seville, Spain) and Eurogin 2016 (Salzburg, Austria). A complete list of publications from the CoheaHr consortium, as well as additional information on the project and the consortium partners, can be found at: The results of CoheaHr will support policy makers and other decision makers at National and EU level, thereby improving public health interventions in relation to HPV prevention and adding to the health of European Citizens.

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