COHEAHR: RESULTS

No yet available

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) has undergone some changes (amendment under review) 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 was conducted in the Netherlands and coordinated by the VU University Medical Center. A total of 187,473 women were invited to participate in the study and 13,925 women provided informed consent and participated in the study. The HPV prevalence was 7.4% in the self-collected and 7.2% in the clinician-collected samples. Cross-test results of over 90% positive women were available in both groups. The histological outcomes of this study have been analysed and will be soon available.

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. The enrolment of the 1992-1994 birth cohorts have been completed and the 1995 birth cohort will be enrolled in 2018. In WP3b a registry-based study will be conducted to evaluate the influence of vaccination on the performance of cervical cancer screening.

The fourth study (WP4) aims to assess the acceptability and feasibility of HPV vaccination in screen-eligible 25 to 45-year-old women in eight countries. Seven countries have completed enrolment, in Sweden recruitment has started in March 2018 and is still open. The UK performed a questionnaire-only survey investigating the hypothetical acceptability of HPV vaccination among older women.

The modelling work (WP5) focused on simulation of the effects of vaccination on screening in different populations. Alternative vaccination strategies targeting different age and gender specific groups were simulated. It was shown for example, that within the Dutch setting, sex-neutral vaccination is a cost-effective alternative to girls’ only vaccination and also more resilient against a sudden decline in vaccine uptake than girls’ only vaccination. Modelling was also used to replicate observed herd effects and quantify the contribution of herd effects to the control and elimination of different HPV types. The HPV progression/screening model was used to elucidate the biological mechanism underlying the performances of cytology-based screening programs as observed in the major EU screening trials. The model is currently used to assess the impact and resource requirement of selected HPV-based screening strategies.

In WP6 – Pooled analyses have been done on the data of the European randomised controlled trials using the updated data warehouse. Models are being used to explore observed patterns in the data. A statistical procedure was developed to perform diagnostic network meta-analysis. Multiple meta-analyses have been conducted and published in the field of HPV testing, complications after treatment of CIN23, and efficacy and safety of HPV vaccines. An extensive review of over 100 European HPV vaccine tender procedures revealed important information on the tender price development of the bivalent, quadrivalent, and nonavalent vaccine. The contents of an e-learning course on cervical cancer prevention have been developed in WP7. The course has been translated to several languages and the virtualization of the course has been done.

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-ling 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.

Since its initiation in November 2013, two randomized controlled clinical trials (RCT) have started enrolment, ne vaccinate and screen trial and a multi-country feasibility study are in the final stages of preparations.

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, the first invitations were sent out in April 2015. The researchers aim to enrol half of the total 18,000 women by the end of 2015.

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) will be 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 April 2015, 50% of the 1992 birth cohorts was enrolled and the first invitations were sent out to the birth cohort of 1993.

In the third trial (WP3b), the influence of vaccination at age 22-23 will be evaluated on the performance of cervical HPV-based screening. This study will be conducted in both Sweden (Karolinska Institutet) and Italy (Cancer Prevention and Epidemiology Unit, University of Turin). Women entering the screening ages will be vaccinated 1-2 years prior to receiving their first screening invitation. The country-specific protocols have been finalized and are ready for submission to the ethical review committees. These trials plan to initiate enrolment late 2015.

The fourth study aims to assess the acceptability and feasibility of HPV vaccination in screen-eligible 25-45 year old women. In total 11 countries will participate in this study, each enrolling 250-300 participants. It is expected that the first country will start enrolment at the end of 2015 and the study follow-up will finish by 2018. These results will provide mathematical modellers with key information to evaluate models considering “screen and vaccinate” strategies in unvaccinated women and form the basis for a possible future large randomised trial aiming at accelerating the reduction of cervical disease and cancer incidence in Europe using a once-in-a-lifetime “screen and vaccinate” strategy.

With respect to the modelling work (WP5) in the first 18 months of the project: the HPV transmission model was finalized and the cancer progression was ready for calibration.

Furthermore, an updated, web-based survey for EU countries is in progress and will collect information on cervical cancer prevention strategies, quality assurance and associated costs.

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.