What has been your area of expertise in relation to HPV screening?

Currently our main expertise comprises synthesiz- ing the evidence related to prevention and treatment of HPV-related cancer by performing systematic reviews, meta-analyses and Cochrane reviews. Within our Unit of Cancer Epidemiology which is part of the Belgian Cancer Center (Scientific Direction of Public Health & Surveillance) of the Sciensano (previously Institute of Public Health) in Brussels, we have built up a core group of young scientists who have learnt the methodology of performing high-quality meta-analyses who are sharing their skills with other international teams. This work is done as contribution to the development of evidence-based practice guidelines. We also have developed new statistical methods and software for synthesizing data, such as the metaprop for procedure to pool proportions, diagnostic network meta-analysis and pretest-posttest probability plots. Pooling of survival data by digitizing Kaplan-Meier curves is an ongoing statistical project that was initiated at our unit. We also conducted age-cohort-period analyses of the incidence of and mortality from cervical cancer at European and world level.

What is the Cochrane collaboration and which contributions have they made to the HPV field?

The Cochrane Collaboration is an international, independent not-for-profit organization involving a network of researchers, health professionals, patients, carers and people interested in health. Its main objective is to evaluate interventions for prevention, treatment & rehabilitation by producing systematic reviews of primary research using established methods for summarising and reporting evidence. These reviews are published in the Cochrane Database of Systematic Reviews (http://www.cochranelibrary.com/cochrane-database-of-systematic-reviews/).

A few years ago, we received a grant from the Gynaecological Cancer Cochrane Review Collaboration to conduct a number of Cochrane reviews. Several new Cochrane reviews have been accom- plished such as those on triage of women with minor cervical cytological abnormalities, the comparison of the accuracy of cytology and HPV tests in primary cervical cancer screening, safety and efficacy of HPV vaccines, and on obstetrical harm associated with treatment of cervical precancer.^1-4

We observe today that systematic reviews of important clinical questions are too often repeated by national or regional health technology assessment agencies. This yields a multiplicity of reports of heterogeneous quality, sometimes with conflicting conclusions. We advocate international collab- oration and coordination to avoid a waste and dilution of resources and maximising quality. The Cochrane collaboration has a world-wide focus and is accessible for all motivated and skilled experts. It can contribute in making future high quality reviews. We invite young scientists to contact the Cochrane website and to follow their courses. We are happy to observe that our unit in Brussels receives funding from the European Union and also from national organisations (France, the Netherlands, Germany, USA, Australia…) to perform reviews on HPV testing on self-samples, triage of HPV+ women and obstetrical complications following excision of cervical precancer.

Which are currently the guidelines of the EU in relation to HPV screening?

The 2^nd edition of the EU Guidelines on Quality Assurance of Cervical Cancer Screening published in 2008 recommended HPV testing in triage of women with atypical cervical cytology and in surveillance after treatment of cervical precancer.^5,6 The supplements to these guidelines, published in 2015, recommend primary HPV screening in all member states at an interval of at least 5 years and starting from the age of 30-35 years.⁷

Which countries in Europe have clearly switched to HPV screening as an alternative to cytology-based screening?

An overview of countries that have switched or that are planning to switch to HPV-based screen- ing is included in the 2016 Eurogin Roadmap.⁸ The Netherlands and Sweden were the two first countries that introduced nationwide HPV-based screening in 2017. In Italy, HPV-based screening is running already in several regional programmes. Several other European countries have made decisions to introduce screening with validated HPV assays. We are proud to announce that also in our country, ministers of health decided (July 2018) to introduce screening with HPV testing only instead of cytology, after long discussions on screening with both cytology and HPV (co-testing). The introduction of new HPV-based screening policies in several countries is described in more detail in the papers of this HPV World issue.

What is your view on self-sampling for HPV testing in Europe?

From our reviews we concluded that HPV testing on vaginal self-samples using a valid PCR-based assay is as accurate as on a clinician-taken self-samples. Offering devices for self-sampling generally is more effective to reach non- or under-screened women than sending mailed invitations to have a cervical sample taken by a clinician. More details from an updated meta-analysis can be found in Arbyn et al. (this issue in article: "HPV testing on self-samples: the evidence of Today"). 

How many HPV tests are considered validated for screening programs?

Two high-risk (hr) HPV tests were validated for cervical cancer screening in randomised trials showing improved protection against cervical cancer: Hybrid Capture II test and the GP5/6+ PCR-EIA. Five more hrHPV DNA tests, fulfilling all the international minimal accuracy and reproducibility crit- eria, were included in a review of 2015 list- ing all the validated tests.9 Three other tests fulfilled partially the criteria. An updat- ed list, actualised in July 2018, adding three more test, is included in Arbyn and Hillemanns (this issue in article: "HPV assays validated for primary cervical cancer screening").

Which triage methods seem most suitable for a screening program based on HPV testing?

Many options are available to triage HPV-posi- tive women. We can distinguish the reflex-triage applied on the sample used for HPV-screening and 2nd time triage applied when reflex triage was negative. The most often recommended reflex-triage methods are cytology at cut-off ASCUS or LSIL combined or not with genotyping for HPV16/18. Cytology and/or hrHPV retest- ing are the most often recommend options for 2^nd time triage for women with negative reflex (1st time) triage result. Many more alternative possibilities are being evaluated including mRNA testing, protein markers (p16/Ki67, E6/7), methylation and other markers. Triage of HPV+ women is currently one of priorities for ongoing meta-analytical work at our unity.

Which are the most visible changes in the organization of HPV based screening programs as opposed to cytology based programs?

The use a machine-based test detecting nucleic acids of the virus and restriction of cytology to triage of HPV-positive women will have a huge impact on laboratory practice. HPV testing will facilitate automation, scale increase, high-through- put and accompanying cost reductions. It is not surprising that at least a part of the cytopathology society is opposed against introduction of HPV screening. Therefore careful planning and respect-full communication with the concerned stakeholders is and will be crucial. HPV-based screening at longer intervals including adher- ence to triage guidelines will require a higher level organisation and good communication between women, screening organisations and health professionals. As already mentioned, HPV testing will enable strategies including use of self-samples.

What is the influence of receiving HPV vaccinated cohorts into the screening programs?

In vaccinated cohorts, we will observe a reduction in the incidence and prevalence of infection with HPV types included in the vaccines or genetically linked with the vaccine types. Also the burden of associated lesions will decrease yielding lower predictive values of all tests. The reduction of infection and lesions will be lower in women who were vaccinated at an older age than in those who were vaccinated before sexual exposure to HPV. How this shift will influence screening policies of vaccinated cohorts is discussed in this issue in the paper of Giorgi-Rossi et al. (this issue page 60). Vaccinated cohorts may need less frequent screening starting at an older age with more specific methods.

What is your opinion on the recent declaration of cervical cancer as an eliminable disease?

This recent declaration will boost countries with already well organised screening and vaccination programmes to perform even better than before. Karen Canfell and colleagues, describe in this issue how Australia is going to tackle this challenge (this issue page 50). At the same time, it invites countries who did not (yet) develop fully organised preventive programmes or who still have to start – in particular developing countries – to do so. The availability of and access to new point-of-care HPV tests applicable in field conditions and the possibility to perform HPV testing on self-samples increase the possibilities to reach the generations of currently adult women already exposed to HPV infection. Integrating the implementation of these new screening tools with vaccination of young girls and young women should make cervical cancer a rare disease in many parts of the world.

References

1. Arbyn M, Roelens J, Simoens C, et al. Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions. Cochrane Database Syst Rev 2013;3:1-201
2. Arbyn M, Xu L, Simoens C, et al. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev 2018;5:CD009069.
3. Koliopoulos G, Nyaga VN, Bryant A, et al. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane Database Syst Rev 2017;8: CD-008587.
4. Kyrgiou M, Athanasiou A, Kalliala IEJ, et al. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. Cochrane Database Syst Rev 2017;11:CD012847.
5. Arbyn M, Anttila A, Jordan J, et al. European Guidelines for Quality Assurance in Cervical Cancer Screening. Second Edition - Summary Document. Ann Oncol 2010;21:448-58.
6. European Commission. European Guidelines for Quality Assurance in Cervical Cancer Screening. 2nd ed. Editors: Arbyn M, Anttila A, Jordan J, et al. Luxembourg: Office for Official Publications of the European Communities. 2008.
7. von Karsa L, Arbyn M, De Vuyst H, et al. European guidelines for quality assurance in cervical cancer screening. Summary of the supplements on HPV screening and vaccination. Papillomavir Res 2015;1:22-31.
8. Wentzensen N, Arbyn M, Berkhof H, et al. Eurogin 2016 Roadmap: How HPV knowledge is changing screening practice. Int J Cancer 2017;140:2192-200.
9. Arbyn M, Snijders PJ, Meijer CJLM, et al. Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening? Clin Microbiol Infect 2015;21:817-26.