MTC 03 I-07WHICH HPV ASSAYS FULFILL REQUIREMENTS FOR CERVICAL CANCER SCREENING

10. HPV testing
M. Arbyn 1, C. Meijer 2, P. Snijders 3, J. Berkhof 4, K. Cuschieri 5, M. Poljak 6, I. Heard 7, J.P. Bogers 8, C. Depuydt 9, D. Vanden Broeck 8, I. Benoy 8, V. Hutse 10, S. Van Gucht 10, J. Bonde 11, T. Gheit 12, M. Tommasino 12, M. Pawlita 13, D. Geraets 14, W. Quint 14.
1Unit of Cancer Epidemiology & Belgian Cancer Centre, Scientific Institute of Public Health, Brussels (Belgium), 2Department of Pathology, VU University Medical Centre, Amsterdam, (Netherlands), 3Department of Pathology, VU University Medical Centre, Amsterdam (Netherlands), 4Department of Clinical Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam (Netherlands), 5Scottish HPV Reference Laboratory, Royal Infirmary of Edinburgh, Edinburgh, Scotland (United Kingdom), 6Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana (Slovenia), 7French HPV Reference Laboratory, Institut Pasteur, Paris (France), 8Laboratory of Molecular Pathology, Algemeen Medisch Laboratorium, Antwerp & National Reference Centre for HPV, Brussels (Belgium), 9Laboratory of Molecular Pathology, Algemeen Medisch Laboratorium, Antwerp (Belgium), 10National Reference Centre for HPV, Scientific Institute of Public Health,Brussels (Belgium), 11Department of Pathology and Clinical Research Center, Copenhagen University Hospital, Hvidovre (Denmark), 12International Agency for Research on Cancer, Lyon (France), 13Division Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg (Germany), 14DDL Diagnostic Laboratory, Rijswijk (Netherlands)

Background / Objectives

Several countries are in the process of switching to hrHPV testing for cervical cancer screening.  Given the multitude of available tests, validated assays which assure high-quality screening need to be identified.


Methods

A systematic review was conducted to answer the question which hrHPV tests fulfil the  criteria defined by an international expert team in 2009, based on reproducibility and relative sensitivity and specificity of the candidate test compared to HC2  or GP5+/6+ PCR-EIA.  Results of recent test validations according to the VALGENT-2 protocol (1) were added. A first review published in 2015 (2) was updated.


Results

The cobas 4800 HPV Test, Abbott RealTime High Risk HPV, BD Onclarity and the PapilloCheck HPV test were each consistently validated in two or three studies, whereas the HPV Risk Assay was validated in one study.  Other tests which partially fulfil the 2009-guidelines are: Cervista HPV HR Test, GP5+/6+  PCR-LMNX, an in-house E6/E7 RT qPCR, and MALDI-TOF (matrix-assisted laser desorption-ionization time-of-flight). The APTIMA HPV assay targeting E6/E7 mRNA of hrHPV was also fully validated. However, the cross-sectional equivalency criteria of the 2009-guidelines were set up for HPV DNA assays.

The updated review (March 2016) revealed two new studies evaluating Anyplex II HPV HR (Seegene, Seoul, Korea) and Xpert HPV (Cepheid, Sunnyvale, USA), respectively.  Both assays showed non-inferior sensitivity and specificity for high-grade cervical intraepithelial neoplasia, compared to HC2 or GP5+/6+ PCR-EIA and demonstrated excellent reproducibility.


Conclusion

Only a limited number of existing HPV assays are clinically validated. VALGENT is an international comprehensive framework for HPV test comparison which allows verification of the clinical accuracy criteria for use in cervical cancer screening.  Validation protocols may suffer from selection and ascertainment biases.  Continuous monitoring of test performance, updating of the list of validated tests and further international consolidation is needed to assure optimal safety of HPV-based screening programmes. Only clinically validated assays should be used. Two new high-risk HPV assays can be added to the list of tests validated for primary cervical cancer screening.


References

1. Arbyn M, Depuydt C, Benoy I, et al. VALGENT: a protocol for clinical validation of human papillomavirus assays. J Clin Virol 2016;76: S14-S21.

2.  Arbyn M, Snijders PJ, Meijer CJ, et al. Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening? Clin Microbiol Infect 2015;21: 817-26.