Marc Arbyn1, Marie Simon2, Eliana Peeters3, Lan Xu4, Chris J L M Meijer5, Johannes Berkhof6, Kate Cuschieri7, Jesper Bonde8, Anja Ostrbenk Vanlencak9, Fang-Hui Zhao10, Remila Rezhake11, Murat Gultekin12, Joakim Dillner13, Silvia de Sanjosé14, Karen Canfell15, Peter Hillemanns16, Maribel Almonte17, Nicolas Wentzensen18, Mario Poljak9. 1. Unit of Cancer Epidemiology, Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, Belgium; Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, University Ghent, Ghent, Belgium. Electronic address: marc.arbyn@sciensano.be. 2. Haute Autorité de Santé, Saint Denis, France. 3. Unit of Cancer Epidemiology, Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, Belgium. 4. Unit of Cancer Epidemiology, Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, Belgium; School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 5. Department of Pathology, Amsterdam University Medical Centre, location VUMC, Amsterdam, the Netherlands. 6. Department of Clinical Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, the Netherlands. 7. Scottish HPV Reference Laboratory, Royal Infirmary of Edinburgh, Edinburgh, UK. 8. Molecular Pathology Laboratory, Department of Pathology, Copenhagen University Hospital, Hvidovre, Denmark. 9. Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. 10. Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 11. Unit of Cancer Epidemiology, Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, Belgium; Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Urumqi, China. 12. Hacettepe University Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynaecological Oncology, Ankara, Turkey. 13. Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. 14. National Cancer Institute, Rockville, USA. 15. Cancer Research Division, Cancer Council NSW, Sydney, Australia; School of Public Health, University of Sydney, Sydney, Australia. 16. Departments of Gynaecology and Obstetrics, Hannover Medical School, Germany. 17. International Agency for Research on Cancer, Lyon, France. 18. Division of Cancer Epidemiology and Genetics, National Cancer, Institute, Bethesda, MD, USA.
Abstract
BACKGROUND: Only clinically validated HPV assays can be accepted in cervical cancer screening. OBJECTIVES: To update the list of high-risk HPV assays that fulfil the 2009 international validation criteria (Meijer-2009). DATA SOURCES: PubMed/Medline, Embase, Scopus, references from selected studies; published in January 2014 to August 2020. STUDY ELIGIBILITY CRITERIA: HPV test validation studies and primary screening studies, involving testing with an index HPV test and a comparator HPV test with reporting of disease outcome (occurrence of histologically confirmed cervical precancer; CIN2+). PARTICIPANTS: Women participating in cervical cancer screening. INTERVENTIONS: Testing with an index and a comparator HPV test of clinician-collected cervical specimens and assessment of disease outcome (<CIN2, CIN2+). Comparator HPV assays were HC2, GP5+/6+ PCR-EIA, recommended in validation guidelines, or tests with consistent previous validations. METHODS: Assessment of relative clinical accuracy (including non-inferiority statistics index vs comparator assay) and test reproducibility in individual studies; random effects meta-analyses of the relative clinical sensitivity and specificity of index vs comparator tests. RESULTS: Seven hrHPV DNA tests consistently fulfilled all validation criteria in multiple studies using predefined test positivity cut-offs (Abbott RealTime High Risk HPV, Anyplex II HPV HR Detection, BD Onclarity HPV Assay, Cobas 4800 HPV Test, HPV-Risk Assay, PapilloCheck HPV-Screening Test and Xpert HPV). Another assay (Alinity m HR HPV Assay) was fully validated in one validation study. The newer Cobas 6800 HPV Test, was validated in two studies against Cobas 4800. Other tests partially fulfilled the international validation criteria (Cervista HPV HR Test, EUROArray HPV, Hybribio's 14 High-Risk HPV, LMNX Genotyping Kit GP HPV, MALDI-TOF, RIATOL qPCR and a number of other in-house developed assays) since the non-inferior accuracy was reached after a posteriori cut-off optimization, inconsistent accuracy findings in different studies, and/or insufficient reproducibility assessment. The APTIMA HPV Assay targeting E6/E7 mRNA of hrHPV was fully validated in one formal validation study and showed slightly lower pooled sensitivity but higher specificity than the standard comparator tests in seven screening studies. However, the current international validation criteria relate to DNA assays. The additional requirement for longitudinal performance data required for non-DNA based HPV assays was not assessed in this review. CONCLUSIONS: Eleven hrHPV DNA assays fulfil all requirements for use in cervical cancer screening using clinician-collected specimens.
BACKGROUND: Only clinically validated HPV assays can be accepted in cervical cancer screening. OBJECTIVES: To update the list of high-risk HPV assays that fulfil the 2009 international validation criteria (Meijer-2009). DATA SOURCES: PubMed/Medline, Embase, Scopus, references from selected studies; published in January 2014 to August 2020. STUDY ELIGIBILITY CRITERIA: HPV test validation studies and primary screening studies, involving testing with an index HPV test and a comparator HPV test with reporting of disease outcome (occurrence of histologically confirmed cervical precancer; CIN2+). PARTICIPANTS: Women participating in cervical cancer screening. INTERVENTIONS: Testing with an index and a comparator HPV test of clinician-collected cervical specimens and assessment of disease outcome (<CIN2, CIN2+). Comparator HPV assays were HC2, GP5+/6+ PCR-EIA, recommended in validation guidelines, or tests with consistent previous validations. METHODS: Assessment of relative clinical accuracy (including non-inferiority statistics index vs comparator assay) and test reproducibility in individual studies; random effects meta-analyses of the relative clinical sensitivity and specificity of index vs comparator tests. RESULTS: Seven hrHPV DNA tests consistently fulfilled all validation criteria in multiple studies using predefined test positivity cut-offs (Abbott RealTime High Risk HPV, Anyplex II HPV HR Detection, BD Onclarity HPV Assay, Cobas 4800 HPV Test, HPV-Risk Assay, PapilloCheck HPV-Screening Test and Xpert HPV). Another assay (Alinity m HR HPV Assay) was fully validated in one validation study. The newer Cobas 6800 HPV Test, was validated in two studies against Cobas 4800. Other tests partially fulfilled the international validation criteria (Cervista HPV HR Test, EUROArray HPV, Hybribio's 14 High-Risk HPV, LMNX Genotyping Kit GP HPV, MALDI-TOF, RIATOL qPCR and a number of other in-house developed assays) since the non-inferior accuracy was reached after a posteriori cut-off optimization, inconsistent accuracy findings in different studies, and/or insufficient reproducibility assessment. The APTIMA HPV Assay targeting E6/E7 mRNA of hrHPV was fully validated in one formal validation study and showed slightly lower pooled sensitivity but higher specificity than the standard comparator tests in seven screening studies. However, the current international validation criteria relate to DNA assays. The additional requirement for longitudinal performance data required for non-DNA based HPV assays was not assessed in this review. CONCLUSIONS: Eleven hrHPV DNA assays fulfil all requirements for use in cervical cancer screening using clinician-collected specimens.
Keywords:
Cervical cancer; Cervical cancer screening; Diagnostic test accuracy: validation of tests; Human papillomavirus; Meta-analysis; Systematic review
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