American, Australian and European guidelines recommend implementation of HPV-based cervical cancer screening. As described elsewhere in this issue of HPV World, several countries have recently introduced the HPV test for primary screening or are considering to switch from cytological to viral screening in the near future. The evidence supporting this paradigm shift is derived from randomised trials demonstrating a reduced incidence of cervical precancer and cancer among women with a negative HPV test compared to those with a negative cytology result. Two essays were used in the pivotal trials: Hybrid Capture II (HC2, Qiagen, Gaithersburg, MD, USA) and GP5+6+ PCR-EIA which both detect DNA of 13 or 14 high-risk (hr) HPV types. Based on international consensus, equivalency criteria have been accepted that other hrHPV DNA tests have to fulfil in order to accept them in cervical screening. These criteria include good intra- & inter-reproducibility and non-inferior accuracy to detect CIN2 or worse lesions compared to the two standard comparator tests.¹ In 2015, a systematic reviewof screening and validation studies was performed which yielded a list of assays fulfilling the international criteria.² The following commercially available hrHPV DNA assays were considered as fully validated (in alphabetic order): cobas 4800 HPV test (Roche Molecular System, Pleasanton, CF, USA); HPV-Risk assay (Self-Screen BV, Amsterdam, Netherlands); Onclarity HPV assay (BD Diagnostics, Sparks, MD, USA); PapilloCheck HPV-screening test (Greiner Bio-One, Frickenhausen, Germany), and RealTime hrHPV test (Abbott, Wiesbaden, Germany). Three hrHPV DNA tests were considered as partially validated: Cervista (Hologic, Bedford, MA, USA), LMNX genotyping kit HPV GP (Diassay B.V., Rijkswijk, Netherlands), the in-house RIATOL qPCR (Antwerp, Belgium). The first of these three partially validated tests showed in-consistent non-inferiority compared to HC2, and the latter two showed non-inferior accuracy but had incomplete reproducibility information.¹

Since the publication of the previous list,² more studies have been conducted in agreement with the VALGENT3 or Meijer1 validation protocols (Table 1). Four reports corroborated the validation status of the HPV-Risk assay,⁴the Onclarity HPV assay^5,6 and the PapilloCheck HPV-screening test.⁷ Two new assays could be added to the list of validated hrHPV DNA assays. The Anyplex II HPV HR (Seegene, Seoul, Korea), a full-genotyping assay identifying separately 14 hr types by RT PCR was evaluated in two studies.8,9 Xpert HPV (Cepheid, Sunnyvale, USA), a cartridge-based point-of care test that distinguishes HPV16, HPV18/45 and the aggregation of 11 other hrHPV types, was assessed in the Scottish VALGENT 2 framework.¹⁰ Both assays showed similar accuracy for detection of CIN2+ compared to the standard comparator tests and demonstrated excellent reproducibility. The Linear Array HPV Genotyping Test (Roche Molecular Diagnostics, Branchburg, NJ, USA) enables type-specific identification of 37 HPV types. The aggregate of 13 hrHPV types identified with this test was found in VALGENT 3 to be as sensitive but more specific for CIN2+ compared to HC2.¹¹

The international cross-sectional equivalency criteria for validation of hrHPV DNA assays usable for screening have received a high level of acceptance in the HPV community and among decision makers. However, at the Cape Town Workshop (31^st International Conference of the Papillomavirus Society [IPV], 2017), the need was expressed to adapt the validation guidelines. A future version should define longitudinal criteria applicable for assays that target other molecules than HPV DNA (RNA, pro- teins, methylation markers). Lack of such a criterion has divided the HPV community regarding validation of the APTIMA assay, which has demonstrated similar sensitivity and better specificity compared to HC2, but for which 5-year safety (similar five-year cumulative incidence of CIN3+ after negative APTIMA or HC2) still had to be demonstrated in a published peer-reviewed report. Table 2 contains the list of items that need further definition.

Intensive work is being done and a draft for the future validation guideline is planned to be presented for further debate at the next conference of the IPV society (Sidney, October 2018).

This systematic review was supported by the German Guideline Program in Oncology (Hannover, Germany).

M. Arbyn received support from the COHEAHR Network (grant No. 603019), funded by the 7th Framework Programme of DG Research and Innovation, European Commission (Brussels, Belgium).

References

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