Accuracy of genotyping for HPV16 and 18 to triage women with low-grade squamous intraepithelial lesions: a pooled analysis of VALGENT studies

ABSTRACT

Background: Genotyping for the most carcinogenic human papillomavirus (HPV) types (HPV16/HPV18) can identify high risk of underlying cervical precancer and guide further management.

Research design and methods: A pooled analysis was performed of the clinical accuracy of high-risk HPV (hrHPV) testing and HPV16/18 genotyping in triage of women with low-grade squamous intraepithelial lesions (LSIL). Data regarding 24 assays evaluated in four VALGENT validation panels were used.

Results: In women with LSIL, hrHPV had a pooled sensitivity for CIN2+ of 95.5% (95% CI: 91.0–97.8%) and a specificity of 25.3% (95% CI: 22.2–28.6%). HPV16/18 genotyping had a sensitivity and specificity for CIN2+ of 52.9% (95% CI: 48.4–57.4%) and 83.5% (95% CI: 79.9–86.5%), respectively. The average risk of CIN2+ was 46.1% when HPV16/18-positive, 15.5% in women who were HPV16/18-negative but positive for other hrHPV types and 4.3% for hrHPV-negative women.

Conclusions: Triage of women with LSIL with HPV16/18 genotyping increases the positive predictive value compared to hrHPV testing but at the expense of lower sensitivity. Arguably, women testing positive for HPV16/18 need further clinical work-up. Whether colposcopy referral or further surveillance is recommended for women with other hrHPV types may depend on the post-test risk of precancer and the local risk-based decision thresholds.

KEYWORDS:

• Cervical cancer screening
• HPV genotyping
• triage
• low-grade squamous intraepithelial lesions
• diagnostic test accuracy

Author’s contributions

Conception and design of the study: MA and LX

Panel testing and reporting: IB, KC, MP and JB

Statistical analysis: LX

Writing of the manuscript: LX and MA

Revising of the paper critically: all

Decision to submit: all

Declaration of interest

• LX was supported by COHEAHR Network (grant No. 603019), coordinated by the Free University of Amsterdam (The Netherlands), funded by the 7th Framework Programme of DG Research and Innovation, European Commission (Brussels, Belgium). Sciensano the employer of LX has received support from VALGENT as explained in Arbyn et al. J Clin Virol 2016 PM:26,522,865 and in Bonde et al. J Clin Virol 2018 PM:30,253,376. LX has not received financial advantages from test manufacturers for work conducted in the framework of VALGENT.

• IB is a clinical pathologist working in the private laboratory AML. AML has received research support in the form of free kits, reduced prices or funding from Abbott, Hologic, Cepheid, Roche, Becton Dickinson, Seegene, Biomérieux, Rover Medical devices, Aprovix and My Sample. IB has also received travel grants to attend symposia, conferences, and meetings from Hologic and Abbott. IB, nor AML, has received any financial advantage from test manufacturers nor any payment for work and tests conducted in the framework of VALGENT.

• KC has no conflicts of interest to declare, KC’s institution has received research funding and/or associated gratis consumable from the following in the last 3 years: Hologic, Cepheid, Qiagen, Becton-Dickinson, Euroimmun, SelfScreen, LifeRiver, Genomica, Genefirst.

• MP was supported by COHEAHR Network (grant No. 603019), coordinated by the Free University of Amsterdam (The Netherlands), funded by the 7th Framework Programme of DG Research and Innovation, European Commission (Brussels, Belgium). Faculty of Medicine, University of Ljubljana, Slovenia, the employer of MP has received free-of-charge reagents from test manufacturers involved in VALGENT as explained in Arbyn et al. J Clin Virol 2016 PM:26,522,865 and in Bonde et al. J Clin Virol 2018 PM:30,253,376. MP has not received financial advantages from test manufacturers for work conducted in the framework of VALGENT.

• JB attended meetings with various HPV test manufacturers. JB has received honoraria from Hologic, Roche, Qiagen, Genomica, and BD Diagnostics for lectures, and is the principal investigator on studies partly funded and/or received reagents at reduced or no cost by BD diagnostics, Biocartis, and Genomica SAU. The employer of JB has received free-of-charge reagents from test manufacturers involved in VALGENT as explained in Arbyn et al. J Clin Virol 2016 PM:26,522,865 and in Bonde et al. J Clin Virol 2018 PM:30,253,376. JB has not received financial advantages from test manufacturers for work conducted in the framework of VALGENT.

• MA was supported by COHEAHR Network (grant No. 603019), coordinated by the Free University of Amsterdam (The Netherlands), funded by the 7th Framework Programme of DG Research and Innovation, European Commission (Brussels, Belgium). Sciensano the employer of MA has received support from VALGENT as explained in Arbyn et al. J Clin Virol 2016 PM:26,522,865 and in Bonde et al. J Clin Virol 2018 PM:30,253,376. MA has not received financial advantages from test manufacturers for work conducted in the framework of VALGENT.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Funding was received from the COHEAHR Network (grant No. FP7-F3-2013-603019), funded by the European Union's 7th Framework Programme of DG Research and Innovation (Brussels, Belgium)