Triage strategies and colposcopy referrals in HPV-positive women with low-grade cytology 139 6 in the Netherlands, reaches an NPV of at least 98% 32, 33. Consequently, it becomes evident that immediate referral should be contingent on the mPPV, underscoring the need for effective risk stratification and follow-up procedures. Moreover, the methylation analysis is applicable to self-collected samples, enhancing convenience and accessibility for women. However, there may additional costs associated with the implementation of methylation assays, the overall reduction in colposcopy referrals also contributes to cost savings. Our study’s proposed algorithms add value to the management of hrHPV-positive women. In the Netherlands, hrHPV-positive women with ASC-US/LSIL cytology are either directly referred for colposcopy if HPV16/18 positive or upon cytological evidence of HSIL for non-HPV16/18 positive cases (Figure 6.2A). To address the issue of unnecessary colposcopy referrals, we propose incorporation of FAM19A4/miR124-2 methylation in combination with HPV16/18 genotyping as a secondary triage method for hrHPV-positive women with ASC-US/LSIL cytology (Figure 6.2B). This approach offers valuable insights for primary HPV screening and contributes to a more efficient management. For methylationnegative women, the follow-up may be extended from 1 to 2 years, incorporating HPV and/or methylation retesting. Previous research underlines the importance of secondary triage for hrHPV-positive women with ASC-US/LSIL cytology in a retrospective, co-testing 19 and cross-sectional study 15. Our study builds upon these findings, capitalising on its distinct strength, and using samples from the prospective IMPROVE trial in Dutch primary HPV-based screening, aligned with the national protocol and offers an important population-based perspective. A limitation of our study is the relatively modest number of CIN3 cases in women with ASC-US/LSIL cytology. However, it is important to note that these samples are derived from an HPV-based screening cohort, making the number of CIN3 cases representative for the entire population. Polman et al. conducted a randomised, paired screen-positive, non-inferiority trial as part of the Dutch cervical cancer screening, revealing an HPV prevalence of 7.3% 21. In a study by Inturissi et al., a marked increase in the HPV prevalence was observed, reaching nearly 10% 34. This notable increase in HPV prevalence highlights the mounting importance of implementing a conservative approach, particularly in the management of HPV-positive women with ASC-US/LSIL cytology. When assessing the full implications of a triage strategy, it is also important to consider the potential costs associated with incorporating an additional methylation test in comparison to HPV16/18 genotyping, which is already included in the cervical cancer
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