Long-Term Outcomes of Co-Testing with 3-Type HPV mRNA (16/18/45) and Cytology in Women Under 40: A Real-World Cohort from Northern Norway (8–10 Years of Follow-Up)

In Norway, organized cervical cancer screening was cytology-based until 2023, and women screened in 2013–2015 were largely unvaccinated. We conducted a retrospective, population-based cohort study to assess whether co-testing with a 3-type HPV mRNA assay improves detection of high-grade cervical lesions in women < 40 years. Among 11,395 women screened in Northern Norway and followed for 8–10 years, 2807 formed a co-testing cohort (ThinPrep cytology plus PreTect SEE; HPV16/18/45) and 8588 formed a cytology-only cohort. The endpoint was histologically confirmed CIN2+. Sensitivity for CIN2+ was 63.7% with cytology alone and 71.0% with co-testing (absolute +7.3 percentage points; p = 0.034). In the co-testing cohort, HPV mRNA was detected in 10.2% of women, of whom 46.0% developed CIN2+, while CIN2+ risk in HPV mRNA-negative women was 5.2%. Co-testing produced wide risk gradients: CIN2+ risk was 58.3% in double-positive women (HPV mRNA-positive and ASC-US+) and 3.3% in double-negative women (HPV mRNA-negative and normal cytology), with no cervical cancers observed in the latter group. In this cytology-based, largely unvaccinated setting, co-testing with a 3-type HPV mRNA assay improved detection performance and long-term risk stratification in women < 40 years, supporting its use as a quality-assurance and triage tool within organized screening programs.