HPV, Cytology, and Cotest Cervical Cancer Screening and the Risk of Precancer.

Importance: There is a global call to end cervical cancer, and various jurisdictions are still determining optimal strategies to accelerate elimination. Human papillomavirus (HPV)-negative testing confers lower risk of future precancer vs normal cytology; high-quality longitudinal data are needed comparing risk after a negative HPV test vs negative cotest (HPV and cytology). Objective: To compare long-term risk of cervical precancer based on HPV, cytology, and cotest screening results. Design, Setting, and Participants: This cohort study linked data from a randomized clinical trial to a comprehensive screening program in British Columbia. Participants were recruited between 2006 and 2012 and followed from trial exit to 10 years postexit. Eligible participants were women who completed trial exit cotesting. Data were analyzed between January and April 2025. Exposure: HPV and cytology status from exit cotesting were considered, stratified by status of each test. Main Outcome and Measures: Cumulative risk of precancer was calculated over follow-up using Kaplan-Meier techniques. Risk was compared among groups who tested HPV-negative with normal cytology, HPV-negative with abnormal cytology, HPV-positive with normal cytology, and HPV-positive with abnormal cytology. Additionally, risk among those who were HPV-negative (regardless of cytology result), with normal cytology (regardless of HPV results), or were cotest negative were compared in order to simulate outcomes in primary HPV screening, cytology, and cotest programs, respectively. Results: In this cohort of 8078 women (median [IQR] age at exit screen, 49 [41-57] years; 1636 Asian [22.4%], 223 Indigenous [3.0%], 5568 White [76.1%]) who participated in a British Columbia-based cervical cancer screening trial, the HPV-positive with abnormal cytology group had the highest cumulative incidence risk (CIR) of cervical intraepithelial neoplasia grade 2 or higher at the end of follow-up (CIR, 43.47%; 95% CI, 23.45%-58.26%), followed by the HPV-positive and cytology-negative group (CIR, 22.21%; 95% CI, 11.49%-31.62%). The HPV-negative with abnormal cytology (CIR, 4.83%; 95% CI, 0%-10.03%) and the HPV-negative with normal cytology (CIR, 0.37%; 95% CI, 0.13%-0.60%) groups had significantly lower CIR at the end of follow-up. Less than 1% of the population was HPV-negative with abnormal cytology (69 of 8078 [0.85%]). Women who were HPV-negative regardless of cytology results (CIR, 0.41%; 95% CI, 0.17%-0.65%) had a similar risk as those who cotested negative (CIR, 0.37%; 95% CI, 0.13%-0.60%); both groups had lower risk than those with normal cytology results (regardless of HPV result) (CIR, 1.28%; 95% CI, 0.78%-1.78%) throughout follow-up. Conclusions and Relevance: In this cohort study of cervical cancer screen testing approaches and risk of cervical precancer, after a negative HPV test (regardless of cytology results) risk of precancer remained acceptably low throughout long-term follow-up. This suggests that cotesting yielded limited benefits, while increasing costs, relative to primary HPV testing.