Evaluation of the multiple HPV-based “screen and triage” algorithms in real-world settings of rural China

Objective: Drawbacks of human papillomavirus (HPV) primary screening, including high referral rates and low specificity, highlight the necessity for triage strategies to balance the screening benefits with potential harms. Methods: A cross-sectional, population-based diagnostic study was conducted in rural Xinjiang, China involving 8,638 women ≥ 25 years of age who participated in organized cervical cancer screening between 2023 and 2024. The study evaluated the accuracy and efficiency of multiple HPV-based “screen-triage” strategies. Histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+ and CIN3+) served as disease outcomes. Results: Among single-step triage strategies, only extended genotyping for the seven most carcinogenic HPV types (HPV16/18/31/33/45/52/58) maintained sensitivity for CIN2+ comparable to HPV screening without triage (90.0% vs. 92.5%, P = 0.50) but significantly improved specificity (94.7% vs. 90.8%, P < 0.001). This approach led to a 38% reduction in colposcopy referrals (relative rate, 0.62; 95% CI: 0.59–0.65). Two-step triage algorithms (HPV16/18 with reflex ASC-US+ or methylation) showed slightly lower but non-significant sensitivity (87.5%, P = 0.13/89.6%, P =0.50) than HPV primary screening without triage, yet achieved significantly increased specificity (> 95%, P < 0.001) and reduced colposcopy referral by ~50% (relative rate, 0.5; P < 0.001). If negative for cytology or methylation, women positive for 12 high-risk HPV types (excluding HPV16/18) had a < 2% risk of CIN2+ (CIN3+ risk < 1%), indicating delayed follow-up. Conclusions: Focusing on the seven high-risk HPV types within a one-step “screen-triage” framework effectively balances minimal sensitivity loss with significant gains in specificity, reducing unnecessary referrals and treatments, especially valuable in resource-limited settings. Integrating HPV genotyping with methylation results improves the accurate identification of women requiring immediate referral, which is advisable when resources allow.