HPV16/18 Genotyping Combined With PAX1 Methylation Triage Reduces Immediate Colposcopy While Improving CIN3+ Detection: A Real-World Study of 3,233 Chinese Women

IntroductionCurrent cervical cancer screening guidelines recommend colposcopy referral for women co-positive for high-risk human papillomavirus (hrHPV) and abnormal cytology (≥ASC-US). However, cytology exhibits suboptimal sensitivity, and this strategy leads to high colposcopy burdens, especially in populations where non-HPV16/18 genotypes predominate. We evaluated a novel triage strategy using HPV16/18 genotyping and PAX1 methylation to optimize resource allocation.MethodsThis was a retrospective cohort study. In a cohort of 3,233 hrHPV-positive women who underwent HPV genotyping, liquid-based cytology (TCT), PAX1 methylation testing, colposcopy, and histopathological confirmation, we compared two strategies: (A) standard referral (hrHPV+ (B) novel referral (HPV16/18+ → immediate colposcopy; non-16/18 hrHPV+ → colposcopy if PAX1 methylation ΔCt ≤ 8.79). CIN3+ (CIN3 or cancer) served as the clinical endpoint.ResultsNon-16/18 hrHPV types (especially HPV52/58) accounted for over 30% of infections and 60% of CIN2+ lesions. PAX1 methylation was strongly associated with lesion severity (median ΔCt: chronic cervicitis 17.92 vs. CIN3 7.36 vs. cancer 5.97; P < 0.001) and predicted CIN3+ with high accuracy (AUC = 0.82 in non-16/18 group). Strategy B detected 40 additional CIN3+ cases (+30.5%), reduced colposcopy referrals by 853 cases (absolute -25%, relative -46%), and increased the positive predictive value (PPV) from 6.6% to 14.6% (2.2-fold improvement) compared to Strategy A.ConclusionA triage algorithm combining HPV16/18 genotyping with PAX1 methylation significantly enhances CIN3+ detection while substantially reducing immediate colposcopies. This strategy is particularly well-suited for Chinese and other Asian populations where non-16/18 hrHPV types are prevalent, offering a more precise, cost-effective approach toward WHO's 2030 cervical cancer elimination goals.