Abstract
WHAT IS ALREADY KNOWN ABOUT THIS TOPIC? Persistent infection with high-risk human papillomavirus (hrHPV) is recognized as the primary cause of cervical cancer and its precancerous lesions. However, most HPV infections are transient and naturally clear. Currently effective triage tools for distinguishing between transient HPV infections and clinically relevant hrHPV-induced diseases are lacking, leading to excessive referrals and overtreatment. WHAT IS ADDED BY THIS REPORT? This is the first large-scale, prospective, multicenter study to evaluate the triage performance of host DNA six-methylation marker assay (ASTN1, DLX1, ITGA4, RXFP3, SOX17, and ZNF671) in women who are hrHPV-positive in China. Compared with HPV genotyping and cytology [≥ atypical squamous cells of undetermined significance (ASCUS)] screening, the six-methylation marker assay demonstrated superior triage performance, with sensitivities of 82.2% and 90.3% and specificities of 92.4% and 84.1% for cervical intraepithelial grade II/III and worse (CIN2+ and CIN3+), respectively. Further subgroup analysis of women <30 years of age revealed its efficacy. The methylation positivity rate increased with the severity of cervical lesions, and the most significant marker was ZNF671. Moreover, the six-methylation marker assay required the fewest colposcopy referrals, with only 1.32 and 2.39 per CIN2+ and CIN3+ cases, respectively, highlighting its strong health and economic advantages. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE? The large number of women with HPV infections in China each year has led to excessive cytological screenings and colposcopy referrals. A feasible triage tool for women who are hrHPV-positive significantly reduces unnecessary medical resource utilization and offers substantial health and economic benefits.