Association between HPV 16/18, HPV integration status, and CIN3 + in high-risk HPV-positive women: a multicenter cross-sectional study

This study aimed to investigate the association between human papillomavirus (HPV) 16/18, HPV integration status, and cervical intraepithelial neoplasia grade 3 or worse (CIN3 +), and to provide evidence and theoretical support for the clinical translation of HPV integration testing. This was a multicenter cross-sectional study conducted within a cervical cancer screening program in China. HPV integration was detected using high-throughput viral integration detection (HIVID). Structural equation modeling (SEM) was employed to examine the mediating effect of HPV integration. A total of 3,077 high-risk HPV-positive women were included in the final analysis. Among these participants, 29.5% were infected with HPV 16/18, 12.9% tested positive for HPV integration, and 5.9% had biopsy-confirmed CIN3 + . Multivariable logistic regression analysis demonstrated that both HPV integration and HPV 16/18 were independently associated with CIN3 + . In mediation analysis, the standardized path coefficient for the direct effect of HPV 16/18 on CIN3 + was 0.087. For the indirect effect, the standardized path coefficient from HPV 16/18 to HPV integration was 0.404, and from HPV integration to CIN3 + was 0.771. The mediating effect of HPV integration accounted for 78.1% of the total effect. This study elucidates the mediating role of HPV integration in the progression from HPV 16/18 infection to CIN3 + , offering new insights into HPV risk stratification and clinical management.