How Can a High-Performance Screening Strategy Be Determined for Cervical Cancer Prevention? Evidence From a Hierarchical Clustering Analysis of a Multicentric Clinical Study

BACKGROUND: This study aimed to explore the cluster patterns of cervical cancer screening strategies for detecting high-grade precancerous lesions in terms of benefits, costs, and efficiency. METHODS: A total of 2,065 referral women aged 25–64 years were recruited and underwent human papillomavirus (HPV) testing, liquid-based cytology with manual reading, and cytology with artificial intelligence (AI)-assisted reading. All women were assessed by colposcopy and histological examination. We formed 14 screening strategies based on primary cytology screening, primary HPV screening incorporating HPV-16/18 genotyping triage, cytology triage, or both, and co-testing. The primary outcomes were cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+). The hierarchical clustering method was applied to multifaceted indicators, and then, the resulting clusters were described in terms of benefits, costs, efficiency, and their interaction. This study was registered (No. ChiCTR2000034131). RESULTS: The relative sensitivity of HPV-based strategies compared with cytology alone with the threshold of LSIL+ ranged from 0.68 to 1.19 for CIN2+ detection and from 0.72 to 1.11 for CIN3+ detection, whereas the relative specificity ranged from 0.55 to 1.43 for CIN2+ detection and from 0.51 to 1.51 for CIN3+ detection. Five significant clusters according to the trade-off among benefits, costs, and efficiency were identified. The cluster including four primary HPV screening strategies showed the optimal balance. HPV testing with HPV-16/18 genotyping and AI-based cytology triage presented the optimal trade-off for CIN3+ detection relative to cytology alone in terms of relative sensitivity (1.06), relative specificity (0.72), colposcopies for 1 CIN3+ (3.7 vs. 3.1), a load of follow-up for women with HPV-positive and normal cytology (7.0% vs. 22.3%), and the work of manual cytology reading (35.1% vs. 100%). CONCLUSIONS: Our study provided clinical and methodological evidence on the choice of HPV-based screening strategies. The cluster including primary HPV screening with genotyping and cytology triage showed an optimal balance among benefit, cost, and efficiency.