The study aimed to compare the performance of human papillomavirus (HPV)-based strategies to cytology for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in routine program in China. The study included 50,434 women ages 30–64 years from January 2015 to December 2019, to assess four strategies: cytology with HPV triage (strategy 1), primary HPV testing with reflex cytology (strategy 2), primary HPV testing with HPV-16/18 genotyping and reflex cytology for non-16–18 high-risk HPV genotypes (strategy 3), and co-testing (strategy 4). The main outcomes were sensitivity for CIN3+ and colposcopy referral rate. Overall, the rates of HPV positivity and cytologic abnormality were 7.0% [95% confidential interval (CI), 6.8–7.2] and 3.5% (95% CI, 3.3–3.6], respectively. The sensitivity for CIN3+ were 88.5% for strategy 4, 83.2% for strategy 3, 64.6% for strategy 1, and 60.1% for strategy 2. The relative sensitivity of strategy 4 and strategy 3 compared with strategy 1 for detecting CIN3+ were 1.38 (95% CI, 1.24–1.54) and 1.29 (95% CI, 1.14–1.46), respectively. The colposcopy referral rates of strategies 4 and 3 were significantly higher than that of strategy 1 (2.4% and 2.2% vs. 1.4%, P < 0.001). In conclusion, co-testing and primary HPV testing with HPV-16/18 genotyping and reflex cytology improved the sensitivity for CIN3+ compared with cytology but increased the colposcopy referral rate. Long-term negative predicted value for HPV-negative women should be studied to determine the screening interval. Our study provides further evidence to the introduction of HPV-based strategies in China.

Prevention Relevance: Both co-testing and primary HPV testing with HPV-16/18 genotyping and reflex cytology triage provided higher sensitivity for detecting CIN3+; however, the number of colposcopy referrals also increased compared with cytology in a routine program. It has great public health implications for the introduction of HPV-based screening strategies in China.