BACKGROUND: The study presents cross-sectional accuracy of E6/E7 mRNA detection and p16/ki67 dual staining, alone or in combination with cytology and HPV16/18 genotyping, as triage test in HPV DNA-positive women and their impact on CIN2+ overdiagnosis.
METHODS: Women aged 25-64 were recruited. HPV DNA-positives were triaged with cytology and tested for E6/E7 mRNA and p16/ki67. Cytology positives were referred to colposcopy, while negatives were randomised to immediate colposcopy or to one-year HPV retesting. Lesions found within 24 months since recruitment were included. All p-values were two-sided.
RESULTS: 40,509 women were recruited and 3147 (7.8%) tested HPV DNA-positive; 174 CIN2+ were found: sensitivity was 61.0% (95% CI = 53.6 to 68.0), 94.4% (95% CI = 89.1 to 97.3), and 75.2% (95% CI = 68.1 to 81.6) for cytology, E6/E7 mRNA, and p16/ki67, respectively. Immediate referral was 25.6%, 66.8%, and 28.3%, respectively. Overall referral was 65.3%, 78.3%, and 63.3%. Cytology or p16/ki67 when combined with HPV16/18 typing reached higher sensitivity with a small impact on referral. Among the 2306 HPV DNA-positive/cytology-negative women, relative CIN2+ detection in those randomized at 1-year retesting vs. immediate colposcopy suggests a -28% CIN2+ regression (95% CI = -57% to + 20%); regression was higher in E6/E7 mRNA-negatives (pinteraction =.29). HPV clearance at 1 year in E6/E7 mRNA and in p16/ki67 negatives was about 2 times higher than in positive women (Pinteraction < .001 for both).
CONCLUSIONS: p16/ki67 showed good performance as triage test. E6/E7 mRNA showed the highest sensitivity, at the price of too high a positivity rate to be efficient for triage. However, when negative, it showed a good prognostic value for clearance and CIN2+ regression.