Long term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial

Abstract

Objectives: To assess whether the increased sensitivity of screening for human papillomavirus (HPV) may represent overdiagnosis and to compare the long term duration of protective effect against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in HPV based and cytology based screening.

Design: 13 year follow-up of the Swedescreen randomised controlled trial of primary HPV screening.

Setting: Organised cervical screening programme in Sweden.

Participants: 12,527 women aged 32-38 attending organised screening were enrolled and randomised to HPV and cytology double testing (intervention arm, n=6257) or to cytology only, with samples frozen for future HPV testing (control arm, n=6270).

Main outcome measures: Cumulative incidence of CIN2+ and CIN3+ (Kaplan Meier curves). Longitudinal test characteristics were calculated for cytology only, HPV testing only, and cytology and HPV testing combined, adjusting for censoring.

Results: The increased detection of CIN2+ in the intervention arm decreased over time. After six years, the cumulative incidence of CIN3+ was similar in both trial arms, and after 11 years the cumulative incidence of CIN2+ became similar in both arms. The longitudinal sensitivity of cytology for CIN2+ in the control arm at three years was similar to the sensitivity of HPV testing in the intervention arm at five years of follow-up: 85.94% (95% confidence interval 76.85% to 91.84%) v 86.40% (79.21% to 91.37%). The sensitivity of HPV screening for CIN3+after five years was 89.34% (80.10% to 94.58%) and for cytology after three years was 92.02% (80.59% to 96.97%).

Conclusions: Over long term follow-up, the cumulative incidence of CIN2+ was the same for HPV screening and for cytology, implying that the increased sensitivity of HPV screening for CIN2+ reflects earlier detection rather than overdiagnosis. The low long term risks of CIN3+ among women who tested negative in HPV screening, support screening intervals of five years for such women.

Trial registration: Clinicaltrials.gov NCT00479375.

Fig 1 Study population and analyses by group. HPV=human papillomavirus

Fig 2 Cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) over 13 years of follow-up by study arm and baseline test result (test result groups not mutually exclusive). HPV=human papillomavirus

Fig 3 Cumulative incidence of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) over 13 years of follow-up by study arm and baseline test result (test result groups not mutually exclusive). HPV=human papillomavirus