Organized primary human papillomavirus-based cervical screening: A randomized healthcare policy trial

Abstract

Background: Clinical trials in the research setting have demonstrated that primary human papillomavirus (HPV)-based screening results in greater protection against cervical cancer compared with cytology, but evidence from real-life implementation was missing. To evaluate the effectiveness of HPV-based cervical screening within a real-life screening program, the organized, population-based cervical screening program in the capital region of Sweden offered either HPV- or cytology-based screening in a randomized manner through a randomized healthcare policy (RHP).

Methods and findings: A total of 395,725 women aged 30 to 64 years that were invited for their routine cervical screening visit were randomized without blinding to either cytology-based screening with HPV triage (n = 183,309) or HPV-based screening, with cytology triage (n = 212,416 women) between September 1, 2014 and September 30, 2016 and follow-up through June 30, 2017. The main outcome was non-inferior detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Secondary outcomes included superiority in CIN2+ detection, screening attendance, and referral to histology. In total, 120,240 had a cervical screening sample on record in the study period in the HPV arm and 99,340 in the cytology arm and were followed for the outcomes of interest. In per-protocol (PP) analyses, the detection rate of CIN2+ was 1.03% (95% confidence interval (CI) 0.98 to 1.10) in the HPV arm and 0.93% (0.87 to 0.99) in the cytology arm (p for non-inferiority <0.0001; odds ratio (OR) 1.11 (95% CI 1.02 to 1.22)). There were 46 cervical cancers detected in the HPV arm (0.04% (0.03 to 0.06)) and 48 cancers detected in the cytology arm (0.05% (0.04 to 0.07)) (p for non-inferiority <0.0001; OR 0.79 (0.53 to 1.18)). Intention-to-screen (ITS) analyses found few differences. In the HPV arm, there was a modestly increased attendance after new invitations (68.56% (68.31 to 68.80) vs. 67.71% (67.43 to 67.98); OR 1.02 (1.00 to 1.03)) and increased rate of referral with completed biopsy (3.89% (3.79 to 4.00) vs. 3.53% (3.42 to 3.65); OR 1.10 (1.05 to 1.15)). The main limitations of this analysis are that only the baseline results are presented, and there was an imbalance in invitations between the study arms.

Conclusions: In this study, we observed that a real-life RHP of primary HPV-based screening was acceptable and effective when evaluated against cytology-based screening, as indicated by comparable participation, referral, and detection rates.

Trial registration: ClinicalTrials.gov NCT01511328.

Fig 1. CONSORT flowchart of study population and outcomes.

* Cervical sample on record: any cervical sample result following the first invitation to screening in the study period. **Abnormal cytology: includes ASCUS/AGC+. ***Includes protocol violations, inadequate samples, pathology samples without proceeding smear, non-organized screening samples, and clinically indicated samples (total: n = 10,043 in the primary HPV arm and n = 8,499 in the primary cytology arm). Note: Bolded text denotes the PP population participation and outcomes. AGC+, atypical glandular cells or worse; AIS+, adenocarcinoma in situ or worse; ASCUS, atypical squamous cells of undetermined significance; CIN2+, cervical intraepithelial neoplasia grade 2 or worse; CONSORT, Consolidated Standards of Reporting Trials; Cyto, cytology; HPV, human papillomavirus; PP, per protocol.