Long-term HPV type-specific risks for ASCUS and LSIL: A 14-year follow-up of a randomized primary HPV screening trial

Human papillomavirus (HPV) infections result in a significant burden of low-grade cervical lesions. Between 1997 and 2000, our randomized trial of primary HPV screening enrolled 12,527 women participating in population-based screening. Women between 32 and 38 years of age (median: 34, interquartile range: 33-37) were randomized to HPV and cytology double testing (intervention arm, n=6,257 enrolled, n=5,888 followed-up) or to cytology, with samples frozen for future HPV testing (control arm, n=6,270 enrolled, n=5,795 followed-up). We estimated the HPV type-specific, long-term absolute risks (AR), and population attributable proportions (PAR) for cytological diagnoses of atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) and for histopathologically diagnosed cervical intraepithelial neoplasia grade 1 (CIN1). The women were followed using comprehensive, nationwide register-based follow-up. During a mean follow-up time of 11.07 years, 886 ASCUS and LSIL lesions were detected, 448 in the intervention arm and 438 in the control arm. Poisson regression estimated the incidence rate ratios (IRRs) of low-grade lesions by HPV type. The IRRs were strongly dependent on follow-up time. The IRRs for ASCUS/LSIL associated with high-risk HPV positivity were 18.6 (95% CI: 14.9-23.4) during the first screening round, 4.1 (95% CI: 2.8-6.2) during the second, 2.6 (95% CI: 1.7-4.1) during the third, and 1.1 (95% CI: 0.7-1.8) for >9 years of follow-up, with similar declines seen for the individual types. Type 16 contributed consistently to the greatest proportion of ASCUS, LSIL, and CIN1 risk in the population (first screening round PAR: ASCUS: 15.5% (95% CI: 9.7-21.9), LSIL: 14.7% (95% CI: 8.0-20.9), and CIN1: 13.4% (95% CI: 3.2-22.5)), followed by type 31 [8.4% (95% CI: 4.2-12.5) for ASCUS to 17.3% (95% CI: 6.8-26.6) for CIN1]. In summary, most ASCUS/LSIL lesions associated with HPV infection are caused by new HPV infections and most lesions are found during the first screening round. What's new? Low-grade cervical lesions are among the most common clinical manifestations of human papillomavirus (HPV) infection. However, the contribution of different HPV types to those lesions has been difficult to estimate. Here, in a 14-year nationwide follow-up of a randomized HPV screening trial, high-risk HPV types 16,18, 31, 33, 45, and 52 were found to contribute substantially to low-grade squamous intraepithelial lesions (LSILs). HPV-associated risks for atypical squamous cells of undetermined significance (ASCUS)/LSIL were strongly time-dependent. The data could be useful for design and evaluation of HPV type-specific vaccines, screening tests and clinical management algorithms.