Research Article The Age Distribution of Type-Specific High-Risk Human Papillomavirus Incidence in Two Population-Based Screening Trials Nienke J. Veldhuijzen 1 , Johannes Berkhof 1 , Anna Gillio-Tos 2 , Laura De Marco 2 , Francesca Carozzi 3 , Annarosa Del Mistro 4 , Peter J.F. Snijders 5 , Chris J.L.M Meijer 5 , and Guglielmo Ronco 6 Abstract Background: Age- and type-specific high-risk human papillo- mavirus (hrHPV) incidence estimates in screen-eligible women are relevant from a public health perspective because they provide an indication of the effect of vaccination on the occurrence of screen-positives in HPV-based screening. However, limited data from women over 25 years of age are available. Methods: In 24,105 hrHPV-negative women participating in Dutch (Population-Based Screening Study Amsterdam: POBAS- CAM) and Italian (New Technologies for Cervical Cancer: NTCC) population-based randomized controlled screening trials the age- and type-specific distribution of incident hrHPV infections detected at the next screening round was assessed. HPV types were grouped into vaccine (bivalent: HPV16/18; polyvalent HPV16/18/31/33/45/52/58) and nonvaccine types. Results: The incidence of screen-detected hrHPV among women ages 29 to 56 years was 2.54% (95% confidence interval, 2.30–2.78) in POBASCAM and 2.77% (2.36–3.19) in NTCC. In both studies, the incidence of bivalent, polyvalent, and nonpolyvalent infections decreased with age (P < 0.0001). Among women with incident infection(s), vaccine-type posi- tivity changed quadratically with age, in particular for the polyvalent vaccine (P values: POBASCAM: bivalent 0.264, polyvalent 0.038; NTCC bivalent 0.039, polyvalent 0.005). However, more than 20% and 50% of women with incident hrHPV were positive for bivalent and polyvalent vaccine types, respectively, in all ages in both studies. Conclusions: We observed decreasing age trends of hrHPV vaccine and nonvaccine type incidences and age-related differ- ences in the vaccine-type positivity among women with incident infections. Most importantly, hrHPV infections continued to be detected in all ages and the contribution of vaccine types remained substantial. Impact: Our results indicate a considerable reduction of new hrHPV infections in vaccinated cohorts, ensuing revision of screening guidelines. Cancer Epidemiol Biomarkers Prev; 24(1); 111–8. Ó2014 AACR. Introduction Human papillomavirus (HPV) is an ubiquitous, sexually trans- mitted infectious pathogen with high transmission potential. Some HPV types (high-risk, hrHPV) are oncogenic and persistent infection with hrHPV is a necessary prerequisite for the develop- ment of cervical cancer. HPV types 16 and 18 are associated with about 70% of cervical cancer and HPV16 is the most common type in HPV-positive women worldwide (1, 2). A decreasing trend of hrHPV prevalence with age has been well documented among women with normal cytology in most regions of the world where organized screening programs have been implemented (1). Age- and type-specific HPV incidences are less well documented, especially not in women over 25 years of age, but provide information that is relevant from a public health perspective and that cannot be directly inferred from HPV prevalence. HPV-type distribution by age in prevalent infections, for example, suffer from variation in infection onset times because of differences in screening history, whereas HPV-type incidences do not. Type- specific incidences can therefore provide an estimate of the effect of vaccination on the occurrence of screen positives in HPV-based screening and about the necessity of continuing screening for hrHPV-negative women beyond a certain age. Here, we report the age- and type-specific distribution of screen- detected incident hrHPV infections among participants of two large European population-based screening trials over the course of two screening rounds, including a total of 24,105 women. Materials and Methods Studies Data collected in the context of two population-based ran- domized controlled clinical trials evaluating the efficacy of HPV- based screening compared with cytology-based screening were included in the current analyses: the Population Based Screening Study Amsterdam (POBASCAM) and the New Technologies for Cervical Cancer (NTCC) screening study. Both trials were 1 Department of Epidemiology & Biostatistics, VU University Medical Centre, Amsterdam, the Netherlands. 2 Cancer Epidemiology Unit, CERMS, University of Turin, Turin, Italy. 3 Cancer Prevention and Research Institute (ISPO), Florence, Italy. 4 Veneto Institute of Oncol- ogy IOV-IRCCS, Padua, Italy. 5 Department of Pathology,VU University Medical Centre (VUmc), Amsterdam, the Netherlands. 6 Center for Cancer Epidemiology and Prevention, AO City of Health and Science, Turin, Italy. Corresponding Author: N.J. Veldhuijzen, Department of Epidemiology & Bio- statistics, VU University Medical Centre, Boelelaan 1117, Amsterdam 1081HV, the Netherlands. Phone: 0031-20-4444935; Fax: 0031-20-444475; E-mail: n.veldhuijzen@vumc.nl doi: 10.1158/1055-9965.EPI-14-0628 Ó2014 American Association for Cancer Research. 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