Efficacy of catch-up strategies administered at different ages.

<p>Efficacy is represented in terms of number (a) and percentage (b) of additionally averted cervical cancer cases with respect to the baseline scenario of immunization at 12 year only. In each panel, a sensitivity analysis of the baseline scenario with respect to the best and worst case is represented.</p

Results of model fitting.

<p>a) prevalence of HPV 16/18 in Italian women <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091698#pone.0091698-Ronco1" target="_blank">[25]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091698#pone.0091698-Giambi2" target="_blank">[27]</a> by age groups and corresponding curve predicted by the model, disaggregated by infection type; b) cervical cancer incidence data by age due to HPV 16 and 18 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091698#pone.0091698-AIRTUM1" target="_blank">[28]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091698#pone.0091698-Mariani1" target="_blank">[31]</a> and as predicted by the model over time. Data refer to the period 2004–2006 and need to be compared with the 2005 curve (darkest line in Figure). Note the change in shape with the appearance of a second peak at ages >70 years after the introduction of screening in 1996, consistently with observations in other countries <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091698#pone.0091698-Lynge1" target="_blank">[45]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091698#pone.0091698-Kjellgren1" target="_blank">[46]</a>; c) comparison between observed <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091698#pone.0091698-AIRTUM1" target="_blank">[28]</a> and predicted screening effectiveness over time in terms of percent reduction in number of cases with respect to the baseline value of 1996.</p

Evaluation of different prevention strategies.

<p>Predicted number of cervical cancer cases (a) and treatments of cervical cancer (b), carcinoma in situ (CIS) (c) and cervical intraepithelial neoplasia (CIN) grade 3 (d) over time under different prevention strategies are compared in this figure. <i>No action</i>: model equilibrium, in the absence of both screening and vaccination; <i>screening only</i>: screening with realistic effective coverage until 2008, and then kept constant coverage from 2009; <i>actual vaccination</i>: as screening only, with the addition of the implemented program of immunization of 12-years-old girls in 2008–2012, with realistic coverage, assumed to be discontinued from 2013 on; <i>baseline</i>: as actual vaccination, but the vaccination program is assumed to continue indefinitely with coverage equal to 2012; <i>catch-up</i>: as baseline, including a catch-up program for 25 year-old women.</p

A simplified flowchart of the compartmental model including the main compartments and transitions.

<p>The scheme is stratified by 100 one-year age-classes and replicated by 3 sexual activity levels. U: sexually inactive women; UV: sexually inactive, vaccinated women; X: sexually active, susceptible women; Y: women with HPV infection; CIN1–CIN3: women with cervical intraepithelial neoplasia, grades 1–3; CIS: women with carcinoma in situ; CC: women with cervical cancer; Z: immune women; V: vaccinated women; HX: hysterectomized susceptible women; HY: hysterectomized women with HPV infection; HZ: hysterectomized immune women; VH: vaccinated, hysterectomized women; U_m: sexually inactive men; X_m: sexually active, susceptible men; Y_m: men with HPV infection; Z_m: immune men.</p

The Impact of HPV Female Immunization in Italy: Model Based Predictions

<div><p>The Human Papillomavirus (HPV) is a sexually transmitted virus that causes cervical cancer. Since 2008 a vaccination program targeting 12-year-old girls has been initiated in Italy, backing up the cervical screening program already active since 1996. We propose a mathematical model of HPV transmission dynamics with the aim of evaluating the impact of these prevention strategies. The model considers heterosexual transmission of HPV types 16 and 18, structured by sex, age and sexual activity level, where transition to sexual activity is explicitly modeled from recent survey data. The epidemiological structure is a hybrid SIS/SIR, where a fraction of individuals recovering from infection develops permanent immunity against reinfection. Infections may progress to cervical lesions and cancer and heal spontaneously or upon treatment. Women undergoing hysterectomy (either after treatment of HPV lesions or by other causes) also transmit HPV infection. The model fits well both the age-specific prevalence of HPV infections and the incidence of cervical cancers in Italy, and accurately reproduces the decreasing trend in cancer incidence due to the introduction of the screening program. The model predicts that if the screening coverage is maintained at current levels, even in the absence of vaccination, such trend will continue in the next few decades, eventually plateauing at 25% below the current level. The additional initiation of routine vaccination targeting 12-year-old girls will further reduce cervical cancer incidence by two thirds at equilibrium, under realistic assumptions of 70% coverage and a duration of protective immunity of 50 years. If catch-up immunization of 25-year-old women at first cervical screening is also introduced, about 3,000 cervical cancer cases overall can be averted, corresponding to 9.6% of all cases expected in the scenario without catch-up. We conclude that HPV vaccination in addition to cervical screening will significantly reduce the burden of cervical cancer in Italy.</p></div

Sensitivity analysis of model predictions with respect to different assumptions on vaccine parameter values.

<p>a) vaccine coverage; b) duration of protection; c) vaccine efficacy; d) sensitivity of model predictions when considering the worst and best case of the three parameters together.</p

Impact of different prevention strategies on age at onset of severe lesions.

<p>Mean age at onset of cervical cancer (a), carcinoma in situ (CIS) (b) and cervical intraepithelial neoplasia (CIN) grade 3 (c) over time, under different prevention strategies. <i>Screening only</i>: screening with realistic effective coverage until 2008, and then kept constant coverage from 2009; <i>actual vaccination</i>: as screening only, with the addition of the implemented program of immunization of 12-years-old girls in 2008–2012, with realistic coverage, assumed to be discontinued from 2013 on; <i>baseline</i>: as actual vaccination, but the vaccination program is assumed to continue indefinitely with coverage equal to 2012; <i>catch-up</i>: as baseline, including a catch-up program for 25 year-old women; <i>best</i>: as baseline, but with best-case vaccine parameters (coverage: 95%; efficacy: 100%; duration of protection: permanent); <i>worst</i>: as baseline, but with worst-case vaccine parameters (coverage: 50%; efficacy: 82%; duration of protection: 20 years).</p

Reference studies for HPV prevalence data and study details.

<p>Reference studies for HPV prevalence data and study details.</p

Best estimates of model parameters.

<p>CIN: cervical intraepithelial neoplasia; CIS: carcinoma in situ; CC: cervical cancer.</p

Pearson’s correlation coefficient between ILI morbidity and query volume of selected entry terms.

<p>^a: Popular brand name of Paracetamol;</p><p>^b: Only monthly data were available</p><p>Pearson’s correlation coefficient between ILI morbidity and query volume of selected entry terms.</p