Optimizing cervical cancer prevention through screening and HPV vaccination

Abstract: Effective primary and secondary prevention tools exist for cervical cancer in the form of human papillomavirus (HPV) vaccines and cervical screening. In order to maximize the impact of prevention strategies in Sweden and European countries, this thesis sought to investigate the long-term effectiveness of different screening strategies and the long-term risk associated with HPV infections, the organization and quality of existing screening programs, and the effectiveness of alternative vaccination strategies. HPV-based screening has been evaluated using intermediate outcomes while its effectiveness against cancer had not been fully examined. In Study I, the European randomized controlled trials (RCT) of screening methods were pooled to investigate the relative efficacy of HPV-based versus cytology-based screening for the prevention of invasive cervical cancer. We found that HPV-based screening provides 60-70% greater protection against invasive cervical cancer compared to cytology-based screening. To address the issue of determining intervals for HPV-based screening and to investigate concerns regarding overdiagnosis with HPV-based screening, a long-term follow-up of the Swedescreen RCT was completed in Study II. The longitudinal performance of cytology- and HPV-based screening was explored and the sensitivity for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) of HPV testing at 5 years of follow-up was similar to that of cytology testing at 3 years. Over 13 years of follow-up, we found that the increased sensitivity of HPV screening for CIN2+ reflects earlier diagnosis rather than overdiagnosis and low long-term risks among HPV negative women suggest that extending screening intervals with HPV-based screening would be possible. The incidence of low-grade cervical lesions is increasing in Sweden. Low-grade lesions require follow-up, creating a burden to the woman and the healthcare system. Examining the long-term HPV-type-specific risk for atypical squamous cells of undetermined significance (ASCUS), low grade squamous intraepithelial lesions (LSIL) and cervical intraepithelial neoplasia grade 1 (CIN1) is of interest to inform screening and vaccination programs. In Study III, we investigated the long-term type-specific absolute risk, population attributable proportion, and incidence rate ratios for ASCUS/LSIL by HPV type. The type-specific IRRs for ASCUS/LSIL were high in the first screening round but decreased over subsequent screening rounds. Type 16 contributed to the greatest proportion of low-grade lesions in the population followed by type 31. Most lesions were caused by new infections and found in the first screening round. Organized, population-based screening with quality assurance (QA) at all levels is recommended by the European Commission to ensure equity and cost-effectiveness of programs. Significant differences in cervical cancer incidence and mortality exist between European countries. In Study IV, a comprehensive questionnaire was developed and circulated among EU/EFTA countries to map current organization of programs and quality assurance efforts to understand prevention activities and inform future guidelines. The findings show that organized efforts for QA, monitoring and evaluation differed between and within countries, making it difficult to compare program effectiveness. HPV vaccination is underway in most European countries but efforts to organize and standardize vaccination program monitoring and evaluation are limited. Using the same questionnaire as in Study IV, we collected detailed information on HPV vaccination programs in EU/EFTA countries for Study V. Our findings suggest that the monitoring being performed varies across programs with regard to level of detail and the organization and quality of programs differ. There was a strong interest in the survey which affirms the significance of the issues addressed and the importance of continuing to evaluate program development and strengthen surveillance of vaccination program efforts. Since the introduction of HPV vaccination, vaccine prices have decreased significantly making upscaling of vaccination efforts more attractive. Specifically, questions have arisen regarding vaccination of older girls and extending the vaccination program to boys. Using a dynamic transmission model, in Study VI we compared different vaccination strategies and assessed the resilience of the vaccination program to a reduction in coverage. We found that vaccination strategies including an extended catch-up of women and introducing male vaccination may accelerate the prevalence reduction of vaccine HPV types among women. Further, including males in routine vaccination improved the resilience of vaccination programs. Taken together, the results of these studies seek to add evidence for the incremental optimization of prevention programs. The challenge will be translating research findings into practice and ensuring that programs have the tools they need to effectively monitor and evaluate changes.