Matthew Palmer

National genotype prevalence and age distribution of human papillomavirus from infection to cervical cancer in Japanese women: a systematic review and meta-analysis protocol

Abstract Background Despite prophylactic human papillomavirus (HPV) vaccination being a safe, effective and cost-effective public health intervention for the prevention of cervical cancer, the HPV vaccine is not actively recommended or promoted by the Ministry of Health Labour and Welfare in Japan. With already very low levels of cervical screening below 30%, and vaccination levels that are below levels that award any population effect at 0.3% of the eligible population, cervical cancer mortality is higher than other similar high-income countries at 4.4/100,000 (2900) deaths per year in 2015. There is limited population-based or nationally representative data for HPV genotype distribution in Japan, thus making an assessment of the burden of vaccine-preventable cervical cancer difficult. Therefore, this systematic review and meta-analysis aims to determine the HPV genotype prevalence and age distribution of HPV infection in women with a cytological or histological diagnosis of normal through cervical cancer in Japan. We anticipate this information will guide and enhance programme interventions to reduce vaccine-preventable cervical cancer mortality in Japan. Methods PubMed, Embase and the Japan Medical Abstract Society Database will be searched from the date of establishment to March 2021 to identify original research articles that report the prevalence of HPV genotypes in Japanese women with normal cervical cytology, low grade, high grade and cancerous cervical lesions. No exclusion criteria relating to language or publication date will be applied. The quality of the studies will be assessed using the Joanna Briggs checklist for prevalence studies. Randomised control trials, cohort studies, cross-sectional and prevalence studies will be considered eligible. Study findings will be combined using a traditional random-effects or fixed-effects meta-analysis to summarise pooled prevalence and 95% confidence intervals depending on heterogeneity. Subgroup analyses and meta-regression will be used to investigate heterogeneity, and sensitivity analyses will be conducted to assess the robustness of the findings. Discussion To our knowledge, this is the first systematic review protocol that includes both Japanese and English peer-reviewed articles for the determination of genotype-specific HPV prevalence in cytological or histological confirmed normal cervical specimens, low- and high-grade intraepithelial lesions and cervical cancers by age in Japan. We anticipate this information will guide and enhance programme interventions to reduce vaccine-preventable cervical cancer mortality in Japan. Systematic review registration PROSPERO CRD42018117596

Genotype prevalence and age distribution of human papillomavirus from infection to cervical cancer in Japanese women: A systematic review and meta-analysis

National HPV vaccination coverage in Japan is less than one percent of the eligible population and cervical cancer incidence and mortality are increasing. This systematic review and meta-analysis aimed to provide a comprehensive estimate of HPV genotype prevalence for Japan. English and Japanese databases were searched to March 2021 for research reporting HPV genotypes in cytology and histology samples from Japanese women. Summary estimates were calculated by disease stage from cytology only assessment - Normal, ASCUS, LSIL, HSIL and from histological assessment - CIN1, CIN2, CIN3/AIS, ICC (ICC-SCC, and ICC-ADC), and other. A random-effects meta-analysis was used to calculate summary prevalence estimates of any-HPV, high-risk (HR) and low-risk (LR) vaccine types, and vaccine genotypes (bivalent, quadrivalent, or nonavalent). This study was registered with PROSPERO: CRD42018117596. A total of 57759 women with normal cytology, 1766 ASCUS, 3764 LSIL, 2017 HSIL, 3130 CIN1, 1219 CIN2, 869 CIN3/AIS, and 4306 ICC (which included 1032 ICC-SCC, and 638 ICC-ADC) were tested for HPV. The summary estimate of any-HPV genotype in women with normal cytology was 15·6% (95% CI: 12·3-19·4) and in invasive cervical cancer (ICC) was 85·6% (80·7-89·8). The prevalence of HR-HPV was 86·0% (95% CI: 73·9-94·9) for cytological cases of HSIL, 76·9% (52·1-94·7) for histological cases of CIN3/AIS, and 75·7% (68·0-82·6) for ICC. In women with ICC, the summary prevalence of bivalent vaccine genotypes was 58·5% (95% CI: 52·1-64·9), for quadrivalent genotypes was 58·6% (52·2-64·9) and for nonavalent genotypes was 71·5% (64·9-77·6), and of ICC cases that were HPV positive over 90% of infections are nonavalent vaccine preventable. There was considerable heterogeneity in all HPV summary estimates and for ICC, this heterogeneity was not explained by variability in study design, sample type, HPV assay type, or HPV DNA detection method, although studies published in the 1990s had lower prevalence estimates of any-HPV and HR HPV genotypes. HPV prevalence is high among Japanese women. The nonavalent vaccine is likely to have the greatest impact on reducing cervical cancer incidence and mortality in Japan.

Impact of a Human Papillomavirus Vaccination Program within Organized Cervical Cancer Screening: Cohort Study

Abstract Background: We assessed the effectiveness of an HPV (human papillomavirus) vaccination program in lowering cervical abnormality risk, and conferring herd protection. Methods: Retrospective cohort study using linked screening and vaccination administrative health data of the general population of Ancona Province, Italy. We included all female residents born in 1990–1993, eligible for catch-up HPV vaccination up to age 25 years, and adhering to organized screening in 2015–2020 (n = 4,665). Cervical abnormalities rates were compared between: Vaccinated and unvaccinated women, and cohorts with high and low vaccination uptake. Analyses were adjusted for age, country of birth, screening tests number, laboratory, and municipality average income. Main outcomes were ASC-US+ or LSIL+ Pap smears, and CIN1+ or CIN2+ histology. Results: Mean screening age was 26.6±1.5 years, and 1,118 screened women (24.0%) were vaccinated (mean vaccination age 19.2±1.5 years). The diagnosed cervical abnormalities were: 107 LSIL+ (2.3%), 70 CIN1+ (1.5%), and 35 CIN2+ (0.8%). The adjusted odds ratios of LSIL+, CIN1+, and CIN2+ among vaccinated versus unvaccinated women were, respectively: 0.55 [(95% confidence interval (CI), 0.33–0.91)], 0.43 (95% CI, 0.22–0.86), and 0.31 (95% CI, 0.11–0.91). Among the unvaccinated, those in the highest-uptake (45.3%) 1993 cohort, versus the last pre-vaccination 1990 cohort, showed AORs of LSIL+ and CIN1+ of 0.23 (95% CI, 0.10–0.50), and 0.22 (95% CI, 0.07–0.69), respectively. Conclusions: In the first evaluation from Central Italy, catch-up HPV vaccination considerably reduced the risk of all cervical abnormalities diagnosed within organized screening, and conferred an elevated degree of herd protection among unvaccinated women. Impact: The high protection conferred by HPV vaccination suggests the need to update cervical screening.