Prevalence of cervical disease at 20 years after immunization with bivalent HPV vaccine aged 12-13 in Scotland: A retrospective population study

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Tim Palmer, Clinical Lead for Cervical Cancer Screening in Scotland1
Lynn Wallace, information analyst2
Kevin G Pollock, Senior Epidemiologist and Principal Investigator3 4,
Kate Cuschieri, director5
Chris Robertson, Statistics Officer, Principal Investigator and Professor3 6 7,
Kim Kavanagh, Lecturer7
Margaret Cruickshank, honorary consultant gynecologist8

Correspondence to: T Palmer timothy.palmer {at} nhs.net

Abstract

Goal To quantify the effect on cervical disease at the age of 20 years of vaccination with the bivalent vaccine against human papillomavirus (HPV) at the age of 12-13 years.

Design Retrospective study of the population, 1988-1996.

Setting National vaccination and cervical screening programs in Scotland.

participants 138,692 women born between January 1, 1988 and June 5, 1996, with a smear test result of 20 years.

Main outcome measures Effect of vaccination on cytological findings and associated histological diagnoses from the first year of screening (in the 20 years), calculated using a logistic regression.

Results 138,692 records were retrieved. Compared with unvaccinated women born in 1988, vaccinated women born in 1995 and 1996 had a 89% reduction (95% confidence interval between 81% and 94%) of prevalent cervical intraepithelial neoplasia (grade 3 or higher). serious) (0.59% (0.48%)). 0.71%) at 0.06% (0.04% to 0.11%)), a 88% (83% to 92%) reduction in CIN 2 grade or worse (1.44% (1%) , 28% to 1.13%) at 0.17% (0.12% to 0.24%), and a 79% (69% to 86%) reduction in the CIN 1 score (0.69% (0.58% to 0.63%) to 0.15% (0.10% to 0.21%).) The increase in vaccine efficacy was associated with a younger age at the time of treatment. vaccination: 86% (75% to 92%) of grade 3 CINs or less for vaccinated women aged 12 to 13, compared to 51% (28% to 66%) of women vaccinated at this age 17. In cohorts in 1995 and 1996, evidence of herd protection against high-grade cervical disease was found in unvaccinated girls.

conclusions Routine vaccination of the bivalent HPV vaccine in girls aged 12-13 in Scotland has led to a dramatic reduction in pre-invasive cervical disease. The evidence of clinically relevant herd protection is evident in unvaccinated women. These data are consistent with the reduction in the prevalence of high-risk HPV in Scotland. The bivalent vaccine is recognized as a highly effective vaccine and is expected to significantly reduce the incidence of cervical cancer. The results will need to be taken into account by cervical cancer prevention programs around the world.

introduction

Cervical carcinoma is the fourth most common cancer in women and a leading cause of morbidity and mortality worldwide.1 In developed countries where organized cervical cancer screening programs have been implemented, the incidence and mortality of cervical cancer have decreased, although in number of cases of cervical cancer. between them there is no further decrease or even increase in incidence. Many factors could contribute to these trends, including decreased screening participation, increased rates of human papillomavirus (HPV) infection, and changes in sexual behavior23. Most middle- and low-income countries lack the resources to support organized screening and cervical cancer. remains a considerable problem. The development of vaccines against the most important types of oncogenic HPV could be a major step in the prevention of cervical cancer.

In 2008, Scotland launched a national HPV vaccination program with the aid of the bivalent vaccine used until 2012. This vaccination program targeted 12- and 13-year-old girls (routine immunization ) and was taught in schools. It has been supplemented by a three-year catch-up period. program until the age of 18 years. Participation in the catch-up cohort has been about 65% overall, but has consistently exceeded 85% 45 .45

Up to and including June 5, 2016, Scottish women had been invited to undergo cervical cancer screening at the age of 20. They were then examined from the age of 25. Women in the catch-up cohorts have been screened since 2010 and women in the immunized cohorts screened since 2015. Scotland has comprehensive cervical screening data that contains the woman's complete screening file, her immunization status and his unique personal identifier (Community Health Index Number (CHI)). We were able to show the effectiveness of vaccination on various outcomes, including HPV prevalence, herd immunity, cervical disease, colposcopy results and cervical cancer screening. This is a comprehensive immunization surveillance program.

Recently, we reported the effect of the bivalent HPV vaccine on the prevalence of HPV types in immunized women aged 12 to 13 years who were screened at age 20.12 In the 1995 birth cohort (associated with a 90% uptake of the vaccine at age 13)) virtual eradication of HPV types 16 and 18 infection and a statistically significant reduction in the number of types of cross-protection were observed. In addition, no evidence of replacement with other HPV types was evident and statistically significant herd protection in unvaccinated women was identified. Similar reductions have been reported in the Netherlands, where the bivalent vaccine is used.13 The considerable reduction in the most carcinogenic HPV types clearly has implications for the associated diseases and how they are clinically managed.

In this study, we report at the national level, at the program level and through screening records, the effect of routine vaccination of girls aged 12-13 with the bivalent HPV vaccine on HIV levels. Cytological abnormalities and cervical intraepithelial neoplasia (CIN). These findings complement earlier studies in Scotland and the Netherlands that the bivalent vaccine would provide protection against most HPV-related cervical cancers.

The methods

Scottish Cervical Screening Program

Scotland has set up an organized national cervical cancer screening program, which provides about 70% of its patients14. Up to and including June 5, 2016, women aged 20 to 60 were eligible for screening. Subsequently, the age range increased from 25 to 64 years, 364 days per year. line with the rest of the UK. Eligible women are screened every three years until the age of 50, then every five years until the age of 65. The screening is extended by five years if necessary to complete the monitoring of detected anomalies. Scotland uses Thinprep liquid-based cytology with image-assisted screening (ThinPrep Imaging System, Hologic, Marlborough, MA). Eight cytology laboratories in the National Health Service provided the program during the reporting period and processed approximately 400,000 samples per year. Cytological and histological results are classified according to the criteria of the British Association for Cytopathology cervical cancer screening program and NHS.1516. Table 1 compares the three commonly used notification systems.

Table 1

Comparison of notification systems used to classify cervical cytology

Women are referred for colposcopy after a finding of high grade dyscaryosis or ASCH (atypical squamous cells, can not exclude high grade squamous intraepithelial lesion), two findings of low grade dyscaryosis, or three marginal changes during pregnancy. 39, an abnormal follow-up episode, or three abnormal results in the last 10 years. Women with low grade dyscaryosis or marginal changes are followed by cytology at six months if they are not referred for colposcopy. The smears are repeated within three months if the results are not satisfactory and women with three consecutive unsatisfactory results are referred for colposcopy. Ablation or excision is routinely performed for grade CIN 2 or worse. Conservative management is the expected treatment for low-grade diseases. Scotland does not use the HPV test for triage of low grade cytology.

Extraction of data, annotations and exclusions

The Scottish Cervical Call Reminder System (SCCRS) is a national computer system that contains comprehensive screening data and serves as an active management tool. We interviewed the SCCRS to obtain screening data on all women born between January 1, 1988 and June 5, 1996, from the date of first screening eligibility (20 years) to the date of Data extraction (August 2017). The extracted data included the CHI number, the postal code of the residence, the date of birth, the presence, the vaccination status, the cytological result, the colposcopy reference and the associated histological diagnosis. The postal code of the residence was used to calculate the multiple deprivation index of Scotland (the fifth out of five represents the poorest), and the index of rurality (derived from the Scottish government's eight-level indicator) , with three levels: urban, rural accessible (30-60 minutes drive up to an agglomeration of 10,000 ≥) and remote rural areas (> 60 minutes drive up to an agglomeration of 10,000 ≥) ). Duplicate registrations for a woman are linked in the SCCRS under the latest CHI number, and personal data (including postal code) is updated daily from the Scottish National Population Register used in school and health systems Scottish.

For all cohorts, we restricted data to people who had cytological tests and colposcopy appointments at the age of 20. The results for most women were their first smear or first colposcopy exam; for the few women who had more than one Pap smear or biopsy during their first year of screening, we used the most serious result. We excluded from the analysis records without deprivation score and rurality. Although data on all screening events were extracted, for this analysis we used only data on participation during the first year of eligibility, thus minimizing bias resulting from age differences. at the time of screening and the possibilities of detecting the disease. Age at vaccination was calculated according to age at first vaccination. Figure 1 shows the relationship between vaccination, the year of the first screen and the extraction of data.

Fig. 1

Schedule of vaccination, screening and data collection. Only a few years of birth in the 1990s were eligible. Girls born in 1994 are not covered during the first year of catch-up and are immunized on both sides of the fifteenth birthday, depending on their date of birth. For the first invitation to screening at age 20, women born in 1996 are only eligible if their date of birth is before June 6th. Data collected for all screening events in the first year of screening. Women born in 1996 had at least 15 months between the initial invitation to screening and the data extraction

Measures of effect and results

Cytology was noted as negative (no signs of disease), as borderline (including glandular changes), and as low, moderate, or severe dyscaryosis (including glandular abnormalities). The histology was coded as normal (no CIN detected), CIN level 1, CIN level 2 and CIN level 3 or higher (glandular neoplasia or cancer). We classified non-colposcopy women as not having detected CIN. Wilson's method was used to calculate the confidence intervals of the percentages of women in the result groups. We used multivariate multinomial logistic regression models to explore associations between cytology results, colposcopy reference and histological diagnosis, as well as vaccination and demographic variables. Odds ratios for cytological and histological results are reported with 95% confidence intervals. The efficacy of the vaccine for three doses compared to no dose was calculated as 100 × (1-odds ratio), and for those who were fully vaccinated, we estimated vaccine efficacy separately by age at vaccination, with reference to unvaccinated women of the generations preceding vaccination (born in 1988). 90). We used interaction tests to determine whether the trend over time was the same for fully vaccinated and unvaccinated women. In addition to the number of vaccine doses, we studied the influence of the birth cohort, the fifth multiple deprivation indicator of Scotland and the urban-rural indicator of vaccine efficacy. Pre-vaccination cohorts (born between 1988 and 1990) served as a comparison group, although a small proportion of women born in 1990 were eligible for vaccination. Girls in the catch-up group (1991-1994) are more likely to have been exposed to HPV before vaccination, whereas the systematically immunized group (1995-1996) is considered more likely to be exposed naive HPV. We studied herd protection by comparing disease rates among unvaccinated women in the 1991-92, 1993-4 and 1995-96 cohorts with unvaccinated women in the 1989-90 cohort. Statistical analysis was performed in versions R 3.5.1 and SPSS 21.

Patient and public participation

There has been no involvement of the patient or the public in the design or analysis of this study. The recordings were anonymized before analysis, while maintaining the link between immunization, cytology and histology, if any. The Caldicott Guardian Approval, a UK process to ensure that the use of personal data complies with legal data protection requirements and in the public interest, was obtained for the use of the data. The data was generated by the routine activity of the Scottish Cervical Screening Program. Participation in the program gives implicit consent to the use of data from this participation for purposes of monitoring and improving the service. This study does not affect the management of individual patients and no one can be identified from the anonymized dataset used by researchers.

Results

A total of 138,692 women born between January 1, 1988 and June 5, 1996 had a smear test result recorded at the age of 20 years. Table 2 and Supplementary Table 1 show the distribution of records by year of birth and vaccination status. Three groups are identified, roughly corresponding to unvaccinated women (born from 1988 to 1990, aged 18 to 20 in 2008), women vaccinated during the catch-up program (born between 1991 and 1994, aged 14 to 17). years to vaccination) and to women systematically vaccinated. (born in 1995-96, 12-13 years old at the time of vaccination). Cumulatively within the extract, 64,026 women were not vaccinated and 68,480 had three doses of vaccine (fully vaccinated). Only 2051 women received one dose and 4135 women received two doses. The number of women born in 1996 in the data set is lower than in other years, with only women born before June 6 being eligible for screening due to changes in the age group of the screening program. The number of women who received their first dose at age 14 is lower than in other years because of the gradual implementation of the catch-up program (Figure 1).

Table 2

Number (percentage) of records in the stratified data extract by year of birth, number of doses of bivalent human papillomavirus vaccine, cytological abnormality, reference for colposcopy and histological diagnosis

Tables 3 and 4 show the corrected odds ratios for cytological and histological results by immunization status and by age at which the first dose was administered and by year of birth in unvaccinated women, respectively. Figures 2 and 3 show trends in cytological abnormalities and histologically confirmed CINs as a percentage of the population screened by null or complete immunization.

Table 3

Cytological and histological abnormalities at 20 years of age at the first dose of bivalent human papillomavirus vaccine and vaccination status. Values are adjusted odds ratios (95% confidence intervals) unless otherwise noted.

Table 4

Cytological and histological abnormalities at 20 years of age in women who did not receive the bivalent human papillomavirus vaccine, by year of birth. Values are adjusted odds ratios (95% confidence intervals) unless otherwise noted.

Figure 2

Cytological abnormality (% of women screened) by year of birth and vaccination status. 1988-90 = cohort of the pre-immunization program; 1991-1994 = catch-up cohort; 1995-1996 = systematically immunized cohort. Mustaches represent 95% confidence intervals. ASCUS = atypical squamous cells of undetermined significance; LSIL = low grade squamous intraepithelial lesion; HSIL = high grade squamous intraepithelial lesion (HSIL-M = mild dyskaryosis, HSIL-S + = severe dyskaryosis)

Fig 3

Histological abnormality (% of women screened) by year of birth and vaccination status. Mustaches represent 95% confidence intervals. CIN = cervical intraepithelial neoplasia; 1988-90 = cohort of the pre-immunization program; 1991-1994 = catch-up cohort; 1995-96 = systematically immunized cohort

Cytological results

The overall rate of severe dyskaryosis or lower worsening was reduced from 0.75% (0.63% to 0.89%) in women born in 1988 to 0.06% (0.04% to 0.11%). %) in women born in 1995-1996, and moderate dyskaryosis increased from 1.18% (1.04% to 1.36%) to 0.27% (0.21% to 0.35%); which represents reductions of 92% (85% to 95%) and 77% (69% to 83%), respectively (Table 2). Rates of severe and moderate dyskaryosis in unvaccinated women compared to fully immunized women born in 1995 and 1996 were not significantly different (Figure 2). Overall, the limit / ASCUS rates decreased by 34% (30% to 39%), with a similar cohort trend in vaccinated and unvaccinated women (P interaction test = 0.11), although that the rate was lower among vaccinated women (15%). 11% to 19%). The low grade dyscaryosis / LSIL notification increased during the observation period. The trend with the birth cohort was the same for vaccinated and unvaccinated women (interaction test P = 0.17); vaccinated women had lower rates of 19% (14% to 24%) (Table 2 and Figure 2).

The efficacy of the vaccine in fully immunized women aged 12 to 13 compared to unvaccinated women in 1988-90 was 42% (38% to 46%) for borderline treatment / ASCUS, -38% (- 48% to 28%). Low grade dyskaryosis / LSIL, 80% (72% to 86%) for moderate dyskaryosis / HSIL-M and 93% (86% to 97%) for high grade dyskaryosis / HSIL-H (Table 3).

Histological results

High grade CIN showed a significant overall decline (Table 2 and Figure 2). Grade 3 or lower CIN levels decreased by 89% (81% to 94%) from a pre-immunization rate of 0.59% (0.48% to 0.71%) in women 1988, 0.06% (0.04% to 0.11%). %) among women born in 1995-96. CIN grade 2 or lower decreased by 88% (83% to 92%), from a pre-immunization rate of 1.44% (1.28% to 1.63) to 0.17%. % (0.12% to 0.24%) among women born in 1995-1996. . No CIN level 2 or higher (upper confidence limit 0.7%) was found in unvaccinated women in this age group (n = 545). The decline in high-grade CIN was more pronounced among fully vaccinated women (P = 0.005 interaction test), but for the 1995-1996 cohort, high-grade CIN rates were not significantly different between vaccinated and unvaccinated women (P = 0.47) (Figure 3). ).

CIN 1 increased from 0.69% (0.58% to 0.63%) of women before vaccination (1988 cohort) to 0.15% (0.10% to 0.21%) of total women born in 1995-1996: at 79% (69% to 86%)) reduction (Table 2). The trend on the birth cohort was the same for fully immunized and non-immunized women (interaction test P = 0.90) and there was no evidence that rates differed between fully immunized women and non-immunized (P = 0.17, Figure 3).

For fully immunized women, vaccinated for the first time at 12-13 years of age, the effectiveness of the CIN 1 vaccine was 78% (66% to 86%), for CIN 2 of 89% (81% to 94%) and for grade 3 or worse, was 86% (75% to 92%), compared to unvaccinated women in the 1988-90 cohorts. Vaccine efficacy was lower in women vaccinated for the first time at age 17: 41% (14% to 59%) for grade CIN 1, 56% (35% to 70%) for grade 2, and 45% (17% to 64%) for grade CIN 3 or worse (Table 3).

Herd protection was observed in unvaccinated women in the 1995-1996 cohort, with a 63% reduction in the probability of grade CIN1 (11% to 85%), 67% reduction in grade CIN 2 (19% at 86%), and 100% (69% to 100%) reduction for CIN 3 compared to unvaccinated women in 1988-90. Similar reductions were noted for moderate dyskaryosis / HSIL-M (58%, 21% to 78%) and high grade dyskaryosis / HSIL-H (85%, 38% to 96%), but not for dyskaryoses low level / ASCUS LSIL (Table 4).

Results at one and two doses

Tables 2 and 3 show the number of women who received one dose or two doses of vaccine and the results. Although cytological and histological results were reduced with two doses, no statistically significant effect was observed for one or two doses. The numbers were too small to allow analysis by year of birth.

Discussion

This study reports statistically significant reductions in all degrees of cervical intraepithelial neoplasia (CIN), equivalent to estimates of vaccine efficacy of 80% or more after routine vaccination at 12 years of age. 13 years. The prevalence of high grade dyscaryosis has been reduced similarly. Herd protection has been demonstrated in unvaccinated women in the routinely vaccinated cohort. Changes in cytologic abnormality and histologically confirmed cervical involvement in women who were first screened for cervical cancer at age 20, associated with routine vaccination at age 12-13 with the bivalent vaccine against human papillomavirus (HPV) in a setting offering both a catch-up program and that has achieved high and consistent absorption. The results of this study were derived from data directly linking the status of vaccination and screening results at the individual level. We are convinced that the reduction of the disease does not relate to the inability of cytological screening to detect disease in vaccinated women, given previous data on cytologic performance showing no loss of sensitivity in vaccinated women compared to to unvaccinated women, and the deterioration of clinical significance. or positive predictive value of low-grade disease defined cytologically described elsewhere.5

The increase in low-grade / LSIL dyscaryosis reports in immunized women was statistically significant, in contrast to the reduction in all other cytological categories and all CIN grades. Scottish surveillance data indicate that vaccine types and cross-protection types (HPV 16, 18, 31, 33 and 45) are found in a higher proportion of samples with borderline cytology / ASCUS than in samples with a low grade dyscaryosis / LSIL cytology, which could, in part, explain this observation. The types of human papillomavirus (HPV) that remain after vaccination may not be associated with a persistent disease. The differential cytologic diagnosis of borderline changes / ASCUS is often a moderate dycaryosis / HSIL rather than a low grade dyscaryosis / LSIL (Atypical borderline squamous cell cases can not rule out high grade squamous intraepithelial lesions ( ASCH) reported but not recorded separately). In addition, the classification of HPV-related cytologic changes and the management of grade 1 or lower CIN at colposcopy had effects on the relationship between low-grade cytology and the diagnosis of Level 1 CIN.

Strengths and limitations of this study

The strengths of this study include the direct coupling of data between the state of vaccination and screening results, and the fact that the data come from the screened population rather than a selected cohort. The completeness of the screening database and the organized and long-standing nature of the surveillance program allow to show trends and examine their correlation with several variables. The data therefore provide a solid foundation for the development of cervical cancer prevention strategies.

This study has limitations. The analysis was limited to women participating in cervical cancer screening at the age of 20 years. Screening in fully immunized women aged 20 to 21 is 51% and only 23% in unvaccinated women1418. It is therefore possible that the effectiveness of the vaccine has been overestimated. However, the high prevalence of vaccination, the similarity in the distribution of HPV type among participants and non-participants, and the appearance of herd protection provide assurance that observations can be extrapolated to the general public. in general.19

The shorter follow-up period for women born in 1995 and 1996 necessarily affects the robustness of estimating the effectiveness of the vaccine for younger women; However, other longitudinal studies planned will help elucidate true protection against the effects of routine immunization. The formal adoption of a conservative management protocol for women with CIN 1 grade in colposcopy during the study period could have affected the number of biopsies performed. However, it is unlikely that this change in practice will explain the magnitude of the CIN 1 grade reductions, particularly considering CIN 2 and 3 level reductions, for which no changes have been made to the CIN 1 reduction. clinical management or treatment during the study. period.

Le grade CIN 3 est maintenant considéré comme le meilleur prédicteur du risque de cancer invasif, mais une proportion continuera à régresser. On sait que la probabilité de développer un grade 3 de CIN varie avec le génotype du VPH et est plus élevée avec les types de VPH 16, 31 et 33.20. La propension à la régression du CIN est également liée au type de VPH, et il y a moins de cancers attribuables à VPH de type 33 supérieur à celui attendu par la prévalence de ce génotype dans les lésions de grade 3 de CIN21. Comme les types les plus oncogènes ont été efficacement éliminés de la population, il est possible que la régression du grade de CIN 3 soit plus probable chez les femmes vaccinées, effet sur les taux de grade CIN 3.

L'incapacité d'évaluer l'impact de moins de trois doses est une autre limitation inévitable de la conformité élevée avec les calendriers complets de vaccination. Les caractéristiques des femmes partiellement immunisées en Écosse ont déjà été décrites5. En résumé, la vaccination partielle était associée à une privation accrue, à la sortie de l'école et à un âge plus avancé. Chez les filles qui ont reçu la vaccination systématique à l'école, seulement 1,6% ont été partiellement immunisées, contre 9,8% au cours de la première année complète de rattrapage.

Comparaison avec d'autres études

Ces résultats sont la contrepartie clinique des réductions d'infection à HPV spécifiques au type observées chez les femmes vaccinées de manière systématique.12 Kavanagh et ses collègues ont montré une efficacité vaccinale statistiquement significative contre les types de HPV 16 et 18 (90%) et les types de HPV à protection croisée (80 à 85%). , avec protection croisée d’une durée minimale de sept ans. Une protection du troupeau contre les infections par les VPH 16 et 18 a également été trouvée chez les femmes non vaccinées de la cohorte vaccinale. La réduction du grade CIN 3 et les estimations de l'efficacité du vaccin rapportées sont d'une ampleur similaire à celles rapportées par Kavanagh et ses collègues pour l'infection à HPV12. Les types de HPV spécifiques du vaccin et à protection croisée couverts par le vaccin (HPV 16, 18, 31, 33 et 45) sont impliqués dans 90% des cancers en Écosse22. La CIN de grade 3 est le précurseur du carcinome invasif du col utérin, avec la plus faible variabilité diagnostique et le plus faible taux de régression spontanée, et elle est reconnue comme le meilleur indicateur du risque. Il est donc raisonnable de s’attendre à ce que la réduction du grade CIN 3 entraîne une réduction du cancer du col de l’utérus dans les années à venir. L'impact prévu de la vaccination sur le cancer mettra plus de temps à se manifester.

Une récente analyse Cochrane de l'efficacité de la vaccination anti-HPV bivalente et quadrivalente dans le cadre d'essais randomisés a montré des preuves sans équivoque et de grande qualité des avantages de la vaccination26. Nos résultats sont cohérents avec cette analyse. Des études de population menées dans d'autres contextes ont montré que le vaccin quadrivalent avait un impact majeur sur l'infection et les maladies bénignes et néoplasiques associées.2728293031323334 Le présent travail complète ces études en étant le premier rapport sur l'impact du vaccin bivalent sur la maladie lors de l'administration aux filles 12-13 ans dans un programme national. Il sera maintenant intéressant de voir l'impact du vaccin non-valent sur la population. Il est postulé que le vaccin non alcalin protégera contre 90% des cancers du col utérin au niveau mondial35. Cependant, une protection supplémentaire méritoire contre le cancer en raison du vaccin non triangulaire sera difficile à démontrer en Écosse, compte tenu de la répartition des types de HPV au Le programme de dépistage du cancer du col utérin en Écosse incorpore la vaccination contre le VPH dans ses statistiques de suivi de routine. Ceci, associé au passage prévu au dépistage primaire du VPH, facilitera la surveillance des changements dans l'efficacité du vaccin à l'avenir.

Implications politiques

Les faibles taux de cancer du col utérin après la vaccination systématique ont clairement des conséquences sur le dépistage des femmes vaccinées. Bien que le nombre de maladies principales soit réduit en Écosse, il n’a pas été éradiqué et un dépistage continu est donc nécessaire, d’autant plus que, depuis plusieurs années, la plupart des femmes participant au programme de dépistage n’auront pas été vaccinées. Des travaux antérieurs ont suggéré que les performances du dépistage basé sur la cytologie et sur le VPH se détérioraient chez les femmes vaccinées, malgré le maintien de la sensibilité78. maladie importante. L'efficacité du dépistage primaire du VPH chez les populations hautement immunisées nécessitera une surveillance étroite. De nouvelles méthodes pour améliorer la participation au dépistage, l'efficacité du dépistage et, surtout, le test de triage seront nécessaires pour maintenir la performance du dépistage cervical en tant que processus. Le taux réduit de maladies chez les patients référés pour une colposcopie compliquera également le maintien des normes de colposcopie1011. Différentes méthodes de modélisation ont été utilisées pour éclairer les scénarios optimaux de dépistage des femmes vaccinées, mais ont convergé sur la conclusion que, pour certaines femmes, deux Le dépistage du VPH pourrait suffire de trois dépistages au cours de la vie.3637. Ce dépistage sporadique, associé à une maladie beaucoup plus réduite et au nombre décroissant de femmes référées pour une colposcopie et un traitement, nécessite une nouvelle conception des programmes de dépistage du col utérin. En fin de compte, les raisons cliniques et économiques du dépistage du col utérin devront être réexaminées.

Conclusion

Nous avons présenté des données couplées, provenant d'une population à forte absorption de vaccins et d'un programme de rattrapage complet, qui montrent qu'une vaccination systématique avec trois doses de vaccin bivalent à l'âge de 12-13 ans est associée à une réduction profonde de la maladie cervicale sept ans plus tard. mesurée par des anomalies cytologiques et histologiques et une référence pour une colposcopie. La maladie a également été réduite chez les femmes non vaccinées, probablement en raison de la protection du troupeau. Routinely vaccinated populations will also have a lower risk of other HPV related diseases.38 The reduction in disease in routinely immunised women, who will form the bulk of the screened population in years to come, mandates revision of screening and referral guidelines. The findings emphasise the credibility of using high risk HPV infection as an early marker of the effectiveness and success of the vaccine and underpin the recent call for global action on cervical cancer from the World Health Organization.

What is already known on this topic

Immunisation against human papillomavirus (HPV) reduces the prevalence of target HPV types and cervical disease in women immunised in catch-up programmes
Population data on the effect on HPV prevalence in women routinely immunised at age 12-13 years show substantial reductions in target and cross protected HPV types
Population data on the effect on disease in routinely immunised women are lacking

What this study adds

Routine immunisation using the bivalent HPV vaccine against high grade cervical disease was found to be highly effective
In the setting of high uptake and a catch-up programme, unvaccinated women also show a reduction in disease, possibly because of herd protection
Cervical cancer prevention programmes and colposcopy services will need reappraisal, and data from Scotland will feed into models to support such review

Acknowledgments

The manuscript was reviewed by Jo’s Trust, which supports the conclusions. It made the following statement: We think (it has) massive implications for the screening programme, vaccine and also impact on diagnoses in the future. It gives weight for activity to increase vaccine uptake, has implications on screening intervals. The clinically relevant herd protection is very interesting too. It also feeds into our policy calls for a new IT infrastructure (for the screening programme in England) to record and enable invitations based on whether someone has at the vaccine if intervals can be extended.

Footnotes

Contributors: TP was the lead author, conducted the literature search, produced the initial drafts, and collated comments. He specified the data extracted and worked with LW, CR, and the Cervical Screening system managers to confirm the quality of the extracted data. TP is the guarantor for this study. LW undertook the data analysis under the guidance of CR and reviewed early drafts. CR directed the statistical analysis and reviewed successive drafts. KC and KP provided support with analysis or interpretation, contextualisation, and generation of manuscript drafts. KK and MC provided additional statistical and clinical input and reviewed the later drafts. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: This study has been undertaken as part of the programme of surveillance of immunisation against human papillomavirus in Scotland, included within the routine work of Health Protection Scotland, a part of the Scottish National Health Service. No funding has been received from industry.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: KP has received travel monies from both Merck and GSK to attend conferences. KC’s institution has received monies to deliver research, or associated consumables to support research, from: Qiagen, Hologic, Selfscreen, GeneFirst, Euroimmun, Cepheid, Genomica, and LifeRiver. No personal conflicts of interest are declared.
Ethical approval: No ethical approval was required for this study as patient treatment was not altered by the observations. Caldicott approval for use of personal data was obtained.
Data sharing: No additional data available.
Transparency: The manuscript’s guarantor (TP) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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