Early Impact of Human Papillomavirus Vaccination on Cervical Neoplasia—Nationwide Follow-up of Young Danish Women

JNCI Journal of the National Cancer Institute, Mar 2014

Background In clinical trials, vaccines against human papillomavirus (HPV) have been highly effective against HPV16- or HPV18-associated cervical lesions. The quadrivalent HPV vaccine was licensed in 2006 and subsequently implemented in the Danish vaccination program. The study aim was to use individual information on HPV vaccination status to assess subsequent risk of cervical lesions.

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Early Impact of Human Papillomavirus Vaccination on Cervical Neoplasia—Nationwide Follow-up of Young Danish Women

JNCI J Natl Cancer Inst ( e arly impact of Human Papillomavirus Vaccination on c ervical Neoplasia-Nationwide Follow-up of Young Danish Women BirgitteBaldur-Felskov 0 Christian Dehlendorff 0 ChristianMunk 0 Susanne K.Kjaer ) 0 0 Affiliations of authors: Virus , Lifestyle and Genes (BB-F, CM, SKK) and Statistics, Bioinformatics and Registry (CD) , Danish Cancer Society Research Center , Copenhagen , Denmark; Gynaecological Clinic, Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital , Copenhagen, Denmark (SKK) Methods In clinical trials, vaccines against human papillomavirus (HPV) have been highly effective against HPV16- or HPV18-associated cervical lesions. The quadrivalent HPV vaccine was licensed in 2006 and subsequently implemented in the Danish vaccination program. The study aim was to use individual information on HPV vaccination status to assess subsequent risk of cervical lesions. Using a cohort study design, we identified all girls and women born in Denmark in the period from 1989 to 1999 and obtained information on individual HPV vaccination status in the period from 2006 to 2012 from nationwide registries. Incident cases of cervical lesions were identified by linkage to the nationwide Pathology Data Bank. We compared vaccinated and unvaccinated girls and women stratified by birth cohort in Cox proportional hazards models. Risk of atypia or worse (atypia+) and of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) were statistically significantly reduced among vaccinated women in birth cohorts 1991 to 1994 (1991-1992atypia+: hazard ratio [HR]=0.46, two-sided 95% confidence interval [CI]=0.39 to 0.56; 1991-1992CIN2/3: HR=0.56, 95% CI=0.37 to 0.84; 1993-1994atypia+: HR=0.40, 95% CI=0.29 to 0.56; 1993-1994 CIN2/3: HR=0.27, 95% CI=0.10 to 0.67). The birth cohort 1989 to 1990 had a statistically significantly reduced risk of atypia+ (HR=0.75; 95% CI=0.65 to 0.86); the risk of CIN2/3 was also decreased but not statistically significant. No events occurred among girls in the birth cohort 1997 to 1999, whereas for the birth cohort 1995 to 1996 a hazard ratio could be calculated only for atypia+. Results Conclusions Six years after licensure of the quadrivalent HPV vaccine in Denmark, a reduced risk of cervical lesions is observed at the population level. Two vaccines are currently available against human papillomavirus (HPV) (1,2), the main etiological factor for cervical cancer (3). The bivalent vaccine contains viruslike particles of HPV types 16 and 18 (1), whereas the quadrivalent vaccine contains viruslike particles of HPV types 6, 11, 16, and 18 (2). Both vaccines have been shown to be highly effective against HPV16/18associated cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3) and adenocarcinoma in situ, endpoints accepted in trials for vaccine efficacy against cervical cancer (48). The quadrivalent HPV vaccine was licensed in Denmark in 2006. Subsequently, the vaccine was chosen by tender and included in the free-of-charge general childhood vaccination program for girls aged 12 years on January 1, 2009 (birth cohort 19961997). A free-of-charge catch-up vaccination program for girls aged 13 to 15-years was added in fall 2008 (birth cohorts 19931995) (9). Older girls and women and boys and men are not covered by the HPV vaccination program but can pay to receive the vaccine. HPV types are categorized into high risk and low risk based on their biological properties and oncogenic potential (10). HPV16 and HPV18 are the most common high-risk types, accounting for about 70% of all cervical cancer cases and about 50% of all CIN3 cases (10,11), whereas HPV6 and HPV11 are low-risk types associated with nearly 90% of all genital warts cases (12). Thus, it is estimated that HPV vaccination could prevent up to 70% of cervical cancer cases (13,14). Because progression from infection with a high-risk HPV to invasive cervical cancer can take decades (10), it may be many years before the effect of HPV vaccination on the incidence of cervical cancer can be assessed. Nevertheless, recent ecological studies have shown a decrease in the incidence of genital warts among young women since introduction of the vaccine (1518). In another ecological study, Brotherton etal. (19) found a statistically significant decrease in the incidence of high-grade cervical lesions among girls aged less than 18years in Australia, which began shortly after introduction of a nationally funded program for vaccination with the quadrivalent vaccine. An important limitation of these studies is that the data were not analyzed by individual vaccination status. To our knowledge, data on individual vaccination status was used in only four studies (2023) besides the studies based on the vaccination trials. All showed a protective effect of vaccination. However, so far no nationwide population-based study has been published on the occurrence of cervical abnormalities in vaccinated and nonvaccinated women based on information about vaccination status on the individuallevel. The aim of the study reported herein was to determine the association between individual HPV vaccination status and subsequent risk of cervical lesions in a nationwidestudy. Cohort Data Collection The study design is shown in Figure 1. In Denmark, all citizens are assigned a unique personal identification number, which is used throughout society, including in all health registries, and is registered in the computerized Civil Registration System, which was established in 1968 (24). From this system, we identified all women born in the period from 1961 to 1999 and living in Denmark and obtained information on their date of emigration, death, or disappearance. To obtain information on HPV vaccination status, we linked this cohort with the National Health Service Registry and the Danish National Prescription Registry. The National Health Service Registry holds data since 1990 on the activities of primary health professionals and includes information about citizens, providers, and health services (25). From this registry, we identified girls who had received HPV vaccination within the general childhood vaccination or catch-up program since it started in 2008 up to July 1, 2011. Data on all girls and women who purchased an HPV vaccine on prescription between October 1, 2006, and March 1, 2012 were obtained from the Danish National Prescription Registry, which holds information on all prescription drugs sold in Danish community pharmacies since 1994 (26) and information on more than 90% of HPV vaccinations given outside the program. Hence, we were able to identify almost all women in each birth cohort who had been vaccinated and those who had not and the date of vaccination for each vaccinated woman. We included only birth cohorts with a vaccination coverage rate greater than 10%, corresponding to birth cohorts 1989 to 1999. Because we examined only the effect of the quadrivalent HPV vaccine used in the Danish program, we excluded women who had received the bivalent vaccine (n=148). Cytology and Assessment of Outcomes In Denmark, cervical cytology testing is recommended every third year for women aged 23 to 49years and every fifth year for women aged 50 to 64 years (9), but opportunistic screening is also common. To identify cases of cervical lesions, the cohort was linked to the nationwide Danish Pathology Data Bank, established in 1999, which holds information on all cervical cytology (organized and opportunistic) and all cervical biopsies and cones from all Danish pathology departments (27). Abnormal cervical diagnoses are usually reported as atypia, mild dysplasia, moderate dysplasia, severe dysplasia, carcinoma in situ, or cancer. The Bethesda nomenclature (28) is increasingly being used for cytological diagnoses, whereas the CIN nomenclature is used for histological diagnoses, with moderate dysplasia categorized as CIN2 and severe dysplasia and carcinoma in situ as CIN3 (29). We assessed three outcomes. The first, atypia or worse, comprised cytological diagnoses of atypia or atypical squamous cells of undetermined significance or worse. The second outcome, CIN2/3, comprised histological diagnoses of CIN2, CIN3, carcinoma in situ (CIS), and adenocarcinoma in situ (AIS). The third outcome, CIN3, consisted of diagnoses of CIN3, CIS, and AIS. No cervical cancers were detected during follow-up. To identify all cervical lesions in the study period and before, we collected information on all cervical examinations (cytology, biopsy, cone) undergone by the women in our cohort registered in the Pathology Data Bank and excluded women who had any cervical abnormalities before study start (n=72). Collection of SocioeconomicData Lastly, we investigated socioeconomic factors for vaccinees and nonvaccinees. To obtain this information, our cohort was linked with data from the population-based Statistics Denmark. Socioeconomic position variables comprised mothers highest attained education at the beginning of follow-up (basic school/ high school, vocational education, higher education, unknown) and disposable income (categorized in tertiles). Statistical Analysis A Cox proportional hazard regression model stratified by five birth cohorts (19891990, 19911992, 19931994, 19951996, and 1997 1999) was used to estimate hazard ratios (HRs) and corresponding Figure1. Study design. HPV, human papillomavirus. two-sided 95% confidence intervals (CIs) for the three outcomes among vaccinees and nonvaccinees in each stratum. In model 1, we included the entire cohort, on the assumption that women who did not undergo cervical cytology during the follow-up period did not have cervical lesions. In a more restricted model (model 2), we included only women who had cervical cytology during followup. Both models were fitted to the data with calendar time as the underlying time scale. The assumption of proportional hazards was checked by the scaled Schoenfeld residuals (ie, testing deviations from zero slope with respect to time). Moreover, in a subset analysis, we adjusted our risk estimates for socioeconomic position variables. The follow-up period was from October 1, 2006, to March 1, 2012 in the Pathology Data Bank, the end date (ie, emigration or death) in the Civil Registration System, the first abnormal examination or the last normal examination (model 2 only), whichever occurred first. A woman was considered as a nonvaccinee to 28 days after the first HPV vaccination and subsequently as a vaccinee, the lag time being included to allow the vaccine to take effect. We nevertheless investigated the sensitivity of our results for this interval by performing analyses with the lag time ranging from 7days after the first vaccination until the second dose was usually given (60days). P values of less than .05 were considered statistically significant, and all statistical tests were two-sided. The statistical software program R version 2.15.1 was used (30). The study was approved by the Danish Data Protection Agency, and written informed consent from individuals in the cohort was not required. r esults From the Civil Registration System, we identified 399 244 Danish women in the birth cohorts 1989 to 1999. Characteristics of this population are shown in Table1. Atotal of 247 313 (62%) women were vaccinated during the period. The vaccination coverage was high (>85%) in the youngest birth cohorts of 1993 to 1999, which were included in the childhood and catch-up vaccination program, and much lower in the birth cohorts not covered by the program (19891990: 14%; 19911992: 27%). The total number of events was 3629 for atypia or worse, 708 for CIN2/3, and 365 for CIN3. The women constituting the study population contributed more than 2 million person-years of follow-up in the analysis for each outcome. Overall, the event rate for atypia or worse was 2.4 times higher among unvaccinated women (0.22%) than among vaccinated women (0.09%) and that for CIN2/3 and CIN3 were both increased twice (nonvaccinees: 0.04%; vaccinees: 0.02%; nonvaccinees: 0.02%; vaccinees: 0.01%, respectively). Screenings rates for nonvaccinees and vaccinees were estimated separately using the respective number of screenings records and person-years. Subsequently we calculated screenings rate ratios (RRs) by dividing the screenings rates of vaccinees by that of the nonvaccinees and found that in all birth cohorts, vaccinees had higher screenings rates than nonvaccinees (19891990: RR=1.55, 95% CI=1.48 to 1.63, P < .001; 19911992: RR=1.22, 95% CI=1.14 to 1.30, P < .001; 19931994: RR=3.75, 95% CI=3.25 to 4.33, P < .001; 1995 1996: RR = 8.87, 95% CI = 5.19 to 15.13, P < .001; 19971999: RR=17.03, 95% CI=1.99 to 143.76, P=.005). Table2 shows the hazard ratios for cervical lesions among vaccinated women compared with unvaccinated women in the birth cohorts in the two models. There were too few events in birth cohort 1995 to 1996 to estimate hazard ratios for CIN2/3 or for CIN3, and hazard ratios could not be calculated for any outcome for the birth cohorts 1997 to 1999 because there were no events. In model 1 (Table2), the risk of atypia or worse was statistically significantly lower among vaccinated women in the birth cohorts 1989 to 1994 (19891990: HR=0.75, 95% CI=0.65 to 0.86, P < .001; 19911992: Atypia or worse * Vaccination status attained at end of follow-up. CIN2/3 = cervical intraepithelial neoplasia grade 2 or 3. Total population Number of vaccinees, (%)* 11 243 (14.3) 19 867 (26.7) 63 922 (88.1) 63 912 (89.8) 88 369(86.0) Screened population 7718 3412 Atypia or worse HR (95% CI) 0.75 (0.65 to 0.86) 0.46 (0.39 to 0.56) 0.40 (0.29 to 0.56) 0.43 (0.16 to 1.12) HR (95% CI) Birth cohort 19891990 19911992 19931994 19951996 19971999 Birth cohort 19891990 19911992 19931994 19951996 19971999 HR (95% CI) HR=0.46, 95% CI=0.39 to 0.56, P < .001; 19931994: HR=0.40, 95% CI=0.29 to 0.56, P < .001). The risk was also reduced for the birth cohort 1995 to 1996, but the result was not statistically significant. The risk for CIN2/3 was statistically significantly reduced among vaccinees in the birth cohorts 1991 to 1994 (19911992: HR=0.56, 95% CI=0.37 to 0.84, P=.005; 19931994: HR=0.27, 95% CI=0.10 to 0.67, P=.005). For birth cohort 1989 to 1990, we found a reduced risk of 0.88, which was not statistically significant. The results for CIN3 were similar to those for CIN2/3. However, only the result for birth cohort 1993 to 1994 reached statistical significance (HR=0.20, 95% CI=0.06 to 0.71, P=.01). When we restricted the analysis to women who had cervical cytology during follow-up, we still found statistically significantly reduced risks for atypia or worse among all vaccinees, except for those in the birth cohort 1995 to 1996, for whom the reduction was not statistically significant (Table3). The risks for CIN2/3 and for CIN3 were reduced for all birth cohorts 1989 to 1994, but only the hazard ratio for the birth cohorts 1993 to 1994 reached statistical significance (HRCIN2/3=0.33, 95% CI=0.13 to 0.83, P=.02; HRCIN3=0.25, 95% CI=0.07 to 0.90, P=.03). Mothers highest attained education and disposable income are shown for vaccinees and nonvaccinees in Table 4. In all birth cohorts, mothers of vaccinees had higher education and higher disposable income compared with mothers of nonvaccinees, although the difference was reduced in the youngest birth cohorts. However, when we adjusted for the socioeconomic position variables, this did not substantially alter the results (ie, the magnitude of the risk estimates was virtually unchanged) (data not shown). In the main analyses, we started the counting of outcomes among vaccinated women 28days after the first dose. Because this is an arbitrary cutpoint, we also estimated the hazard ratios using other cutpoints (in the range 760days). The effect of vaccination was virtually unchanged by time between first dose and time of counting cases of cervical lesions when we started counting outcomes in vaccinated women 7 to 60days after vaccination, and the results were similar in the two models. Therefore, the risk of cervical lesions of vaccinated girls was decreased in all birth cohorts (most reaching statistical significance), regardless of the length of the interval (data not shown). Discussion We found a protective effect of the quadrivalent HPV vaccine against cervical precursor lesions among women in the Danish birth cohorts 1989 to 1999. Among women who received at least one dose of vaccine, the risk for atypia or worse was statistically significantly reduced by up to 60%, and the risks for CIN2/3 and CIN3 were statistically significantly reduced by up to 80%, when compared with nonvaccinees. Thus, our results indicate that the quadrivalent vaccine already offers good protection against cervical precursor lesions in this population. For all outcomes in both models, we found the greatest risk reduction in the younger birth cohorts. These results are comparable with those for cervical lesions in the quadrivalent HPV vaccination clinical trials FUTURE Iand II (4,6,7,31). In those trials, women were divided into three cohorts. The most restrictive was an according to protocol population, which comprised of women without HPV6/11/16/18 during the vaccination regimen, who received all three doses of vaccine or placebo and did not violate the protocol; the unrestricted susceptible population was comprised of women with no cervical cytological abnormalities at baseline and no HPV6/11/16/18 on day one; and the intention-to-treat population was comprised of all women in the trials, including those with prevalent HPV. Although we did not have information on sexual debut or HPV status in our study, it is probable that the youngest birth cohorts had limited exposure to HPV and were thus comparable with the according to protocol or the unrestricted susceptible population, whereas our older birth cohorts were comparable with the intention-to-treat group. The clinical trials showed a vaccine efficacy of 97% to 100% against all HPV16/18related cervical lesions among women in the according to protocol and unrestricted susceptible population groups (4,6,7,31), whereas the efficacy against HPV16/18related CIN2 or worse was lower in the intention-to-treat population (44%) (4,6). The results for vaccine efficacy against all CIN2/3 and adenocarcinoma in situ, regardless of causal HPV type, are comparable with our results, especially for CIN2/3 and CIN3. The clinical trials showed a vaccine efficacy of approximately 43% against CIN2 and CIN3 in the unrestricted susceptible population, whereas the overall reduction in risk for CIN2 or worse due to any HPV type was approximately 18% in the intention-to-treat population (4,6). The lower efficacy of the vaccine in the intention-to-treat population was attributed to the fact that some women had prevalent HPV16/18 infection. In comparison, we found a risk reduction against CIN2/3 of 73% and 44% for birth cohorts 1993 to 1994 and 1991 to 1992, respectively, and 80% and 36% against CIN3, whereas the risk reduction for birth cohort 1989 to 1990 was 12% against CIN2/3 and 22% against CIN3. Birth cohort 19891990 19911992 19931994 19951996 19971999 Atypia or worse HR (95% CI) 0.75 (0.66 to 0.86) 0.64 (0.53 to 0.77) 0.47 (0.34 to 0.65) 0.63 (0.25 to 1.61) HR (95% CI) HR (95% CI) )17 ).9 ) .)52 .) )06 ).6 litcadeuno itacuon lisacbenom littrtee litrtee litrtee an de n op ,s1 nd2e ,rts3de now rtshe iscaB lcoho itcaooV ireghH konnUw irtssdhe tseLow li,ddM ighH knnU o s o M M However, it should be noted that some of our estimates had quite wide confidence intervals and not all reached statistical significance. As in the trials, we believe that the smaller risk reduction in our older birth cohorts was probably because of a higher prevalence of HPV16/18 infection before vaccination. The lower risk for cervical lesions among HPV-vaccinated women in our study is almost certainly due to a reduced risk for HPV16/18 lesions, although we had no information on the HPV types responsible for the cervical lesions detected. Our results agree with those of two other studies with individual data on vaccination status (20,21). On the basis of preliminary data, Powell etal. (21) reported that women with a diagnosis of CIN2 or worse who had initiated HPV vaccination more than 2years before the abnormal Pap test that triggered the diagnosis had a statistically significantly lower risk for HPV16/18related CIN2 or worse. In a study with a repeat cross-sectional design, Tabrizi etal. (20) found a statistically significant decrease in the prevalence of HPV6/11/16/18 after introduction of a national HPV vaccination program in Australia. Although those authors investigated HPV prevalence and not cervical neoplasia, their studies are comparable with ours because a reduced prevalence of HPV16/18 is a good proxy for a reduced risk for future cervical lesions (11). Both previous studies had some limitations, however, such as use of preliminary data only, few study subjects, and mainly self-reported information on vaccination status. The results of our population-based study are also in agreement with those of Rana etal. (32), who followed up 1749 Finnish participants in the FUTURE II trial (874 vaccinated, 875 placebo-vaccinated) in the Finnish Cancer Registry and compared them with an unvaccinated cohort of 15 719 women. They found no cases of CIN3 or cervical cancer among the vaccinees, three cases of CIN3 among the placebo vaccinees (incidence rate=87.1 per 100 000), and 59 cases of CIN3 and 3 cancer cases among the nonvaccinees (incidence rate = 93.8 per 100 000). The authors concluded that long-term surveillance by passive follow-up in a cancer registry is feasible and will establish the efficacy of HPV vaccination against cervical cancer within the next 5 to 10years. Our study supports this conclusion because our results already show a reduced risk for precursor lesions among vaccinees. The main strength of our study is that it covers the entire female Danish population in the birth cohorts 1989 to 1999, resulting in reasonable statistical power. Another strength was our ability to make precise linkages of our cohort with several unique population-based registries. Thus, all cervical lesions were identified and included, almost all vaccinees were identified, no women were lost to follow-up, and we could exclude women who had cervical lesions before HPV vaccination. One limitation of our study is that we had no information on the womens HPV status or sexual history at enrollment or on the HPV types responsible for the cervical lesions. The aim of this study was not, however, to investigate HPV16/18specific lesions in HPVnaive women but rather to assess any reduction in disease burden at general population level. Another weakness was the moderate number of outcome cases and the small proportion of screened women, with only 12 188 women examined among approximately 400 000 women in the investigated birth cohorts. Nevertheless, risk estimates for the restricted model 2 confirmed the conclusion from model 1 because the estimates were quite similar. The most important limitation of our study is the possibility of self-selection bias due to inclusion of women not covered by the vaccination program. Socioeconomic position of the mothers could be a marker of this self-selection bias because mothers of vaccinees, especially in the older birth cohorts, generally had a higher socioeconomic position. However, the adjustment for socioeconomic position virtually did not change our results. Furthermore, because women in Denmark are advised to undergo cervical cytology only from the age of 23, only women in the birth cohort 1989 could have been examined within the national screening program, but it is well known that opportunistic screening is common in Denmark. Women may have gynecological examinations and cytological tests before the age of 23 (eg, because of an early sexual debut, having several sexual partners, or having symptoms of cervical infections or neoplasia). Therefore, the women who were screened may have differed from those who were not screened by having another risk for cervical neoplasia. Thus, it is possible that the effect of the quadrivalent vaccine would be different in women with higher- or lower-risk behavior. Lastly, a bias would have been introduced if the vaccinees were screened less frequently than nonvaccinees; however, in all birth cohorts, we found higher screening rates among vaccinees compared with nonvaccinees. In conclusion, our results show that vaccination with the quadrivalent HPV vaccine is already effective in reducing the risk for cervical precursor lesions at population level among young women in Denmark. r eferences Funding This work was supported by the Mermaid project (MERMAID 2). Notes The sponsor of the study had no role in the study design, data collection, data analysis, data interpretation or writing the report. The corresponding author had full access to all the data and had final responsibility for the decision to submit for publication. S.K. Kjaer received scientific advisory board and speakers fees and research grants through her institution from Sanofi Pasteur MSD and Merck and scientific advisory board fee from Roche. C.Munk received travel and speakers fees from Sanofi Pasteur MSD. The other authors report no potential conflict of interest. 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Birgitte Baldur-Felskov, Christian Dehlendorff, Christian Munk, Susanne K. Kjaer. Early Impact of Human Papillomavirus Vaccination on Cervical Neoplasia—Nationwide Follow-up of Young Danish Women, JNCI Journal of the National Cancer Institute, 2014, DOI: 10.1093/jnci/djt460