Vaccine 33 (2015) 2678–2683

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Effectiveness of human papillomavirus vaccine against incident and persistent infections among young girls: Results from a longitudinal Dutch cohort study Madelief Mollers a,b , Audrey J. King c , Mirjam J. Knol a , Mirte Scherpenisse b,c , Chris J.L.M. Meijer b , Fiona R.M. van der Klis c , Hester E. de Melker a,∗ a Department of Epidemiology and Surveillance, Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands b Department of Pathology, VU University Medical Centre (VUmc), Amsterdam, The Netherlands c Laboratory For Infectious Diseases and Screening, Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

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Article history: Received 24 November 2014 Received in revised form 2 April 2015 Accepted 3 April 2015 Available online 14 April 2015 Keywords: Monitoring Vaccination HPV Impact Cervical cancer

a b s t r a c t Introduction: Because of the long interval between infection with high-risk human papillomavirus (hrHPV) and development of cervical cancer surrogate markers for cancer incidence are necessary to monitor vaccine effectiveness (VE). The aim of this study was to calculate VE of HPV16/18 vaccination by annually assessing incident and persistent infections among (un)vaccinated girls from the general Dutch population up to 3 years after vaccination. Methods: In 2009, 1668 girls (54% vaccinated) aged 14–16 years were enrolled in a prospective cohort study. Annually, questionnaire data were obtained, and a vaginal swab was tested for type-specific HPV DNA with SPF10 -LiPA. VE was estimated by a Poisson model comparing type-specific infection rates in (un)vaccinated girls. Results: The adjusted VE (95% CI) was 73% (49–86%) against incident infections with HPV16/18 and 72% (52–84%) against HPV16/18/31/45. VE against persistent HPV16/18 was 100% and 76% (−17 to 95%) against HPV16/18/31/45. This number was lower (36%) when girls who were positive for HPV16 and 18 at baseline were included in the analysis. The overall VE for hrHPV types combined was small. Although 96% of girls were HPV-naïve at baseline, the cumulative 36-month incidence for any HPV was 20%, indicating high sexual activity. Discussion: Vaccination is effective against incident and persistent infections with HPV16/18 and HPV16/18/31/45. Low VE against persistent HPV16/18 infection in girls positive at baseline indicates importance of vaccination before sexual debut. © 2015 Elsevier Ltd. All rights reserved.

1. Introduction Human papillomavirus (HPV) infection causes approximately 10% of all cancers in women, most notably cervical cancer [1,2]. Annually more than half a million women are diagnosed with cervical cancer worldwide, and a quarter of a million die of this disease [2].

∗ Corresponding author at: National Institute for Public Health and the Environment, Department of Epidemiology and Surveillance, 3720 BA Bilthoven, The Netherlands. Tel.: +31 030 274 3958. E-mail address: [email protected] (H.E. de Melker). http://dx.doi.org/10.1016/j.vaccine.2015.04.016 0264-410X/© 2015 Elsevier Ltd. All rights reserved.

Since 2006–2007, two prophylactic vaccines have been registered against oncogenic HPV genotypes 16 and 18, which are responsible for about 70% of cases of cervical cancer [3]. In clinical trials both vaccines have shown efficacy against persistent HPV16 and 18 infection of 6–12 months’ duration and cervical intraepithelial neoplasia (CIN2+) lesions of more than 90% for at least 9 years after adminstration [4–6]. Both vaccines have also shown crossprotective potential. For the bivalent vaccine, the VE for HPV31 infection persisting for 6 months was 77%, and for HPV45 infection it was 79% after 4 years of follow-up [7], although the efficacy seemed to decrease with increased follow-up time [8]. Like other countries, The Netherlands includes HPV vaccination (bivalent HPV16/18 vaccine) for girls in the National Immunization Programme. The vaccine uptake amounted to 52% in the catch-up

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campaign in 2009 for cohorts born from 1993 to 1996 (13–16 years of age) and 59% in the standard programme targeting girls aged 12 years from 2010 onwards [9]. Alongside the introduction of HPV vaccination, the Health Council of the Dutch government advised monitoring its short- and long-term effectiveness in the general population [10]. One factor that complicates monitoring is the long duration (more than 20 years) between infection and development of cancer. With screening starting at the age of 30 years, vaccinated cohorts in the Netherlands are still too young to assess effectiveness against HPVrelated cancers. Early and intermediate surrogate markers allow monitoring the more proximal impact, such as a decreasing trend in genital warts in countries where the quadrivalent vaccine is used [11,12]. Currently, one of the most informative outcomes to measure the potential vaccination impact on HPV-related cancers is the effect of the vaccine on intermediate precursors, such as incident and persistent infections in young girls. This study presents 3-year follow-up results of the HPV Amongst Vaccinated and Non-vaccinated Adolescents (HAVANA) study [13] on effectiveness of early HPV vaccination against incident and persistent high-risk human papillomavirus (hrHPV) infections by comparing the findings in vaccinated and unvaccinated girls from the general Dutch population. In addition, we present data on the burden of DNA infections and sexual behaviour in this young age group pre- and post-sexual debut. 2. Materials and methods 2.1. Study population and data collection In brief, 29,162 girls aged 14–16 years who were eligible for the national catch-up vaccination in 2009 and 2010 were invited to participate in a longitudinal study (HAVANA) to assess HPV VE in the general Dutch population [13]. At baseline (1 month prior to vaccination), 1800 (6%) girls were enrolled, and 1668 of those were included in the analysis (girls who did not receive the complete 3-dose regimen and girls who were vaccinated after baseline were excluded from the analysis). During follow up, we received data from 1420 girls at visit 1 (1 year after baseline), 1281 at visit 2 (2 years after baseline) and 1232 at visit 3 (3 years after baseline). All girls signed an informed consent form. In addition, the study was approved by the Medical Ethics Committee of the VU University in Amsterdam (2009/22). Answers to a self-administered, web-based questionnaire and a vaginal swab were collected annually. At home, participants selfsampled the vagina by inserting a swab (Viba brush) 5 cm and rotating it for 5 s according to the manufacturer’s instructions. Samples were stored in 1 ml of phosphate buffered saline for DNA analysis. Individual vaccination status was extracted from the national vaccination registration system ‘Praeventis’ [14]. 2.2. HPV DNA detection and genotyping Vaginal samples were stored at −20 ◦ C. DNA extraction was conducted using a MagNA Pure LC Total Nucleic Acid Isolation Kit (Roche, Mannheim, Germany). DNA was eluted in 100-␮l elution buffer. Broad-spectrum HPV DNA amplification with the highly sensitive SPF10 -PCR [15] was conducted on 10 ␮l of DNA extract. Amplified HPV DNA was detected with a DNA enzyme-linked immunoassay (HPV-DEIA, Labo Biomedical Products, Rijswijk, The Netherlands). HPV-DEIA-positive amplicons were subsequently analyzed in a reverse line blot assay (HPV-LiPA25 , Labo Biomedical Products, Rijswijk, the Netherlands). The reverse line blot assay is able to detect the following hrHPV genotypes: 16, 18, 31, 33, 35,

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39, 45, 51, 52, 56, 58, and 59; it can also detect 12 other genotypes (low-risk HPV) with limited evidence for a causal link with cancer: 6, 11, 34, 40, 42, 43, 44, 53, 54, 66, 70 and 74 (classification based on the most recent report of the International Agency for Research on Cancer) [1]. In addition, HPV types 68, 73, and 97 could be detected on the membrane, although no distinction between them could be made, and they were classified as HPV68. Samples that were HPV-positive in the DEIA analysis but did not reveal any of the 25 HPV genotypes in the line probe assay were considered clinically nonrelevant and classified as negative. 2.3. Statistical analyses Differences in baseline characteristics between vaccinated and unvaccinated girls were determined with a chi-square test. Differences in possible risk factors for HPV among vaccinated and unvaccinated girls during follow-up were analyzed in a generalized estimating equation model (GEE) with a logit link. The dependent variable was the risk factor, and the independent variables were vaccination status, visit, and their interaction. A significant interaction term (p < 0.05) was interpreted as a different trend over time of that particular risk factor between vaccinated and unvaccinated girls. Type-specific incidence and persistence rates were calculated. An incident infection was present if a girl was negative at one visit and positive at the next visit. A persistent infection was present if a girl was positive on at least two consecutive visits. Incidence and persistence rates were calculated as the number of infections divided by the person-years at risk (Poisson approach) Personyears were estimated as the sum of the number of visits in which girls were at risk for developing an incident or persistent infection. Persistence rates were first calculated for all girls for the particular HPV type. Secondly, we estimated persistence rates for girls who were negative at baseline for the particular HPV type to be able to look at new (not present before vaccination) persistent infections. VE (95% CI) was estimated by a Poisson model, comparing type-specific infection rates in vaccinated and unvaccinated girls. The Poisson model for the adjusted VE included possible risk factors for HPV infection (age, ethnicity, urbanization, education, past and current smoking, oral contraceptive use, and sexual activity) measured at baseline. To assess the burden of infection in this young population, the prevalence (percentage of girls who tested positive) per visit was calculated among all girls with data available for that visit (1668 at baseline, 1420 at visit 1, 1281 at visit 2 and 1232 at visit 3). Next, cumulative incidence and persistence of HPV infections were calculated among girls HPV-negative at baseline (n = 1064) who participated in all four rounds and were defined as any incident or persistent infection during the total follow-up period. To identify risk factors for incident and persistent infections, a time-dependent GEE with a Poisson distribution and a log-link was used. If more than 5% of the values per variable was missing an extra category for missing values was introduced to avoid loss of observations. All statistical tests were two-sided. Significance was determined at the 5% level (p-value ≤ 0.05). All statistical analyses were performed using SAS software package version 9.3 (SAS Institute Inc., Cary, NC, USA). 3. Results 3.1. Population characteristics The baseline characteristics of the study population stratified by vaccination status are shown in Table 1. The characteristics that differed significantly at baseline between vaccinated and

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Table 1 Characteristics at baseline of the 1668 girls in the HPV Amongst Vaccinated and Non-vaccinated Adolescents (HAVANA) study from 2009 to 2012, overall and stratified by vaccination status. Significance based on chi-square test. Demography

Total N%

Vaccinated n%

Unvaccinated n%

Total

1668 (100)

905 (54)

763 (46)

15.1 (15.1–15.2)

15.1 (15.1–15.2)

15.2 (15.2–15.2)

0.1

1441 (88) 199 (12)

774 (87) 114 (13)

667 (89) 85 (11)

0.3

290 (17) 427 (26) 921 (56)

162 (18) 219 (25) 505 (57)

128 (17) 208 (28) 416 (55)

0.4

823 (50) 823 (50)

528 (59) 365 (41)

295 (39) 458 (61)

1500 inhabitants ≤1500 inhabitants Ever smoked (n = 1639) No Yes Current smoking (n = 1639) No Yes Anticonception (n = 1637) No Yes Ever had sex (n = 1640) No Yes Sexual debuta (n = 401) ≤14 >14 Current Partnera (n = 400) No Yes Relationshipa (n = 206) ≤6 months 7–12 months ≥13 months Condom usea (n = 268) Always Not always Ever had STIa (n = 401) No No but have been tested Yes Age partnera (n = 267) Mean (95% CI) Nr. Sexpartnersa (n = 398) Mean (95% CI) a

p-Value

Only when ever had sexual intercourse.

unvaccinated girls were as follows: vaccinated girls were more likely to live in a higher urbanized area, were less likely to have ever had sex and were less likely to have a current partner. For the total of girls during follow-up, the number of current smokers increased from 12% at baseline to 40% at 36 months, use of oral contraceptives from 36% to 80%, and number of those sexually active from 24% to 70%. Approximately 68% of the sexually active girls at baseline (n = 274) and 76% of those sexually active at 36 months (n = 624) reported having a casual or steady partner. The mean age of the partners at baseline was 17.2 years (95% CI 16.9–17.4), and the number of lifetime partners was 1.7 (95% CI 1.6–1.9); at 36 months the partners’ mean age was 20.5 years (95% CI 20.3–20.8), with 2.8 lifetime partners (95% CI 2.6–3.0). Consistent condom use decreased from 33% (n = 89) of the sexually active girls at baseline to 11% (n = 62) during the last follow-up. Of the sexually active girls, 1% (n = 4) at baseline and 3.2% (n = 26) at visit 3 reported ever having had a sexually transmitted infection (STI). The increase over time in the number of girls that ever had sex was higher in vaccinated than unvaccinated girls (p for interaction 2 vs. 0 partners [OR = 4.4, 95% CI 1.1–17.6]). For a persistent infection, the risk factors were current smoker

(OR = 4.2, 95% CI 0.6–28.2) and a partner older than 17 years vs. no partner (OR = 11.0, 95% CI 2.0–66.7). The multivariable model for hrHPV persistent infections did not converge. Age, education, ever smoker, oral contraceptive use, and number of years of sexual activity were not significant risk factors for an incident or persistent HPV infection. 4. Discussion Through enrolling a cohort of newly sexually active young girls with minimal previous exposure to HPV, we could monitor the early impact of vaccination for HPV types 16 and 18 by estimating effectiveness against newly acquired incident and persistent infections. We found a high adjusted VE against incident HPV16 and 18 infections (73%) and HPV16, 18, 31, and 45 infections (72%). Although numbers were small, the VE against persistent infections with types 16 and 18 was 100% and 76% for HPV16, 18, 31, and 45. The low effectiveness (36%) against persistent HPV16 and 18 infections in girls who were already positive at baseline indicates the importance of vaccination before sexual debut. Compared with the efficacy found in a clinical trial of the bivalent vaccine among girls aged 15–25 years (92%), the VE in this study against incident HPV16 and 18 infections was slightly lower [16]. This might be due to characteristics of the vaccine target population, such as sexual mixing patterns among different subpopulations, past HPV infections, or a lower immune response to vaccination. Most clinical trials have not used incident infections as an outcome to estimate vaccine efficacy, since many incident infections are transient. However, VE against incident infections provides information on the first step in the HPV-to-cancer process and on HPV circulation after vaccination. This might also be of value for mathematical modelling of HPV transmission. In addition, the VE against type-specific incident (and also persistent) infections is not confounded by co-infections with non-vaccine types, which could be the case for VE against CIN lesions. It is, however, still important to look at co-infections, because it is known that an estimated 20% to 50% of women harbour multiple infections [17]. This could imply that when women are protected against vaccine types, other hrHPV types might still generate precancerous lesions. This phenomenon is referred to as unmasking. In our study, we found that a significant lower number of multiple HPV infections was detected among vaccinated girls 3 years after the introduction of vaccination. Furthermore, when looking at the impact of the vaccine on the combined estimates of any or hrHPV incident or persistent infection, we found that the VE estimates were low. Although this is expected due to the relatively low percentage of HPV16 and 18, these data are relevant to study for example the effect of increased sexual risk behaviour among vaccinated individuals. If sexual risk behaviour increased more among

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vaccinated girls, VE for hrHPV or any HPV would be lower. Indeed, in our study, additional adjustment for covariates that differed significantly over time between vaccinated and unvaccinated girls (ever having had sex and degree of urbanization) gave slightly higher VE estimates (data not shown). Depending on the aim of the study, adjustment for characteristics of the study population at baseline and follow-up is necessary. Differences between vaccinated and unvaccinated girls at followup can be due directly to vaccination, such as less perceived risk and therefore increased risk behaviour, or they may be related indirectly, because girls who choose to be vaccinated are a different population than girls who choose not to be vaccinated. These population differences may only become apparent if the girls start having sex (at follow-up). If the aim is to study the impact of the vaccination programme, adjustment may not be necessary (although it could be considered, given that selective participation in the study cannot be ruled out) as the differences between vaccinated and unvaccinated girls, such as in sexual risk behaviour, also exist in the general population. If the aim is to study the effect of the vaccine itself, adjustment is needed. Irrespective of vaccination status, this cohort is unique in a description of the natural history of HPV in this young age group (median age, 15 years at baseline, some sexually naïve). The cumulative 36-month incidence was lower than in other studies [18,19], although this is not surprising, because these studies included women aged 18 years or older. An age-dependent increase was also observed in our cohort. The HPV prevalence increased during follow-up (almost five times more for any HPV and six times more for hrHPV), in line with the triple increase in the percentage of sexually active girls. Most of the risk factors for incident HPV infections observed in this study have been reported elsewhere and confirm that the risk of an HPV infection is strongly influenced by sexual behaviour [20–22]. Interestingly, we found that being a current smoker was associated with a persistent, but not with an incident, infection. Some studies have shown a positive relationship between risk of HPV infection and smoking [23], suggesting it may be a proxy for high-risk sexual behaviour, although in our study it was not a risk factor for an incident infection. Others suggest smoking may influence the immune system [24]. In conclusion, we observed a high effectiveness of HPV vaccination measured through intermediate outcomes, i.e., incident and persistent HPV16 and 18 infections as well as infections with cross-protective HPV types 31 and 45 infections, shortly after the introduction of a national HPV vaccination programme. A small VE impact was seen when all HPV types or hrHPV types were combined. In addition, a reduction in multiple infections was observed among vaccinated vs. unvaccinated girls. Although in the current study there was not enough power to calculate the adjusted VE for persistent HPV16 and 18 infections, the unadjusted VE of 100% is encouraging. In addition, the low VE (36%) against persistent HPV16 and 18 infection in girls who were already positive at baseline indicates the importance of vaccination before sexual debut. Further follow-up of these girls will enable us to estimate VE more robustly.

Acknowledgements Alies van Lier for her help with the logistics of the study. Hendriek Boshuizen for statistical support. Elske van Logchem for laboratory analyses. Sally Ebeling for English editing. Robine Donken for support with data analysis.

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Effectiveness of human papillomavirus vaccine against incident and persistent infections among young girls: Results from a longitudinal Dutch cohort study.

Because of the long interval between infection with high-risk human papillomavirus (hrHPV) and development of cervical cancer surrogate markers for ca...
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