The Longitudinal Incidence of Human Papillomavirus Vaccination in Spanish Primary Care in the First 10 Years After Approval

Abstract

Background

In Spain, girls are vaccinated against human papillomavirus (HPV) in the primary care setting, according to a national vaccination programme. Vaccination is voluntary and is covered by the public health system.

Objectives

The aim of the study was to estimate the incidence and patterns of HPV vaccination amongst girls in primary care in Spain.

Methods

A cohort study was performed using the information recorded in the Spanish Primary Care Database for Pharmacoepidemiological Research (BIFAP) from 7.9 million patients from seven Spanish regions, between 2001 and 2016 (56.6% of the regional population). Data available in BIFAP include patient age, sex, life-style factors, clinical events, specialist referrals, prescriptions, and vaccinations as recorded by the primary care physician (PCP) or administering nurse. The study cohort comprised all girls aged 9–18 years registered in BIFAP between 1st January of 2007 and 31st December of 2016 who had at least 1 year of clinical record information with their PCP (inclusion criteria). The date the inclusion criteria were met was designated as the start date to the study cohort contribution. In order to estimate the incidence of HPV vaccination (initiation of vaccination schedule), girls with an HPV vaccination recorded before the start date or without vaccination date were excluded. Girls forming the study cohort were followed from start date until there was a recorded HPV vaccination, they reached 19 years of age or died, end of available information, or 31st December 2016. The person-time of all patients forming the study cohort was reckoned in the incidence estimations. The follow-up was replicated yearly from 2007 to 2016. The cumulative incidence (CuIn) of vaccination by birth cohort, year and region, was estimated using life tables (proportion of vaccination by intervals in which the denominator is the initial population corrected for losses).

Results

Of 388,690 girls forming the study population, 154,211 initiated the vaccination during 2007–2016. Ages ranged from 12 to 14 years at first dose in 84.5% of vaccinated girls, 42.79% received a quadrivalent vaccine, 21.86% a bivalent vaccine, and 35.35% an unknown type. Of the vaccinated population, 48.0% were completely vaccinated with a three-dose schedule and 28.9% with a two-dose schedule, 20.2% received one dose and 3.0% two doses in a three-dose schedule, at a maximum of 10 years of follow-up. The CuIn was highest among girls aged either 13 or 14 years over all regions (reaching 92.8% and 89.7%, respectively), and aged 12 in some regions/years (up to 89.8%). Girls aged 15 years were also vaccinated (although showing lower yearly incidence, i.e. < 69.1%) in two regions. The coverage was broadened to younger girls (11 years) during the last years of the study period in some regions.

Conclusions

According to BIFAP primary care data, a high incidence of vaccination among girls aged 13–14 years was observed. Vaccination among younger and older girls were less common, although they reached high incidence in some regions and/or years. Most vaccination patterns adjusted to a complete vaccination regimen, as recommended posology.

FormalPara Key Points
In Spanish primary care, most girls aged 13–14 years were vaccinated from the second year of human papillomavirus (HPV) vaccine availability (2008) to 2016.
In some regions and years, very high vaccination incidence was observed among girls aged 12 years and moderate among those aged 15 years during 2007–2016, broadening to aged 11 years in the last 2 years.
Most girls with HPV vaccinations recorded in Spanish primary care received a complete vaccination regimen that agreed with dosing recommendations and intervals from vaccination programmes.

Introduction

Human papillomavirus (HPV) vaccines are indicated to prevent pre-cancerous and cancerous lesions, and genital warts (condyloma acuminate; type 6 and 11) linked to HPV infection. Since 2007 in Spain, HPV vaccination has been included and freely available in the public national health system schedule for girls aged 11–14 years, in order to immunise before sexual activity begins [1]; in 2011, approval was extended to patients aged ≥ 9 years [2, 3]. Women aged up to 45 years with a cone biopsy with CIN-2 or higher and other women susceptible to HPV infection may also be indicated and covered for vaccination against HPV by the regional health systems [4,5,6].

A quadrivalent vaccine (types 6, 11, 16, 18) was authorised in 2006 and a bivalent vaccine (types 16, 18) became available in 2007; both include virus-like particles, protecting against type 16 and 18 HPV infections, serotypes that are related to 70% of all cervix cancer cases [1, 7]. In 2015, a 9-valent HPV vaccine was approved to also protect against additional HPV types 31, 33, 45, 52 and 58 [8].

In Spain, the prevalence of HPV infection of the cervix in women aged 18–25 years is 29% (7% in women aged 56–65 years) [9]. Overall, HPV type 16 is the most frequent (2.9–3.5% of women with HPV test done) [9, 10] and the infection of the types 6, 11, 16 and 18 combined is 3.8% [9]. Of all cases of invasive cervical cancer in Spain, 89% are HPV positive, with type 16 and 18 the most frequently involved (72% of all HPV positive cancer and 94% of all adenocarcinomas) [11].

In 2007, the Public Health Council and The Inter-territorial Board of the Spanish National Health System (CISNS), recommended universal mass vaccination of girls aged 14 years [1], in a three-dose series (0, 1–2, 6 months). In Spain, the regions have autonomy in their public healthcare services and expenditure, so some differences in vaccination schedule may be observed. Most of the regions followed the age recommendation but a few scheduled it also for younger girls (aged 11–13 years) [12, 13]. Furthermore, the schedule might be slightly different for bivalent (0, 1–2.5 m, 5–12 m) and quadrivalent vaccines (0, 1 m, 3 m; the 3 into 1 year). Mass vaccinations in Spain started between November 2007 and the last school term of 2008 and were administered in primary care practices, schools or other healthcare settings depending on the region [14]. Boys were not included in the universal mass vaccinations. During 2007–2016, several modifications occurred in the posology and recommended ages, overall and by regions. Mainly, a common schedule was agreed by the CISNS and the regions to vaccinate at 14 years-old with a target coverage over 80% for 2014 ahead [15], when also the European Commission was recommended to include an alternative two-dose vaccination schedule in children aged 9–14 years [16, 17] also adopted in Spain.

The coverage of all three doses of HPV vaccine up to 2016 ranged between 64.3 and 79.0% by year [18], being lower than the recommended > 80% by The Inter-territorial Board of the National Health Service [1]. These ecological estimations of coverage result from dividing the number of vaccines bought by the public healthcare administration by the population censuses.

Since patient level vaccination registries are seldom available, primary care electronic health information recorded during the first years of the HPV vaccine use in Spain, offer an opportunity to study the use of this vaccine at the patient level (instead of population/ecological level).

The aim of the study was to estimate the incidence and patterns of HPV vaccination amongst girls in primary care in Spain. The current study was part of a broader project that aimed to assess the potential association between the HPV vaccination and inflammatory bowel disease (among other potential risks) in a young female population in Spain. The estimation of the incidence of use of those vaccines in BIFAP represents a preliminary step in the project.

Methods

Source of Data

In the current study, the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP) was used as the data source. BIFAP includes anonymised longitudinal primary care electronic medical records from the Spanish public national health system [19,20,21].

Spain has a public national health system where primary care physicians (PCPs) act as gatekeepers to and coordinators of primary and secondary care, similar to the role of the UK National Health Service general practitioners. The combination of almost universal coverage and the gatekeeper role of PCPs means that practically the entire population (i.e. 98.88% in 2014 [22]) is covered by the public national health system and so registered with a PCP.

Data available in BIFAP include patient age, sex, life-style factors [body mass index (BMI), weight, height, smoking and alcohol consumption], clinical events [recorded through the International Classification of Primary Care (ICPC) and the International Classification of Diseases 9th Revision (ICD-9) medical terms], primary care paediatrician or physicians free text notes, specialist referrals, primary care vaccinations as recorded by the administering nurse or PCP, prescriptions (and their dispensations in pharmacies), and laboratory test results from around 7.9 million patients from seven participating Spanish regions (Navarra, Aragón, Cantabria, Castilla y León, Madrid, Murcia and Asturias) between 2001 and 2016. At the time of the study, BIFAP population covered 56% of the population of these regions (almost 17% of the Spanish population) as reported by the National Statistics Institute [23]. BIFAP data structure includes a Vaccination File including the following fields: Patient identification number, Vaccine code, Vaccine description, Vaccination date, Batch of administered vaccine, Pharmaceutical company of administered vaccine and Associated clinical events, as described previously [24]. The information about different research studies and scientific publications based on BIFAP data are available online [19].

BIFAP is fully funded by the Spanish Agency for Medicines and Medical Devices (AEMPS), belonging to the Ministry of Health [19]. The local Governments of the participating regions collaborate through sharing the data.

The protocol of the current study was approved by the BIFAP Scientific Committee (number 01_2016).

Study Design and Cohort

A cohort design was followed. The study cohort was made up of all girls aged 9–18 years registered in BIFAP between 1st January of 2007 and 31st December of 2016, with at least 1 year of clinical record information with their PCP (inclusion criteria). The date when inclusion criteria were met was designated as the start date to the study cohort contribution. Girls with an HPV vaccination recorded before the start date, without a clear vaccination date or outlier intervals between recorded doses were excluded. Also, since the aim of the broader project was to evaluate the implication of the HPV vaccination in the development of inflammatory bowel disease, girls with such as diagnosis before the start date were excluded from the study cohort. Girls aged up to 18 years were included in order to account for late vaccinations with a potential preventive indication similar to younger girls included in the vaccination schedule.

Follow-up to HPV Vaccination

In order to estimate the incidence of HPV vaccination, girls forming the study cohort were followed from start date until there was a recorded HPV vaccination, they reached 19 years of age or died, end of available information [no information in the database due to the region ceasing to contribute, or the PCP or patient leaving the database], or 31st December 2016. The end of the follow-up will be called the stop date. The total person-time of all patients forming the study cohort was taken into account in the incidence estimations. In order to study the incidence by calendar year, the same follow-up was replicated yearly from 2007 to 2016.

Identification of the Vaccination Schedule

An algorithm to identify complete HPV vaccinations was established allowing a ± 30-day time lag in the administration of the vaccine versus the strict posology included in the summary of product characteristics (i.e. the second dose given at least 6 months after the first dose for quadrivalent vaccine, and between 5 and 13 months for the bivalent) [25, 26]. Thus, a complete HPV vaccination (two-doses schedule) was assumed among girls aged < 14 years with at least 150 days between 1st and 2nd doses of the quadrivalent vaccine, as were girls aged < 15 years with 120–420 days between 1st and 2nd doses with the bivalent vaccine, or at least 120 days with the unknown type.

A three-doses schedule was assumed for girls with vaccinations recorded at older ages or before 2014 and defined as 27–269 days between 1st and 2nd doses, at least 55 days between 2nd and 3rd doses and less than 366 days between 1st and 3rd doses, as previously described [24].

Statistical Analysis

As aforementioned, the data source for this study was a dynamic longitudinal real-world primary care database, meaning that patients contribute different periods to the database according to their assignment to a practitioner. This implies that information to fixed calendar periods (i.e. January–December) may be incomplete for some patients. Thus, vaccine utilisation was calculated taking into account the follow-up period that each patient contributed. Under this scenario, the cumulative incidence by life table (CuIn) were utilised. The CuIn is the proportion of new events during a given interval in which the denominator is the initial population corrected for losses. The classic life table was applied that, by convention, half of the individuals lost are subtracted from the denominator [27]. It was calculated by the command ltable in Stata software [28], overall and split by calendar year, birth cohort and region. The type of vaccine (bivalent or quadrivalent) is described overall and by calendar year. The interval days between recorded doses were calculated and reported as median and range according to the number of vaccinations recorded per patient and the two- or three-dose schedule. Patients with outlier records were excluded as lacking quality (numbers are reported in the flowchart reported in Fig. 1).

Fig. 1
figure1

Flowchart showing the ascertainment of the study cohort and girls with HPV vaccination records. BIFAP the Primary Care Database for Pharmacoepidemiological Research (BIFAP), HPV human papillomavirus

This study replaces a previous publication [29], which contained a calculation error by calendar year [30].

Results

Overall Incidence of HPV Vaccination

Out of a base population of 7.9 million people registered in BIFAP with the aforementioned criteria during the study period, a total of 388,690 girls entered the study cohort when aged 9–18 years in the studied period (2007–2016), 154,211 of whom had a recorded HPV vaccination in that period. Few vaccinations were recorded in the first year of the study period (i.e. 2007; 1.79%) in comparison with subsequent years. The flowchart reporting the study cohort ascertainment is shown in Fig. 1. Table 1 shows the distribution of the calendar year and age at start date as well as Table 2 the age at vaccination.

Table 1 Distribution of calendar year and age at start date
Table 2 Distribution of age at first recorded vaccination

Most girls were completely vaccinated either in a three- (N = 73,959; 48.0%) or two- (N = 44,502; 28.9%) dose schedule (see Table 3). Around 3.0% of subjects had only the first and second dose recorded (N = 4568) under the 3-dose schedule. Finally, 20.2% had only one recorded dose (N = 31,183).

Table 3 Distribution of girls vaccinated against human papillomavirus by number of recorded vaccinations, intervals days between them and derived doses by vaccination schedule

Overall, 42.79% of all first recorded vaccines were quadrivalent, 21.86% bivalent and in 35.35% the type of vaccination was not recorded (information about the HPV vaccination was recorded without mention to the valence). By calendar year, the quadrivalent vaccine was the most frequent all years, except in 2013–2014 when half of the vaccines recorded were bivalent. Missing information was higher during the first 5 years of the study period (i.e. 34.97–59.3%) than thereafter (below 30.34%) that may be affected by different recording habits of the regions contributing for different years (see Fig. 2).

Fig. 2
figure2

Distribution of girls vaccinated against human papillomavirus by type of first vaccine and year of vaccination

Table 4 shows the CuIn by birth cohort and calendar year, overall and according to region allowing to identify the most frequent age at vaccination. Mass vaccination started in 2008. Along the years, highest incidences were observed among girls aged either 13 or 14 years in all regions (reaching 92.8% and 89.7%, respectively), but also aged 12 in some regions/years (reaching 89.8%). Overall, girls aged 15 years were also vaccinated yearly in two regions although showing lower incidence (< 69.1%). The coverage was observed to be broadened to younger girls (until 11 years) during the last years of the study period in some regions.

Table 4 Cumulative incidence (%) of HPV vaccination (by life table) among girls aged 9–18 years by birth year and region during the period 2007–2016 and yearly

Discussion

The primary care records used showed a high incidence of HPV vaccination among girls aged 13–14 years overall, and among girls aged 12 years in some regions/years, but lower in girls aged 15 years. Data also showed that most girls were completely vaccinated with three or two (for younger girls from 2014) doses according to recommended intervals.

In Spain, the regions have autonomy in their public healthcare services and expenditure, so some differences in vaccination schedules may be observed. As recommended by the Public Health Council and The Inter-territorial Board of the Spanish National Health System, most of the regions scheduled the free universal mass vaccination for girls aged 14 years and a few for girls aged 11–13 years [1]. The implementation of that recommendation was observed in the primary care data utilised in the current study, with the highest rates for girls aged 14 and 13 years at vaccination, but also for girls aged 12 or 15 years. A high incidence in younger girls (down to 11 years) were observed in some regions during 2015–2016 in line with the updated recommendations of the CISNS and regional authority instructions [31, 32] to extend the vaccination to girls aged 12 years [33]. The vaccination recommendations from the Public Health Council were published in February 2007 [34]. One region showed a high vaccination coverage in 2007, while other regions showed this from 2008 onwards.

In Spain, the ecological coverage of complete vaccination among girls aged 11–14 years ranged 64.3–79.0% between 2009 and 2016 according to the Ministry of Health [18]. Similar coverage was published for the school year 2014–2015, i.e. 79.2% (range 65.6–93.4% by regions), by the Ministry of Health [35], being reported as 74.0–91.4% for the specific regions that also provide primary care data to BIFAP. We also observed high proportions of vaccination amongst eligible girls during the study period, although the figures specific for age, calendar year and region must be consulted in order to compare the data.

Furthermore, in a recent study conducted during 2009–2014 in the Valencian population in Spain, 44.9% of girls born between 1994 and 1995 were vaccinated with three doses of the quadrivalent vaccine, as were 13.1% (with quadrivalent vaccine) and 26.7% (with bivalent vaccine) of girls born between 1996 and 2000 [36]. Unfortunately, we did not have enough information about the valence of the vaccines to conduct a similar analysis.

An uptake of 80.1% for the HPV vaccine was also reported to have been achieved in England in the first year following its introduction, mostly through schools-based programmes [37]. In other European countries, the coverage for three doses varied: 84% in Portugal, 79% in Denmark, 69% in Italy, 63% in Norway, 58% in The Netherlands, 55% in Slovenia and 17% in Luxembourg [38]. In a study conducted on health insurance data from the National Health Insurance Information System in France (SNIIRAM), 37.4% of girls were vaccinated during a mean follow-up of 32.7 months [39].

The calculation methods used in our study may result in differences in coverage estimations compared with other published data. For instance, the life-table method used in the current study provides higher coverage than the simple proportion, since it excludes patients lost to follow-up from the denominator (assumed lost at random). In order to compare with the Valencian study, that also used patient-level electronic data, the simple proportion was calculated, being 21.6% (11.35–47.08% by regions) for birth cohorts 1990–1995 (Table 4 footnote) during 2007–2016, which, in some regions, was close to the Valencian coverage (39.8–44.9% for quadri- and bivalent vaccines) [36]. Some estimates refer to particular age- and calendar-year strata at vaccination or to three doses, so differences may still be present.

In electronic healthcare databases, the aim of the records is clinical assistance and not research, and this poses challenges in retrieving all the information needed for a specific study [40]. Both the databases and real-world practice may vary versus vaccination recommendations. For instance, we observed that the dates recorded for the different doses suggest that, in practice, some could have been administered with a delay or advance (that were included in the current study) or within outlier intervals between doses (that were excluded from the study as reported in Fig. 1). Notwithstanding, most of the doses recorded in BIFAP where administered at the recommended intervals. Also, missing values for dose and type (whether bi- or quadrivalent) of vaccinations may occur in some instances, as well as recording typos/errors. Thus, usually after the extraction process, some assumptions may be needed in order to interpret the records and to filter for research only those with an acceptable quality standard as we did in a previous validation study about the HPV vaccination records in BIFAP [24]. However, using electronic medical records poses an opportunity to research the use, safety and effectiveness of vaccines since containing information over time about health status (diseases, signs/symptoms, lab results, etc.) and other medication, among other factors, at patients’ levels. Information about those factors can be used as outcomes or tested as potential confounders in research and are seldom available in specific vaccination registries. Also, primary care electronic health information offers an opportunity to study the use of this vaccine at the patient level (instead of aggregated population/ecological level) used commonly by other sources of data not having information about specific patients at risk.

Limitations of the current study include the potential for false-positive results, as vaccine appointments may have been recorded as actual vaccinations, and appointments may have been missed [24]. The false-positives, quantified at around 9.9% of the doses during validation of the extracted information, would overestimate the incidence. On the other hand, HPV vaccinations not recorded in the vaccine files of BIFAP, but rather in fields not systematically available (text mining or other) and not automatically extracted for the study (quantified at around 0.7% of all vaccinations, during validation), would underestimate the overall incidence in the BIFAP population. According to a survey among PCPs and nurses collaborating with BIFAP, the vaccines administered in other settings are also recorded in the patient clinical histories. Indeed, we observed that the setting of the vaccination is sometimes stated by the PCP or nurse as “school” or “private” vaccination in free text comment fields. Those vaccination records depend on the patient notification to the PCP or nurse. The extent to which vaccinations external to the public health service are recorded in BIFAP is unknown, and we may be underestimating the incidence of HPV vaccination in the population when comparing it with sources using both, schools-based programmes or private data and primary care data. In the current study, the inclusion criteria of having at least 1 year of PCP information was applied in order to guarantee (among other reasons) that the patient seeks the public PCP assistance, instead of private, when needed. Also, when stratifying by calendar year, birth cohort and region, the number of patients could be scarce and consequently provide low precision to the incidences estimated for some groups. Furthermore, the dose reported in the current paper was extracted from the vaccine description field, or was derived from the order and the interval between recorded doses. Evidence of a wrong dose was estimated in 3.0% during data review [24], so misclassification of doses reported should not be disregarded. Finally, missing information of the vaccine valence was substantial. We encourage a complete and accurate recording of the valence, brand, dose, batch and date in the Vaccination File for each administered vaccine that are of great relevance in research on safety of biological products.

The main strength of the current study includes the evaluation and description of the HPV immunisation records in primary care settings among girls regardless of their eligibility to the HPV mass vaccination schedule, and the establishment of a study cohort formed by anonymised clinical profiles of young women with different baseline characteristics that could contribute to further research studies of the short- and long-term safety of HPV vaccines.

Conclusions

According to BIFAP primary care data, a high incidence of vaccination among girls aged 13–14 years was observed. Vaccination among younger and older girls (aged 11–15 years) was less common, although also reaching high incidence in particular calendar years and regions. Most vaccination patterns adjusted to a complete vaccination according to three- or two-dose regimens, as recommended.

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Acknowledgements

The authors would like to acknowledge the excellent collaboration of the primary care general practitioners, paediatricians, and nurses taking part in the primary care records and the support of the regional governments, with special mention to physicians participating in a general survey about vaccination recording in primary care, which helped us to better understand specific information registered in the database. We are also grateful to Mónica Ríos Martinez from BIFAP team for her review of patients’ profiles as well as to Veronica Bryant and Julio Bonis for making the conducting of the survey possible. We also thank the retraction team of Pharmaceutical Medicine for allowing us to retract our previous publication [29] after realizing calculation errors by calendar year and submit the current manuscript with new data and updated calculations. All views expressed in this article are those of the authors and do not represent the views of, and should not be attributed to, the Spanish Agency for Medicines and Medical Devices.

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Correspondence to Elisa Martín-Merino.

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Funding

BIFAP is funded by the Spanish Agency for Medicines and Medical Devices. This study was performed within the framework of a project on the safety of HPV vaccine. This study has been funded by Instituto de Salud Carlos III through the project “PI17/02300” (Co-funded by European Regional Development Fund/European Social Fund “Investing in your future”).

Conflict of interest

Elisa Martín-Merino, Ana Llorente-García, Belén Castillo Cano, Dolores Montero Corominas and Consuelo Huerta-Álvarez have no conflict of interest to declare.

Ethical Approval

The investigators had access to secondary use of only fully anonymised data, and under this condition, no specific ethics review was required according to Spanish law.

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Martín-Merino, E., Llorente-García, A., Castillo Cano, B. et al. The Longitudinal Incidence of Human Papillomavirus Vaccination in Spanish Primary Care in the First 10 Years After Approval. Pharm Med 33, 519–530 (2019). https://doi.org/10.1007/s40290-019-00309-9

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