Abstract: In a large health insurance database in Germany, incidence of anogenital warts among 15- to 19-year-old females decreased from 316/100,000 person-years in 2007 to 242 in 2008 (23% reduction, P = 0.0001). The decrease started between the first and second quarter of 2007 (human papillomavirus vaccination was introduced in March 2007).
This study, based on health insurance data, demonstrated changes in the incidence of anogenital warts after the introduction of human papillomavirus vaccination for the first time in Germany.
From the *BIPS–Institute for Epidemiology and Prevention Research, Bremen, Germany; †Helmholtz Centre for Infection Research, Braunschweig, Germany; ‡Hannover Medical School, Hannover, Germany; §Sanofi-Pasteur MSD GmbH, Leimen, Germany; and ¶Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany
R.T.M. received research funding from Sanofi-Pasteur MSD (SPMSD) and Bayer-Schering. E.G. is running a department that occasionally performs studies for pharmaceutical industries. The companies include Mundipharma, Bayer-Schering, Stada, Sanofi-Aventis, Sanofi-Pasteur, Novartis, Celgene, and GSK. E.G. has been consultant to Bayer-Schering, Nycomed, Teva, and Novartis in the past. A.A.K. participated in projects funded by SPMSD. R.S.R. is an employee of SPMSD.
Supported by SPMSD.
Correspondence: Rafael Mikolajczyk, PhD, MD, Department of Clinical Epidemiology, BIPS–Institute for Prevention Research and Social Medicine, University of Bremen, Achterstraße 30, D-28359 Bremen, Germany. E-mail: email@example.com.
Received for publication February 22, 2012, and accepted September 19, 2012.
Although the main focus of human papillomavirus (HPV) vaccination is on prevention of cervical cancer, anogenital warts (AGWs; mainly caused by the HPV types 6 and 11) can cause emotional distress and substantial health care costs and are therefore an important secondary health outcome.1–5 In clinical trials, a high efficacy of the quadrivalent vaccine against AGW was demonstrated.6–9
In March 2007, the German Standing Vaccination Committee (STIKO) recommended the HPV vaccination for the prevention of cervical cancer for girls between 12 and 17 years of age.10 The STIKO recommendation does not distinguish between the bivalent and the quadrivalent HPV vaccine. However, the quadrivalent vaccine is used predominantly in Germany (almost 90% of sold doses).11 Typically, the vaccination takes place toward the end of the recommended age range. In 2008/2009, the coverage in the age group 16 to 18 years was estimated at approximately 40%.12,13 Using the same database as in the current analysis, we found that approximately 35% of 17-year-old girls received at least 1 HPV vaccine dose in 2008.14 Furthermore, the ratio of third doses to first and second doses administered in federal states where separate codes for the specific doses existed suggested that women usually completed the whole vaccination series.
The impact of the quadrivalent HPV vaccine on the reduction of AGW at population level has been investigated in Australia,15–17 New Zealand,18 and the United States.19 These studies demonstrated a reduction of the AGW incidence soon after the introduction of national vaccination programs, even with some evidence of herd immunity. We recently published an article on the incidence of AGW in 2005 and 2006.20 The aim of the current study was to assess whether there were changes in the incidence of AGW in the period 2005 to 2008, during which HPV vaccination was introduced in Germany. We studied AGW incidence trends by age using a large health care database.
The database was the German Pharmacoepidemiological Research Database, which was described elsewhere.20,21 In the current analysis, we used data from one large health insurance company (>6 million insured persons, 8% of the German population) for which data were available for the years 2004 to 2008. The German Pharmacoepidemiological Research Database contains demographic information, information on hospital admissions, ambulatory physician visits, and prescriptions. The hospital data contain information on admission and discharge dates, diagnoses, and diagnostic and therapeutic procedures carried out in hospital with the respective date. Outpatient physician visit claims data include outpatient treatments, procedures, and diagnoses. Because outpatient physician visits are reimbursed quarterly, outpatient diagnoses can only be allocated to a quarter of the year.
We applied an open-cohort design to assess the incidence of AGW. Cases of AGW were ascertained based on the International Statistical Classification of Diseases, Tenth Revision, German Modification code A63.0.22 For the estimation of incidence rates, only cases with a preceding period of 12 months without AGW diagnoses were included. Confidence intervals for incidence rates were based on Poisson distribution.
We estimated incidence rates for each quarter of the years 2005 to 2008, stratified by 5-year age group and sex and performed trend analysis using a segmented Poisson model. We expected a change of trend in the incidence of AGW after the introduction of the HPV vaccination (“breaking point”). To explore this, we restricted the analysis to females aged 12 to 20 years and used a Poisson regression model with age, calendar time in quarters of the year (to allow for a general trend over time), calendar time within a year, and calendar time since a breaking point. Adjusting for calendar time within a year was necessary to account for effects of aging in the respective cohort. We varied the time of the breaking point across the whole range of the studied period and used the Bayesian Information Criterion to define the best fit for the breaking point.23 In the next step, we applied the estimated breaking point in each of the 1-year age groups for males and females, separately. The reduction in the incidence after the breaking point was approximated by a linear trend. All analyses were conducted with SAS 9.2.
Overall, the incidence of AGWs in the age group 10 to 79 years increased by 17% from 2005 to 2008 (Table 1). In 2005, females had a 52% higher incidence than males; over time, the difference decreased to 31% in 2008. In females, the incidence was highest in the age group 20 to 24 years; in males, it was highest in the next older group (25–29 years) (Fig. 1). In 2008, the peak incidence was 30% higher in women than in men. The general trend over time was an increase in the incidence, which was most visible for the age groups with high incidence. Despite the general upward trend, there was a decrease in the incidence among females in the age group 15 to 19 years (316 per 100,000 person-years in 2007 and 242 in 2008, a 23% reduction; P = 0.0001).
When focusing on 10- to 20-year-olds, a decreased incidence in 2008 could be seen for 16-, 17- and 18-year-old girls and less pronounced among the 15- and 19-year-olds (Fig. 2). In contrast, among 13-, 14-, and 20-year-old females, there was some indication of an increased incidence. Generally, males had a much lower incidence in the age group 10 to 20 years, with some indication of a decreasing incidence among 16- and 17-year-olds over the whole study period.
Based on the lowest Bayesian Information Criterion, there was evidence of a change in trend in the incidence of AGW among females in the age group 12 to 20 years in the second quarter of 2007 (data not shown). Evaluating the trend in 1-year age groups, this change can be attributed to 16-, 17-, and 18-year-old girls (Table 2).
Based on the estimated decrease rate, the incidence among 16-year-old girls was reduced by 47% in the end of 2008, by 45% among 17-year-olds, and by 35% among those 18 years of age compared with the incidence in these age groups before the breaking point. There was no clear breaking point in the incidence of AGW among males.
Our analysis demonstrated a reduction in the incidence of AGW after the introduction of HPV vaccination in Germany among 16- to 18-year-old girls. The decrease started soon after the recommendation of HPV vaccination by STIKO and the reimbursement of HPV vaccination by health insurance companies.
Comparing girls of the same age before and after the introduction of the vaccination showed a reduction of AGW of 35% to 47% (based on the estimated decrease rate). The reduction corresponds to the HPV vaccination coverage in the corresponding age groups.12–14 Because in Germany, the quadrivalent vaccine is predominantly used (it amounts to nearly 90% of all sold doses),11 the vaccinated fraction can directly be translated into the protected fraction (assuming the probability of vaccination does not depend on the risk of HPV infection). In contrast, there was no evidence of a decrease in the incidence for males or older-age groups of females.
To date, the newest data available for the project were from 2008, so we could not investigate whether the incidence remains stable after reaching the level of protection due to direct effects of vaccination. Herd immunity effects could lead to a further decrease in the incidence, but these effects require more time.
The decrease in the incidence of AGW soon after the introduction of the vaccination in the current study is consistent with the observation that AGWs develop within months of the initial infection.15,24,25 Furthermore, although the complete vaccination schedule with 3 doses requires 6 months, there is some evidence that also 2 or even 1 dose of the bivalent HPV vaccine may already provide a substantial protection against HPV infections.26 Similarly, protection against AGW provided by the quadrivalent vaccine might start soon after the initial vaccination, contributing to the short period between the introduction of the vaccine and the start of the decrease in incidence.
Three Australian studies with a smaller study population demonstrated reductions in the incidence of AGW after the introduction of HPV vaccination.15–17 One further Australian study also showed a reduction in the incidence of cervical abnormalities.27 In all these studies, the reduction in the incidence exceeded vaccine coverage and displayed a breaking point coinciding with the introduction of the vaccination program. Recently, similar results were published for New Zealand18 and for the United States.19 Similarly to ours, these studies used ecologic designs, evaluating the trend of incidence over time rather than comparing the risk in vaccinated and not vaccinated individuals. Although such studies can be subject to ecologic fallacy (drawing inferences for individuals from ecologic level data), the evidence of a breaking point coinciding with the introduction of the vaccine and the fact that the observed decrease in the youngest age group accompanies a general increase in the incidence in the whole population support the causal interpretation.
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