Sexually Transmitted Diseases:
Significant Decrease in the Incidence of Genital Warts in Young Danish Women After Implementation of a National Human Papillomavirus Vaccination Program
Baandrup, Louise MD*; Blomberg, Maria MD*; Dehlendorff, Christian MSc, PhD†; Sand, Carsten MD, DMSc‡; Andersen, Klaus K. MSc, PhD†; Kjaer, Susanne K. MD, DMSc*§
From the *Virus, Lifestyle, and Genes and †Statistics, Bioinformatics, and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark; and ‡Department of Dermato-Venereology, Bispebjerg Hospital, and §Gynecologic Clinic, Juliane Marie Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
The authors are grateful to Nick Martinussen for data management assistance.
Supported by the Aragon Foundation, the Aase and Ejnar Danielsen Foundation, and the Mermaid II project.
Conflicts of interest: C.S. received lecture fees from Sanofi Pasteur MSD. S.K.K. received lecture fees, advisory board fees, and research grants through her institution from Merck (manufacturer of the quadrivalent human papillomavirus vaccine) and Sanofi Pasteur MSD. L.B., M.B., C.D., and K.K.A. report no conflicts.
L.B. and M.B. contributed equally to this study.
Correspondence: Susanne K. Kjaer, MD, DMSc, Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. E-mail: firstname.lastname@example.org.
Received for publication June 8, 2012, and accepted September 5, 2012.
Background: Approximately 90% of genital warts (GWs) are caused by human papillomavirus (HPV) types 6 and 11. Denmark has provided the quadrivalent HPV vaccine to all 12-year-old girls since 2009 and catch-up vaccination to girls up to 15 years since 2008, with up to 80% to 85% vaccine coverage. We determined the incidence of GWs in Denmark since 1996, focusing on the period after licensing of HPV vaccination (October 2006).
Methods: From the Danish National Patient Register, we identified all hospitalizations and outpatient consultations for GWs between January 1995 and July 2011. Poisson regression was used to estimate average annual percentage changes.
Results: The overall incidence of GWs in women increased significantly until 2007, followed by an average yearly decline of 3.1% (95% confidence interval [CI], −5.5 to −0.7). In men, the incidence increased by 6.2% per year from 2004 (95% CI, 4.6–7.8). Stratifying on age, a significant decline was seen only for young women, particularly those aged 16 to 17 years, in whom GWs were virtually eliminated (average annual percentage change, −45.3%; 95% CI, −55.8 to −33.3). The incidences of genital Chlamydia, syphilis, and gonorrhea were stable or increased during the study period.
Conclusions: The incidence of GWs decreased substantially among women with high HPV vaccine coverage, pointing to the effect of the national HPV vaccination program.
Genital warts (GWs) are one of the most common sexually transmitted infections (STIs). In a recent population-based study of nearly 70,000 women in 4 Nordic countries, 10.6% of women aged 18 to 45 years reported having received a clinical diagnosis of GWs.1 Among Danish men of the same age group, the self-reported cumulative incidence of clinically diagnosed GWs was 7.9%.2 Studies based on large populations with a wide age span have shown a somewhat lower but still high self-reported cumulative incidence of GWs. In the United Kingdom, 4.1% of women and 3.6% of men reported a history of GWs.3 In the United States and Australia, the cumulative incidence was 7.2% and 4.4% among women, respectively, and 4.0% among men in both countries.4,5
Human papillomavirus (HPV) types 6 and 11 are associated with up to 90% of GWs.6 The quadrivalent HPV vaccine against HPV types 6, 11, 16, and 18 has been shown to be highly effective against not only high-grade genital lesions but also GWs.7 Genital warts have a short incubation period of approximately 3 months8 and are thus an early event in the natural history of HPV infection. A reduction in the incidence of GWs is therefore one of the first markers of the effectiveness of HPV vaccination at population level.
Studies reporting on the incidence of GWs in the period before HPV vaccination show an increasing trend.9–10 Australia began offering HPV vaccination free of charge to women aged 12 to 26 years in 2007 and is therefore one of the first countries to measure the effect of such a program.11 Surveillance data from various areas of Australia, published recently, showed a marked reduction in the incidence of GWs among women in the target age group for HPV vaccination.11–13
In Denmark, the quadrivalent HPV vaccine was licensed for use in October 2006. Since January 2009, vaccination has been offered at no cost to all girls 12 years of age as part of the children’s vaccination program, which is administered by general practitioners. Catch-up vaccination of girls up to 15 years of age (1993, 1994, and 1995 birth cohorts) began in October 2008.14 Before the vaccination program was launched, information about the program was made available via a Website (www.stophpv.dk), and an information package was sent to general practitioners and school health services. Thereafter, the girls and their parents were invited by letter. The latest data show that coverage of the first 2 birth cohorts in the children’s vaccination program (1996 and 1997) with 3 doses of vaccine was 82% and 81%, respectively,14 and coverage of the 3 birth cohort catch-up program was above 85%.15 Data on adverse events after HPV vaccination in Denmark have recently been assessed among girls aged 10 to 18 years from October 2006 to December 2011. No increased risk of autoimmune, neurologic, or thromboembolic events were registered.16
In most countries with disease-reporting systems, GWs are not notifiable,11 and information on GWs at population level is therefore sparse. Studies have been based on data from sexual health clinics,11,13,17 other clinics (e.g., general practitioner, gynecology, and dermatology),18,19 or records from health insurance companies.20,21 Previous population-based studies have been derived from databases9–10 or questionnaires.1,4,5 In this study, we took advantage of a nationwide, population-based registry containing information on all hospitalizations and outpatient consultations. The aim was to determine the incidence of GWs at hospitals and outpatient clinics in Denmark during the period January 1996 to July 2011, focusing on the period after release of the HPV vaccine in 2006.
MATERIALS AND METHODS
In Denmark, every citizen is allocated a unique personal identification number, which is used throughout Danish society, including in all health registries; it contains sex and date of birth. The Danish National Patient Register contains information on all hospitalizations for somatic conditions since 1977 and all outpatient consultations since 1995.22 Since 1994, each hospitalization has been classified according to the International Classification of Diseases, Tenth Revision (ICD-10).22 Between January 1995 and July 2011, all records of GWs (ICD-10 code A63.0) were extracted. To compare trends in the incidence of GWs with those of other STIs, we also obtained all records from the Danish National Patient Register of genital Chlamydia infection (ICD-10 codes A55 and A56), syphilis (ICD-10 codes A51–A53), and gonorrhea (ICD-10 code A54) in the period 1995 to 2010. In Denmark, syphilis and gonorrhea are notifiable infections; therefore, we were also able to retrieve information on the annual numbers of cases notified to the Department of Epidemiology at the National Institute for Health Data and Disease Control in 1995 to 2010.
The study was approved by the Danish Data Protection Agency.
As in other studies,9,20 an episode of GWs was defined as incident if it was preceded by at least 1 year without any contact with a hospital or outpatient clinic for the same complaint. This requirement was included so that the first year of the study period (1995) served to exclude prevalent cases; therefore, incidence was assessed from 1996 onward. We also assessed the incidence of GWs only counting the first episode; however, because this did not change the results, we present only the incidence results defined above. A new episode of genital Chlamydia was defined as one occurring after a 3-month disease-free period, as in other studies.23 The incidence of syphilis and gonorrhea was based only on first episodes because most patients with these infections were registered only once.
In a period approximately between January 2000 and June 2006, registration of GWs in the Danish National Patient Register was incomplete in one large department of dermatovenereology, serving primarily the Greater Copenhagen area. In addition, individuals residing in Zealand but outside the Greater Copenhagen area might seek treatment in this particular department. Consequently, we had to exclude Zealand from the analyses for the full study period (1996 onward) and analyzed only data for the rest of Denmark (Jutland and Funen), representing 55% of the total Danish population (Fig. 1).
Between July 2006 and July 2011, nationwide registration of GWs treated at hospitals and outpatients clinics was complete, and we could calculate the nationwide incidence in half-year intervals from July 2006 onward. The incidence of GWs in nationwide data was also analyzed in the age groups 12 to 15, 16 to 17, 18 to 19, 20 to 21, 22 to 25, 26 to 29, 30 to 35, and 36+ years. To calculate incidence, we used annual population estimates covering all of Denmark, obtained from Statistics Denmark. All incidence rates were expressed per 100,000 person-years. Incidence rates were also age standardized to the 1995 Danish population, but because this did not change the estimates, we chose to present crude rates.
The incidence rates of GWs were modeled by Poisson regression models, that is, by generalized linear models on the log rates.24 To account for overdispersion, the quasi-Poisson family was used.
The annual log rates were initially modeled by separate restricted cubic splines for men and women. We tested simplification of these curves to piecewise linear functions by comparing the changes in deviance with an F distribution, which revealed nonsignificant increases (P > 0.15) in all analyses. For each segment of the piecewise linear functions, an estimate, β, of the annual increase in the log rates was obtained. The estimate was transformed and reported as an average annual percentage change (AAPC), with the transformation AAPC = [exp(β) − 1] · 100%. We present the incidence rates of GWs as fitted rates obtained from the piecewise linear model for the log rates.
All statistical analyses were performed with the statistical software R version 2.14.025 and the “rms” package version 18.104.22.168 A 5% significance level was used.
Incidence of GWs in Jutland and Funen, 1996 to 2010
A total of 18,574 new cases of GWs were diagnosed in Jutland and Funen in 1996 to 2010. Women represented 67% of incident cases. Figure 2A describes the incidence rate of GWs from 1996 to 2010. After an initially stable period, the estimated incidence rate in women increased markedly, from 50.2 in 2001 to 65.9 per 100,000 in 2006, representing a significant average annual percentage increase of 5.6% (95% confidence interval [CI], 4.1–7.0). Between 2007 and 2010, the incidence rate declined significantly to 60.5 per 100,000 in 2010 (AAPC, −3.1%; 95% CI, −5.5 to −0.7). The curve representing the incidence rate in men was stable until 2003 (AAPC, 0.3%; 95% CI, −1.3 to 2.0) but increased significantly, from 26.1 to 37.3 per 100,000 (AAPC, 6.2%; 95% CI, 4.6–7.8) between 2004 and the end of the study period.
Incidence of Other STIs in Denmark, 1996 to 2010
In both sexes, but especially among women, genital Chlamydia was more frequent than syphilis and gonorrhea. The nationwide incidence rates of genital Chlamydia are shown in Figure 2B. From 2002 to the end of the study period, the incidence of genital Chlamydia increased by an average of 4.2% per year (95% CI, 2.5–5.9) in both sexes. The incidences of syphilis and gonorrhea showed similar patterns in women and men (data not shown). The incidence rate of syphilis was stable until the end of the study period, when it showed a sharp increase (women and men: AAPC2008–2010, 47.1%; 95% CI, 23.5–75.0). For gonorrhea, an initially stable period was also observed, followed by an increase and a peak in 2009 (women and men: AAPC2000–2010, 15.4%; 95% CI, 10.0–21.2). The incidences of syphilis and gonorrhea (Danish National Patient Register) were similar to the trends in the annual numbers of notified cases in 1996 to 2010 obtained from the National Institute for Health Data and Disease Control (data not shown).
Nationwide Incidence of GWs, 2006 to 2011
A total of 17,309 new cases of GWs were diagnosed in Denmark between July 2006 and July 2011, with most incident cases in women (57.5%). The median age of women with GWs was 24.1 years, whereas that of men was more than 4 years higher (28.5 years).
The incidence of GWs was also estimated according to age in the period July 2006 to July 2011 with data from all of Denmark (Fig. 3). Among women aged 16 to 17 years, the incidence rate peaked in the second half of 2008 (381.5 per 100,000), followed by a sharp decrease and virtual elimination to 39.8 per 100,000 in the first 6 months of 2011. This represented an average annual percentage decrease of 45.3% (95% CI, −55.8 to −33.3). From the beginning of 2009, more gradual but still significant decreases in the incidences of GWs were also observed among women aged 18 to 19 years (AAPC, −14.4; 95% CI, −24.4 to −3.6), 20 to 21 years (AAPC, −14.7; 95% CI, −24.0 to −4.7), 22 to 25 years (AAPC, −14.0; 95% CI, −24.5 to −4.8), and 26 to 29 years (AAPC, −13.1; 95% CI, −24.5 to −0.5). Although the incidence of GWs among women aged 12 to 15 years was very low, a statistically significant decline was observed (AAPC, −51.9; 95% CI, −74.6 to −20.4). The decrease in incidence among women aged 12 to 17 years was statistically significantly greater than that in women aged 18 to 29 years (P = 0.006 for age 12–17 years vs. age 18–29 years). In men, the incidence rate of GWs was stable; although a tendency toward a decrease was observed in some age groups, none of the AAPCs were statistically significant. The pattern was most evident for men aged 22 to 25 years (AAPC, −10.9; 95% CI, −21.6 to 0.9).
This is the first nationwide study of the incidence of GWs in the general population focusing on the period after initiation of HPV vaccination. On the basis of more than 15 years of registration in Jutland and Funen, covering 55% of the population of Denmark, we found that the incidence of GWs in women increased until initiation of HPV vaccination. In 2007, the increase was reversed and the incidence declined by an average of 3.1% per year to the end of the study period, whereas in men, a significant average increase of 6.2% per year was seen from 2004 onward. Nationwide data for 2006 to 2011 stratified by age showed that the decrease was greatest for younger women and particularly those 17 years and younger, the group to whom HPV vaccination was offered free of charge either in the children’s vaccination program or by catch-up vaccination. In men, who are not included in the HPV vaccination program, the age-stratified incidence rates were more stable, with a nonsignificant decline, especially for men aged 22 to 25 years (P = 0.08). We did not observe declines in the incidences of genital Chlamydia, syphilis, or gonorrhea, indicating that the observed decrease in the incidence of GWs among younger women was due to the HPV vaccination program.
In line with other studies,9,10 we found an increase in the incidence of GWs among women in the period before licensing of the HPV vaccine and implementation of the vaccination program. This pattern probably reflects changes in sexual behavior. The occurrence of GWs at population level has been studied in Australia11–13 and New Zealand17 based on data from one or a group of STI clinics. Comparison of pre- and post-HPV vaccine periods showed that the proportion of young women with GWs in the target age group for HPV vaccination declined significantly.11–13,17 These observations are consistent with those of the present study. In contrast, a continuous increase in the incidence of GWs in men was seen throughout the study period, in line with the fact that the Danish HPV vaccination program does not include boys.
We analyzed data from all of Denmark on the incidence of GWs from just before licensing of HPV vaccination (June 2006) and, in line with data from Australia and New Zealand, observed a decrease in incidence among younger women and particularly among those aged 16 to 17 years, in whom GWs were nearly eliminated. These women correspond to the 3 birth cohorts in the Danish vaccination catch-up program (1993, 1994, and 1995), for whom vaccination coverage was more than 85%.15 The near disappearance of GWs among women aged 16–17 years indicates the effectiveness of HPV vaccination at population level. Although the incidence of GWs in girls 15 years and younger is very low, a significant decline was still observed (P = 0.01). We also observed a decrease in the incidence of GWs among women aged 18 to 29 years, which was, however, significantly less pronounced than in the youngest women. Because these women were not included in the national vaccination program, the decline might be due to women having financed vaccination themselves. As expected, the coverage rate of these women is lower than that for those who are offered vaccination at no cost, the coverage rates being 3% to 31% (July 1, 2011). The Danish Government decided in 2012 to offer HPV vaccination free of charge to all women up to 26 years of age.
The rationale for male vaccination remains an important issue. It is noteworthy that the incidence of anal and HPV related oral and oropharyngeal cancers among men in Denmark is increasing.27,28 In addition, the prevalence of GWs, most often associated with HPV types 6 and 11, is also high in Danish men.2 The quadrivalent HPV vaccine has so far shown a high efficacy in preventing external genital lesions including GWs, penile, perianal, or perineal intraepithelial neoplasia in men aged 16 to 26 years.29 However, in Denmark, boys are currently not included in the HPV vaccination program.
In the age-stratified analyses, we observed no statistically significant change in the incidence of GWs in men after implementation of HPV vaccination. There was a tendency toward a decrease in the incidence among men in some age groups, especially those aged 22 to 25 years. Some boys or young men might have paid to have the HPV vaccine. Another explanation may be indirect protection of men caused by immunization of women. The latter hypothesis is supported by observations in urban areas of Australia showing a decline in the incidence of GWs among young heterosexual men but not among older men or men who have sex with men.11–13 The authors argued that this pattern could be caused by reduced exposure of young heterosexual men to HPV.11–13
In theory, it is possible that some of the observed decline in the incidence of GWs among young women was caused by changes in sexual behavior or in health-seeking behavior (general practice vs. hospital). However, we consider that this is unlikely to be important because the decrease was seen only in particular age groups and virtually only among women. In addition, registration of other STIs (genital Chlamydia, syphilis, and gonorrhea) among women in the Danish National Patient Register showed an increasing or stable tendency, indicating that the decrease in GWs is caused by HPV vaccination. A possible limitation of our study is that the analyses were based on information from a register of hospitalizations and outpatient consultations, and we had no information on GWs treated by general practitioners. The preponderance of women in our study might reflect this data source because, due to differences in anatomy, home-based therapy is more suitable for men than for women. Thus, a larger proportion of men with GWs would be treated by their general practitioners. The incidence of GWs in men might have approached the incidence in women if we had been able to include data from primary health care. Previous studies have reported similar incidences of GWs in women and men30 or even a male dominance.9,10,19 However, in 2 recent questionnaire studies in Denmark, including more than 22,000 women and nearly 23,000 men, the self-reported cumulative incidence of clinically diagnosed GWs was higher in women (10.1%; 95% CI, 9.7–10.5) than in men (7.9 %; 95% CI, 7.6–8.2).1,2 Furthermore, our study was limited by incomplete registration of GWs in a very large department of dermatovenereology located in Copenhagen. We handled this problem by using data only from Jutland and Funen in the overall analysis covering the full study period. Jutland and Funen represent more than half of the Danish population, but nonavailability of data from Zealand could potentially have introduced bias in the early data. However, for the significant period of the study just before licensure of HPV vaccination and onward, we were able to use nationwide data. The strengths of this study include the nationwide population-based data and the long follow-up time. Use of a national register eliminates recall bias, which can distort the findings of studies based on self-reported information. Furthermore, the potential risk of selection bias in studies based on data from one or a group of STI clinics was eliminated. In this study, the trend in incidence of GWs was based on the total population at risk. In contrast, previous studies on the incidence of GWs after initiation of HPV vaccination assessed the proportion of patients with STIs who presented with GWs. Thus, the incidence of GWs would seem to be declining if that of another STI or simply that of healthy individuals presenting at the clinic for STI testing was increasing.
In conclusion, we found a significant decrease in the incidence of GWs among young women in the period after implementation of the HPV vaccination program. In women aged 16 to 17 years, with HPV vaccination coverage of more than 85%, GWs were virtually eliminated. Only a small, statistically nonsignificant decrease was seen in men, for whom HPV vaccination has not been implemented. These results provide strong, plausible indications for a protective effect of the quadrivalent HPV vaccine at general population level. Because of the short incubation period of GWs, a reduction in their incidence is one of the first markers of the effectiveness of a national HPV vaccination program.
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