Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases, with an 80% lifetime probability of infection.1 Most infections clear without symptoms; however, up to 10% persist.1 Human papillomaviruses are categorized as high- and low-risk types, on the basis of their oncogenic potential in the cervix and other infected tissues.2 Persistent infection with high-risk HPV types is associated with a number of anogenital and head and neck cancers, most of which are caused by virus type 16 or 18.1 Low-risk types are associated with the development of genital warts (GWs), which are most commonly (90%) caused by HPV types 6 and 11.3
Denmark started a national HPV vaccination program in 2008 using the quadrivalent HPV vaccine, which protects against HPV types 6, 11, 16, and 18. The quadrivalent vaccine was chosen through a tender process. Since January 2009, girls have been vaccinated at the age of 12 as part of the Danish childhood vaccination program. Between October 2008 and December 2010, 13- to 15-year-old girls were offered HPV vaccination free of charge in a first catch-up program. Women up to the age of 27 years were vaccinated free of charge in a second catch-up program since August 2012. By July 2013, coverage with at least 1 dose of vaccine was 87% to 91% among 13- to 17-year-olds. The coverage for 1 dose in the second catch-up program was 75% in January 2014.4 Boys are not included in the Danish HPV vaccination program, and few have been vaccinated at their own expense.5
In a study based on GWs treated in hospital or outpatient clinics, we showed a significant reduction in the incidence of GWs in women up to 29 years of age between 2008 and 2011.6 These findings were corroborated by a nationwide cohort study based on individual vaccination status.7 Moreover, ecological studies have showed some decrease in the incidence of GWs among young Danish men, potentially indicating herd protection.6,8 However, these studies were conducted when the vaccination program only included girls up to 15 years of age, that is, before introduction of the second catch-up HPV vaccination program covering women up to 27 years.
In Australia, studies have shown decreased incidences of GWs in women and men after introduction of HPV vaccination programs with the quadrivalent HPV vaccine. Studies from other countries have also shown decreases for women, whereas results for men are conflicting.9
In this study, we looked at the incidence of GWs in women and men in Denmark after implementation of catch-up vaccination of women up to 27 years. We also extended our nationwide evaluation of the effectiveness of the Danish vaccination program to include GWs treated by general practitioners by including prescriptions redeemed for podophyllotoxin. In addition, we extended the follow-up time. The primary aim was to assess the potential effect of HPV vaccination in women on the incidence of GWs in boys and men.
Data Sources and Case Definition
We used data from 2 nationwide registries: the Danish National Patient Register and the National Prescription Registry. Both are nationwide registers based on individual-level data. In Denmark, all citizens are assigned a unique 10-digit personal identification number, which contains information on sex and date of birth and is universally used as key identifier in society, including in all health registries, ensuring accurate linkage among registries. The National Patient Register was established in 1977 and contains information on all inpatient and outpatient hospital contacts since 1995. From 1994, diagnostic information was coded according to the International Classification of Diseases, 10th Revision. To identify cases of GWs, we extracted data on all treatments of GWs between 2006 and 2013 using the International Classification of Diseases, 10th Revision diagnostic code A63.0. Most GWs, however, are treated in general practice; we therefore also obtained data on prescriptions for podophyllotoxin, which is the main drug used for GW treatment in general practice. Information on prescriptions for podophyllotoxin between 2006 and 2013 was obtained from the Danish National Prescription Registry, which contains data on all prescriptions redeemed in Danish pharmacies. Podophyllotoxin was identified by the Anatomical Therapeutic Chemical code D06BB04. To prevent inclusion of prevalent cases, an episode of GWs was considered incident if preceded by at least 12 months without hospital or podophyllotoxin treatment. Duration of podophyllotoxin treatment was defined as 1 month, as the recommended treatment duration is 1 week to 1 month. By linking the National Patient Register and the National Prescription Registry, we ensured that incident cases occurring simultaneously in both registries were only counted once. The study was approved by the Danish Data Protection Agency.
Half-yearly incidence rates (IRs) were calculated between 2006 and 2013 and reported as cases of GWs per 100,000 person-years. The IRs were stratified by sex and age (12–15, 16–17, 18–19, 20–21, 22–25, 26–29, 30–35, and ≥36 years). Calculation of IRs was based on annual population estimates covering all of Denmark obtained from Statistics Denmark. Poisson regression was used to estimate trends in incidence, which is reported as estimated annual percentage change (EAPC) with corresponding 2-sided 95% confidence intervals (CIs). Positive EAPCs correspond to increasing trends, whereas negative EAPCs represent decreasing trends. The trends were estimated from piecewise linear models initially consisting of 3 segments. The optimal cutoff points separating the segments were found by minimizing the residual deviance. Moreover, we tested the 3-segment model against a 2-segment model for each age group separately and simplified the model if appropriate. A 5% significance level was used in all analyses. The statistical software program R version 3.1.2 was used.10
Between 2006 and 2013, 117,792 cases of GWs were diagnosed in Denmark. Of these, 9% were treated in hospital and identified from the National Patient Register, 81% were identified through the Danish National Prescription Registry, and 10% where found in both registers. The median age at diagnosis was 25 years (range, 12–97 years) for women and 27 years (range, 12–95 years) for men. Figure 1 shows the age-specific IRs stratified by sex. All age groups experienced an either stable or significantly increasing incidence between 2006 and 2008; thereafter, significantly decreasing trends were seen in women aged 12–35 years and men aged 12–29 years.
In one analysis, we tested whether the IRs were best described in a 2-segment model, that is, before and after implementation of the HPV vaccination program, or in a 3-segment model (data not shown). The latter was more appropriate for age groups 18–19, 20–21, and 22–25 years in both sexes. In these age groups, an initial declining trend in the period after the implementation of HPV vaccination programs was followed by accelerated rates of reduction toward the end of the study; for example, the incidence in 18- to 19-year-old women decreased by nearly 24% (EAPC, −23.8; 95% CI, −26.6 to −20.8) between 2009 and 2011 and accelerated further in 2011 to 2013 to around 58% annually (EAPC, −58.1; 95% CI, −60.7 to −55.5). We also tested the exact time of the beginning of the decrease in each age group and sex (data not shown). In most age groups, the decrease started in 2009; however, a significant reduction was already seen in 12- to 15-year-old girls from 2008. A significant decrease in 20- to 21-year-old and 22- to 25-year-old women was not seen until 2010. The latest onset of a downward trend was seen in 22- to 25-year-old and 26- to 29-year-old men, in whom a decreasing incidence was first seen in 2011.
Table 1 shows the IRs of GWs in women in 2008 and 2013 as well as the overall trend in incidence (EAPC) between 2009 and 2013; the corresponding results for men are shown in Table 2. Among women, the greatest reduction was seen in 16- to 17-year-olds, in whom the incidence decreased from 1071 in 2008 to 58 per 100,000 person-years in 2013, corresponding to an estimated annual decrease of 55% (EAPC, −55.1%; 95% CI, −58.7 to −51.2). Genital warts were most common in women aged 18 to 19 years, with an incidence of 1808 cases per 100,000 person-years in 2008. Thereafter, the incidence showed an estimated annual decrease of 39% (EAPC, −39.0; 95% CI, −44.0 to −33.5) to 168 per 100,000 person-years in 2013. In women aged 30 to 35 years, only a slight decrease was seen between 2009 and 2013, from 397 to 377 cases per 100,000 person-years. In contrast, no change in the incidence of GWs was observed for women 36 years or older.
The greatest reduction in the incidence in GWs in men was seen in 16- to 19-year-olds. In 16- to 17-year-old boys, the incidence decreased from 365 in 2008 to 77 cases per 100,000 person-years in 2013 (EAPC, −36.6%; 95% CI, −40.5 to −32.5), and the incidence in 18- to 19-year-olds decreased from 1130 to 212 cases per 100,000 person-years in 2008 to 2013, corresponding to an estimated annual decrease of 34% (EAPC, −34.4%; 95% CI, −37.5 to −31.2). The highest GW incidence in men in 2008 was seen in the group aged 22 to 25 years, with an incidence of 1828 per 100,000 person-years, which was reduced to 1247 per 100,000 person-years in 2013. In 26- to 29-year-old men, a small significant decrease was seen, from 1207 to 1142 cases per 100,000 person-years during the same period. In contrast, no significant trends in the incidence of GWs were observed in men 30 years or older in the period after introduction of the HPV vaccination program for women.
This nationwide study of the incidence of GWs before and after implementation of the national HPV vaccination programs in Denmark showed either increasing or stable incidences before introduction of the programs (2006–2008) in women and men in all age groups. In contrast, between 2008 and 2013, statistically significant decreases were seen in 12- to 35-year-old women and in men aged 12 to 29 years, with estimated annual decreases of up to 55% and 37%, respectively. Most noteworthy was the decline in GW incidence among 16- to 17-year-olds, with a decrease from 1071 to 58 cases per 100,000 person-years in women and from 365 to 77 per 100,000 person-years in men.
In line with Australian studies, we observed a strong decrease in the incidence of GWs in men.11–13 Although we previously found a decrease in men, it did not reach statistical significance.6 The substantial decrease in GWs among men that we found in this study is likely to be explained by the fact that more and older women were vaccinated during the second catch-up vaccination program, which started in 2012. In addition, the total number of GW cases was increased more than 5 times due to our inclusion of data on self-administered treatment with podophyllotoxin.
The decrease in the incidence of GWs in men indicates herd protection; however, unvaccinated individuals will continue to be vulnerable if they are exposed to HPV, and their protection depends on continually high female vaccination coverage. Moreover, although decreases in GW incidence are expected to herald future decreases in HPV-related cancers, it is uncertain whether this will be the case, as there is still no evidence that herd protection of men applies to the high-risk HPV types 16 and 18. Men who are particularly exposed are those who engage in sexual relationships when traveling outside Denmark to countries with lower HPV vaccination coverage as well as the heterogeneous group of men who have sex with men (MSM), which includes both homosexual and bisexual men. As we were unable to differentiate between men who have sex exclusively with women and MSM, the observed reduction in GWs in men may be due solely to a reduction among heterosexual men. Australian studies have shown little or no change in the incidence of GWs among MSM after vaccine implementation, and the same is probably true in Denmark.11–13
Whether men should be included in HPV vaccination programs has been widely discussed. Human papillomavirus infection is common in men, and, in contrast to women, where the prevalence of HPV decreases with age, the prevalence in men seems to be stable with increasing age.14 The quadrivalent HPV vaccine has been shown in clinical trials to be effective against external genital lesions and persistent HPV infection in 16- to 26-year-old men, with a noninferior immunogenic response in 10- to 15-year-old boys as compared with adolescent and young adult women.15,16 The quadrivalent HPV vaccine has been licensed for administration to boys aged 9 to 26 years for the prevention of anal cancer, anal intraepithelial neoplasia, and GWs. Estimations of cost-effectiveness based on modelling data also plays a role in the discussion. In most studies on HPV vaccination in developed countries, vaccinating boys is not found to be cost-effective unless the female vaccination coverage is less than 50%17 or the vaccination program is merely stretched to include MSM.18 To provide optimal protection, however, vaccination has to take place at an age where sexual orientation is not yet fully established. A recent Danish cost-effectiveness study that considered all HPV-related anogenital and oropharyngeal cancers, however, found that it was cost-effective to include boys in the national HPV vaccination program.19 This would benefit both unvaccinated men and women by reducing the overall burden of HPV in Denmark. Finally, it has been argued that male vaccination is not a question merely of cost-effectiveness but also of the principle of equity in health.20
In line with previous studies, we found strong decreases in the incidence of GWs among younger women, which were most pronounced for age groups with high vaccination coverage.6,8,11 The women aged 18 to 19, 20 to 21, and 22 to 25 years all displayed decreasing trends in the incidence of GWs before they were covered by the HPV vaccination program. In all 3 groups, we found a slower initial decreasing trend which accelerated toward the end of the study period (data not shown). A likely explanation for the early decrease is that some women payed to be HPV vaccinated before they were eligible for the free HPV vaccination program. Self-payment based on a prescription has been possible in Denmark since the licensure of the quadrivalent HPV vaccine in 2006, and we have previously shown vaccination coverage of up to 27% for young Danish women before the start of the second vaccination catch-up program in August 2012.21 We also observed a significant decrease in GWs in 30- to 35-year-old women between 2009 and 2013, although this age group was never eligible for HPV vaccination free of charge. Again the decrease might be explained by the fact that some women financed the quadrivalent HPV vaccine themselves or it could be caused by herd protection due to the reduction in the total burden of HPV in Denmark.
Because the design of the study is ecological, factors other than vaccination, such as changes in sexual or treatment-seeking behavior, might partially explain the decrease in GWs. However, the incidence of chlamydia, syphilis, and gonorrhea has increased during the study period, indicating that the decrease in the incidence of GWs is not due changes in sexual behavior.22–24 In Denmark, common sexually transmitted diseases, such as chlamydia and gonorrhea, are increasingly diagnosed from urine samples, which may result in a reduction in the number of clinical examinations and therefore of diagnosed asymptomatic GWs.25 This explanation alone, however, cannot support the sizeable, rapid decreases seen in women in age groups that were eligible for vaccination free of charge. The advantage of the ecological design is that it allowed us to assess the herd protection of men.
Although podophyllotoxin is the first-choice treatment of GWs in Denmark, both Imiquimod and cryotherapy are also used to treat GWs. However, cryotherapy is not commonly used for GWs in general practice and Imiquimod is also used to other conditions such as actinic keratosis and basal cell carcinoma. That these treatment modalities were not included might have resulted in a slight underestimation of the number of GW cases throughout the study; however, because podophyllotoxin is the main drug used in general practice, these factors are considered to play a nonsignificant role. A further limitation is that we did not have information about sexual orientation, as the study is based on registries that do not contain this information.
The strengths of this study include the use of comprehensive national registries kept in Denmark. Use of both the National Patient Register and the National Prescription Registry allowed for a large cohort and comprehensive identification of GW cases that included those treated in hospital and in general practice. Moreover, this study has a longer follow-up time than previous Danish studies.6,8
This study shows a significant reduction in the incidence of GWs after implementation of the national Danish HPV vaccination program. The reduction is seen in both women up to 35 years of age and men aged 12 to 29 years, suggesting that HPV vaccination is highly efficient and that herd protection has developed.
1. Bosch FX, Broker TR, Forman D, et al. Comprehensive control of human papillomavirus infections and related diseases. Vaccine 2013; 31(suppl 7): H1–H31.
2. Brendle SA, Bywaters SM, Christensen ND. Pathogenesis of infection by human papillomavirus. Curr Probl Dermatol 2014; 45: 47–57.
3. Garland SM, Steben M, Sings HL, et al. Natural history of genital warts: Analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis 2009; 199: 805–814.
6. Baandrup L, Blomberg M, Dehlendorff C, et al. Significant decrease in the incidence of genital warts in young Danish women after implementation of a national human papillomavirus vaccination program. Sex Transm Dis 2013; 40: 130–135.
7. Blomberg M, Dehlendorff C, Munk C, et al. Strongly decreased risk of genital warts after vaccination against human papillomavirus: Nationwide follow-up of vaccinated and unvaccinated girls in Denmark. Clin Infect Dis 2013; 57: 929–934.
8. Sando N, Kofoed K, Zachariae C, et al. A reduced national incidence of anogenital warts in young Danish men and women after introduction of a national quadrivalent human papillomavirus vaccination programme for young women—An ecological study. Acta Derm Venereol 2014; 94: 288–292.
9. Drolet M, Bénard É, Boily MC, et al. Population-level impact and herd effects following human papillomavirus vaccination programmes: A systematic review and meta-analysis. Lancet Infect Dis 2015; 15: 565–580.
10. R Development Core Team (2012): A language and environment for statistical computing. Auckland: R Foundation for Statistical Computing. Vienna, Austria. ISBN 3-900051-07-0. http://www.R-project.org
. Accessed November 2014.
11. Chow EP, Read TR, Wigan R, et al. Ongoing decline in genital warts among young heterosexuals 7 years after the Australian human papillomavirus (HPV) vaccination programme. Sex Transm Infect 2015; 91: 214–219.
12. Read TR, Hocking JS, Chen MY, et al. The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination programme. Sex Transm Infect 2011; 87: 544–547.
13. Ali H, Donovan B, Wand H, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: National surveillance data. BMJ 2013; 346: f2032.
14. Giuliano AR, Lee JH, Fulp W, et al. Incidence and clearance of genital human papillomavirus infection in men (HIM): A cohort study. Lancet 2011; 377: 932–940.
15. Block SL, Nolan T, Sattler C, et al. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics 2006; 118: 2135–2145.
16. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 2011; 364: 401–411.
17. Canfell K, Chesson H, Kulasingam SL, et al. Modeling preventative strategies against human papillomavirus-related disease in developed countries. Vaccine 2012; 30(Suppl 5): F157–F167.
18. Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: A cost-effectiveness modelling analysis. Lancet Infect Dis 2010; 10: 845–852.
19. Olsen J, Jørgensen TR. Revisiting the cost-effectiveness of universal HPV-vaccination in Denmark accounting for all potentially vaccine preventable HPV-related diseases in males and females. Cost Eff Resour Alloc 2015; 13: 4.
20. Baron J, Beresford P, Gould J, et al. Time to vaccinate boys against HPV infection and cancer, say parliamentarians with special interest in public health. BMJ 2014; 349: g5789.
© Copyright 2016 American Sexually Transmitted Diseases Association
21. Baldur-Felskov B, Dehlendorff C, Munk C, et al. Early impact of human papillomavirus vaccination on cervical neoplasia—Nationwide follow-up of young Danish women. J Natl Cancer Inst 2014; 106: djt460.