Genital human papillomavirus (HPV) infection can cause cancer and anogenital warts (AGW). Of the approximately 40 genital HPV types, HPV types 16 and 18 are responsible for most HPV-related cancers, and types 6 and 11 cause 90% of genital warts. Since 2006, HPV vaccines have been licensed and recommended for girls aged 11 to 12 years with catch-up vaccination through age 26 years in the United States.1,2 Vaccination of boys aged 11 to 12 years and catch-up vaccination through age 21 years was recommended in 2011. The quadrivalent vaccine (4vHPV), licensed in 2006, was highly efficacious in preventing AGWs in prelicensure trials (99% efficacy in female individuals, 89% efficacy in male individuals).3–5 The 9-valent vaccine (9vHPV), licensed in 2014, also showed similar efficacy.6
A variety of efforts are currently underway worldwide to monitor postlicensure effectiveness and population impact of HPV vaccines on associated outcomes. Although of primary importance, measuring vaccine impact on cancer outcomes will likely take several decades given the long interval between infection and cancer diagnosis. Genital warts usually develop within a few months of infection,7–10 and data from countries with high 4vHPV vaccine coverage suggest sizeable reductions in AGWs within the first few years after vaccine introduction.11–14 Ecologic analyses from Australia, where high 4vHPV coverage was achieved (approximately 80%) among girls in the adolescent target age group with high coverage also in the catch-up age group through age 26 years, provide the strongest evidence of vaccine impact on AGW incidence among published data to date, showing both direct effects on AGW among female individuals and herd effects among unvaccinated male individuals.12
Several studies from the United States, where HPV vaccination has been lower than in other countries, report declines in AGW prevalence among female individuals.15–19 A few of these have observed decreased AGW among male individuals because of herd protection from female vaccination.
The objectives of this study were to describe overall trends in incident AGW diagnoses in male and female individuals aged 11 through 39 years enrolled in Kaiser Permanente Northwest (KPNW), and to assess the potential impact of HPV vaccination by comparing AGW incidence trends in the years before and after vaccine introduction. We also assessed incidence trends in other sexually transmitted infections (STIs) and described cumulative HPV vaccination coverage to help better contextualize and interpret the observed AGW trends.
We conducted a retrospective analysis of AGW incidence trends using a longitudinal ecologic study design. We defined incidence as the proportion of persons who had a new AGW diagnosis for each calendar year between January 2000 and December 2016 among those continuously enrolled in the health plan during that calendar year. A segmented regression analysis of interrupted time series was conducted to compare AGW incidence in the prevaccine and postvaccine periods. The vaccine period was defined based on the Advisory Committee on Immunization Practices recommendations for HPV vaccine administration as well as HPV vaccine availability at KPNW. For female individuals, the postvaccine period was January 2007 to December 2016, and for male individuals, it was January 2011 to December 2016. We repeated incidence rate calculations for chlamydia and gonorrhea over the study period to compare incidence rate trends with AGW. We calculated cumulative annual HPV vaccination coverage rates during the study period and stratified all analyses by sex and age.
The study was reviewed and approved by the KPNW Institutional Review Board. Because there was no interaction with participants and the study presented minimal risk, a waiver of informed consent from participants was approved.
This study was conducted in KPNW, an integrated health care delivery system serving approximately 580,000 individuals in Southwest Washington and Northwest Oregon. A common electronic medical record system is used at all KPNW clinics, and comprehensive data from all patient encounters (e.g., demographics, diagnoses, procedures, laboratory tests, and results) are captured in clinical and administrative databases. Using these databases, we identified individuals 11 to 39 years of age with at least 1 calendar year of continuous KPNW enrollment during the study period 2000 through 2016.
Ascertainment of AGW Cases
In KPNW clinics, providers enter text-based diagnoses (diagnosis names) from a drop-down list in the electronic medical record. These diagnosis names are automatically mapped by the health plan to International Classification of Diseases (ICD) codes (Ninth Revision [ICD-9] before October 2015; Tenth Revision [ICD-10] thereafter). Because the ICD-9 codes for AGW are not specific for AGW and include other types of warts (e.g., plantar warts), and our study period spanned the ICD-9/ICD-10 transition date, we identified AGW diagnoses using the diagnosis names rather than coded diagnoses. The specific diagnosis names we identified included the following: “condyloma acuminatum,” “genital wart,” “anal wart,” “penile wart,” “vaginal wart,” and “vulvar wart.” These diagnosis names are not used for inpatient or emergency department encounters or for diagnoses made outside KPNW that are captured by insurance claims; therefore, our capture of AGW diagnoses was limited to those made in outpatient clinics.
To compare incidence trends in AGW cases to trends of other STIs over the same period, we identified persons diagnosed as having gonorrhea and/or chlamydia infections from years 2000 to 2016 using the provider-selected text-based diagnoses. We identified diagnosis terms that included the words “chlamydia,” “chlamydia trachomatis,” “chlamydial,” “gonorrhea,” or “gonococcal” and specified genitourinary sites of infection. We did not identify STI diagnoses made in the inpatient or emergency department setting, or those in insurance claims only.
We calculated the annual AGW incidence by dividing the number of individuals who met the case definition in a calendar year by the number of individuals enrolled in the health plan in that year. We only included the first encounter meeting the AGW case definition per year and excluded persons with an AGW diagnosis before that year. We calculated annual sex- and age-stratified incidence rates for the years 2000 through 2016. Age was determined at the time of AGW diagnosis for cases and at December 31 of each year for noncases, and was analyzed in the following categories: 11–14, 15–19, 20–24, 25–29, and 30–39 years. The same methodology was used to calculate the incidence of individual STI diagnoses during the study period.
We used the segmented regression analysis of interrupted time-series method to estimate the changes in levels and trends in AGW incidence rates that followed the adoption of HPV vaccine.20 This method controls for baseline level and trend when estimating expected changes in incidence resulting from HPV vaccination. The time-series regression equation for this analysis is:
y(t) is the yearly AGW incidence rate. Time is the number of years, starting from year 2000 as 1, and then increasing by 1 for each year thereafter. The study period was divided into 2 segments (prevaccine and postvaccine), and the division differed for female and male individuals based on the timing of the Advisory Committee on Immunization Practices HPV vaccine recommendations and availability of vaccine at KPNW. The prevaccine period was defined as 2000–2006 for female individuals and 2000–2010 for male individuals. The postvaccine period was defined as 2007–2016 for female individuals and 2011–2016 for male individuals. Vaccination is a dummy variable, with the value 0 for the prevaccine period and 1 for the postvaccine period. The prevaccine periods contained some vaccinated individuals, but vaccination uptake was minimal in these periods. Time_post is the number of years in the postvaccine period, with the value 0 for the prevaccine period. e(t) is the random variation at time t not explained by the model. The coefficient β0 estimates the baseline level of the AGW incidence rate. The coefficient β1 estimates the yearly trend in AGW incidence in the prevaccine period. The coefficient β2 estimates the change in the level of AGW incidence in the postvaccine period, that is, the measurement of rate change from the last time point in the prevaccine period to the first time point in the postvaccine period. The coefficient β3 estimates the change in the yearly trend of AGW incidence in the postvaccine period compared with the prevaccine period.
We used the Durbin-Watson statistic to test for the serial autocorrelation of the error terms in the regression models. The error terms of up to 6 years apart were evaluated for autocorrelation. All final models had a Durbin-Watson statistic value close to the preferred value of 2, so we did not need to use additional methods to correct for autocorrelation. The statistical package SAS version 9.4 (SAS Institute, Cary, NC) was used for all analyses. A P value less than 0.05 was considered significant.
HPV Vaccination Coverage
We identified all doses of 4vHPV and 9vHPV administered to cohort members during the study period. Vaccination data were available from both the KPNW immunization registry and the Oregon Immunization Information System. We extracted the date of vaccination for all doses; doses received within 14 days of each other were considered duplicate records, and only the earliest date of receipt was retained in analysis.
For each calendar year, we calculated the number of female and male individuals aged 11 to 39 years who were vaccinated with 1, 2, or ≥3 doses from January 2007 to December 2016. For male and female individuals separately, we calculated the number and proportion vaccinated within each age group and dose stratum. Within each stratum, annual percent coverage was calculated as the total number who had received vaccine divided by the total population within the stratum at the end of the year.
During the study period, 288,145 female and 277,211 male individuals 11 to 39 years of age had at least 1 calendar year of enrollment in the health plan. We identified 2873 female individuals with an incident AGW diagnosis: 1272 with “condyloma acuminatum,” 1590 with “genital warts,” 5 with “vulvar warts,” 2 with “vaginal warts,” and 12 with “anal warts.” We identified 3097 male individuals with an AGW diagnosis: 1303 with “condyloma acuminatum,” 1745 with “genital warts,” 20 with “penile warts,” and 33 with “anal warts.” In both sexes, AGW diagnoses were uncommon in the youngest age group, and AGW incidence was the highest among 20-to 24-year-olds (Table 1).
We observed lower annual AGW incidence rates after HPV vaccination introduction at KPNW (Table 1). The average annual AGW incidence rates in the prevaccine periods were 27.8 per 10,000 in female individuals and 26.9 per 10,000 in male individuals. The average annual AGW incidence rates fell to 19.3 per 10,000 female individuals and 24.3 per 10,000 male individuals in the postvaccine periods. Among 15- to 19-year-olds, incidence decreased 67% from 44.2 to 14.6 per 10,000 in female individuals and 45% from 11.9 to 6.5 per 10,000 in male individuals.
The interrupted time-series analysis also predicted a transition from an increasing to a decreasing trend in AGW incidence after the adoption of HPV vaccination (Figs. 1, 2). We estimated that the average rates of increase in AGW incidence in the prevaccine period were 2.21 cases per 10,000 female individuals per year (95% confidence interval [CI], 1.34–3.07; P < 0.001) and 1.10 cases per 10,000 male individuals per year (95% CI, 0.88–1.32; P < 0.001). Increasing rates of AGW in the prevaccine period varied by age group but were highest among the 20- to 24-year-olds for both women (5.04 cases per 10,000 per year; 95% CI, 2.79–7.30; P = 0.001) and men (3.54 cases per 10,000 per year; 95% CI, 1.77–5.31; P = 0.002).
After HPV vaccination introduction (2007 for female individuals, 2011 for male individuals), the interrupted time-series model predicted a reversal from increasing to decreasing trend in the annual AGW incidence rates. Overall, the changes in the yearly trend from prevaccine to postvaccine periods were −4.96 (95% CI, −5.85 to −4.06; P < 0.001) cases per 10,000 female individuals per year (Fig. 1) and −3.68 (95% CI, −4.30 to −3.06; P < 0.001) cases per 10,000 male individuals per year (Fig. 2). The strongest reversal in yearly trends occurred in 20- to 24-year-olds for both women and men, but reversals also were observed in 25- to 29-year-olds (Table 2).
HPV Vaccine Coverage
Human papillomavirus vaccination initiation and completion rates increased throughout the study period (Fig. 3). By the end of the study period (December 31, 2016), the proportions of female and male individuals younger than 20 years who had received at least 1 dose of HPV vaccination were similar; however, in the older age groups, women were more likely to have received at least 1 dose than men. Three-dose coverage rates were less than 50% in all age groups and both sexes (data not shown). More than 95% of the 30- to 39-year-old women and 25- to 39-year-old men in the population were not vaccinated.
STI Incidence Trends
Among female and male individuals, gonorrhea incidence remained relatively constant throughout the study period (Fig. 4). Rates of chlamydia increased among female individuals starting in 2015. Chlamydia incidence generally decreased in male individuals from 2002 through 2013, but then increased from 2014 through 2016.
In a population of young adults from Oregon and Washington with moderate HPV vaccination coverage, we observed declines in AGW incidence among both female and male individuals after the introduction of HPV vaccination. The declines in male individuals occurred later than that in female individuals and were likely due to both direct and indirect effects of the vaccination program. In both sexes, the largest incidence reductions were observed in 15- to 19-year-olds who were the most likely to be vaccinated. In the segmented regression models, we observed the most pronounced reversals in the increasing AGW incidence trends that were noted in the prevaccine period, among 20- to 24- and 25- to 29-year-olds. The trend reversal in men was likely partially attributable to herd effects from female vaccination because vaccine uptake was low among men 20 years and older during the study period. The declines in AGW incidence were observed during a period when rates of gonorrhea remained consistent and chlamydia rates increased slightly, which suggests that changes in sexual behavior did not impact the observed AGW reductions.
A recent systematic review of HPV vaccine effectiveness and impact studies from the United States reports consistent incidence declines in women younger than 26 years and lower rates of decline among men.21 One large US study described AGW prevalence using insurance claims data from 2006 to 2014 for approximately 35 million 15- to 39-year-olds.18 Similar to our study, the highest incidence of AGW in the prevaccine period was among 20- to 24-year-old women and 20- to 24- and 25- to 29-year-old men. The authors reported reductions in AGW prevalence in female individuals 15 to 29 years of age and in men 20 to 24 years of age, and the declines in men occurred later than those in women. They noted either stable or increasing prevalence in the other sex and age groups. Our findings are similar, but with additional years of data after male vaccination was recommended, we also observed reductions in 15- to 19-year-old and 25- to 29-year-old male individuals.
In the periods preceding HPV vaccine recommendations, we observed increasing AGW incidence in both sexes; similar increases were described in other US studies.21 It is possible that the observed increases in AGW incidence reflect increased awareness and diagnosis of AGWs by providers and increased health-seeking behavior in patients rather than true increases, especially because the incidence of the other non-HPV STIs remained relatively constant in the prevaccine period in our study.
In addition to this study of population impact, we have evaluated HPV vaccine effectiveness at the individual level among young adults from the Northwest, Colorado, and Georgia regions of Kaiser Permanente. We found that HPV vaccine was effective for the prevention of AGW in young women (vaccine effectiveness for 3 doses, 77%; 95% CI, 69%–83%).22 We have also monitored HPV prevalence in several cross-sectional samples of residual liquid cytology specimens at KPNW and have observed decreases in HPV types 6, 11, 16, and 18 (vaccine types) from the prevaccine to postvaccine periods.23,24 Vaccine-type HPV prevalence decreased 78% among 20- to 24-year-olds and 38% among 25- to 29-year-olds in the 10 years after vaccine introduction.24 These prior studies in combination with this longitudinal ecologic analysis suggest that HPV vaccination has reduced vaccine-type HPV prevalence and AGW incidence in the KPNW population despite suboptimal vaccination coverage.
This was an ecologic analysis, so we were not able to adjust for other factors that might have changed during the study period and impacted AGW rates, such as changes in diagnostic practices or sexual behaviors. Our case definition was based on diagnostic terms clinicians in the health plan used during the entire study period, so our AGW case definition was not impacted by the change from ICD-9 to ICD-10 coding in 2015. Our case definition excluded diagnoses from the emergency department, hospital, and insurance claims so we likely underestimated AGW incidence; however, only approximately 6% of AGW diagnoses are made outside the outpatient clinic setting at KPNW (unpublished data). In addition, we calculated STI incidence rates as a proxy measure of sexual behaviors during the period, and we observed consistent rates throughout most of the study period, with increases starting in 2014. This is consistent with other national surveys that have noted recent increases in the incidence of non-HPV STIs.25
In combination with other published studies, this study further demonstrates the population impact of HPV vaccination on the incidence of AGWs in countries with moderate to high coverage. Even with suboptimal uptake of vaccine, AGW incidence is declining in both female and male individuals, especially among those who are in their teens and 20s and are most likely to have been vaccinated. Additional years of follow-up and evaluation are needed to demonstrate vaccine impact in older age groups.
1. Markowitz LE, Dunne EF, Saraiya M, et al. Human papillomavirus vaccination: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2014; 63(RR-05):1–30.
2. Petrosky E, Bocchini JA Jr., Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: Updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2015; 64:300–304.
3. Garland SM, Hernandez-Avila M, Wheeler CM, et al, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:1928–1943.
4. Dillner J, Kjaer SK, Wheeler CM, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: Randomised controlled trial. BMJ 2010; 341:c3493.
5. Giuliano A, 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.
6. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med 2015; 372:711–723.
7. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis 2005; 191:731–738.
8. 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.
9. Arima Y, Winer RL, Feng Q, et al. Development of genital warts after incident detection of human papillomavirus infection in young men. J Infect Dis 2010; 202:1181–1184.
10. Anic GM, Lee JH, Stockwell H, et al. Incidence and human papillomavirus (HPV) type distribution of genital warts in a multinational cohort of men: The HPV in men study. J Infect Dis 2011; 204:1886–1892.
11. Oliphant J, Perkins N. Impact of the human papillomavirus (HPV) vaccine on genital wart diagnoses at Auckland Sexual Health Services. N Z Med J 2011; 124:51–58.
12. 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.
13. 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.
14. Drolet M, Bénard É, Pérez N, et al, HPV Vaccination Impact Study Group. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: Updated systematic review and meta-analysis. Lancet 2019; 394:497–509.
15. Bauer HM, Wright G, Chow J. Evidence of human papillomavirus vaccine effectiveness in reducing genital warts: An analysis of California public family planning administrative claims data, 2007–2010. Am J Public Health 2012; 102:833–835.
16. Flagg EW, Schwartz R, Weinstock H. Prevalence of anogenital warts among participants in private health plans in the United States, 2002–2010: Potential impact of human papillomavirus vaccination. Am J Public Health 2013; 103:1428–1435.
17. Nsouli-Maktabi H, Ludwig SL, Yerubandi UD, et al. Incidence of genital warts among U.S. service members before and after the introduction of the quadrivalent human papillomavirus vaccine. MSMR 2013; 20:17–20.
18. Perkins RB, Legler A, Hanchate A. Trends in male and female genital warts among adolescents in a safety-net health care system 2004–2013: Correlation with introduction of female and male human papillomavirus vaccination. Sex Transm Dis 2015; 42:665–668.
19. Flagg EW, Torrone EA. Declines in anogenital warts among age groups most likely to be impacted by human papillomavirus vaccination, United States, 2006–2014. Am J Public Health 2018; 108:112–119.
20. Wagner AK, Soumerai SB, Zhang F, et al. Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther 2002; 27:299–309.
21. Yakely AE, Avni-Singer L, Oliveira CR, et al. Human papillomavirus vaccination and anogenital warts: A systematic review of impact and effectiveness in the United States. Sex Transm Dis 2019; 46:213–220.
22. Hariri S, Schuler MS, Naleway AL, et al. Human papillomavirus vaccine effectiveness against incident genital warts among female health plan enrollees, United States. Am J Epidemiol 2018; 187:298–305.
23. Dunne EF, Naleway A, Smith N, et al. Reduction in human papillomavirus vaccine type prevalence among young women screened for cervical cancer in an integrated US healthcare delivery system in 2007 and 2012–2013. J Infect Dis 2015; 212:1970–1975.
24. Markowitz LE, Naleway AL, Lewis RM, et al. Declines in HPV vaccine type prevalence in women screened for cervical cancer in the United States: Evidence of direct and herd effects of vaccination. Vaccine 2019; 37:3918–3924.
25. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2017. Atlanta: U.S. Department of Health and Human Services, 2018.