Genital warts are one of the most common clinical manifestations of human papillomavirus (HPV) infection. They have been shown to decrease quality of life,1,2 increase psychological distress,3 and create substantial burden on the health care system, costing an estimated $200 million dollars per year.4 Studies conducted before HPV vaccination recommendations have found that the incidence of genital warts is highest among 20- to 24-year-old women (6.2 cases/1000 person-years) and 25- to 29-year-old men (5.0 cases/1000 person-years).5 However, these current estimates come from studies with limited, small samples6–9 or studies that relied on indirect methods to identify genital wart diagnoses from medical claims databases.5,10
The Advisory Committee on Immunization Practices recommends routine use of either bivalent or quadrivalent HPV vaccine for girls aged 11 or 12 years, with catch-up vaccination through age 26 years,11 and routine use of the quadrivalent HPV vaccine for boys aged 11 or 12 years, with catch-up vaccination through age 21 years.12,13 Clinical trials found that quadrivalent HPV vaccine had more than 95% efficacy for prevention of genital warts in females14 and 90% in males.15 Reductions in genital warts will be an early marker of quadrivalent HPV vaccine impact.
In the United States, more complete data are needed on the epidemiology of genital warts among populations targeted by HPV vaccination. Genital wart surveillance is challenging because this is not a nationally reportable condition, and most health systems and administrative databases have nonspecific data on genital warts (typically, diagnostic codes). Using data from Northern California Kaiser Permanente (KPNC), a large integrated health care delivery system that routinely collects detailed genital wart information, we sought to report the incidence of genital warts and describe the specific anatomic location of their presentation among adolescents and young adults before the availability of the HPV vaccine. We also describe repeat visits for, and recurrence of, genital warts.
MATERIALS AND METHODS
This study assessed data from KPNC, an integrated health care delivery system that provides comprehensive medical care for more than 3 million members in 31 clinics and hospitals throughout northern California. Northern California Kaiser Permanente databases include pharmacy, laboratory, diagnostic, and demographic information for all inpatient and outpatient encounters. The study protocol was approved by the institutional review boards at the KPNC, Centers for Disease Control and Prevention, and Yale School of Medicine.
The study sample consisted of a retrospective cohort of females and males continuously enrolled (CE) at KPNC between July 1, 2000, and July 1, 2005, and who were between the ages of 11 and 29 years at some point during the 5-year study period. A greater proportion of individuals who were CE during this period were female (53.4% CE vs. 49.5% non-CE; P < 0.001) and in the 25- to 29-year age group (33.1% CE vs. 24.3% non-CE; P < 0.0001). Individuals with missing sex data were excluded (n = 5). To be included in the incidence calculations, a minimum 5-year interval of continuous enrollment was needed.
Identification of Genital Wart Cases
We identified genital wart cases using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes corresponding to HPV-related genital warts (078.11, condyloma acuminatum) or other/unspecified viral warts (078.10, viral warts, unspecified; 078.19, other specified viral warts). When patients presented with genital warts during out patient, emergency, or urgent care health care visits, KPNC physicians routinely recorded the anatomic locations of diagnosed genital warts in the electronic medical record along with the relevant ICD-9-CM codes. We used an algorithm combining genital wart–specific ICD-9-CM codes with physician-recorded anatomic locations of “genital,” “anal/genital,” “anal/rectal,” “vagina,” “vulva,” “cervix,” “urethra,” or “penis.” Based on the combination of ICD-9-CM codes and physician-recorded anatomic locations, individuals were categorized into 1 of 3 groups that comprised the incidence analysis sample: (1) ICD-9-CM code 078.11 (condyloma acuminatum); (2) ICD-9-CM code 078.10 or 078.19 (unspecified/other viral wart), with a genital wart identifier (i.e., genital-specific anatomic location recorded in the medical chart); or (3) ICD-9-CM code 078.10 or 078.19, with a missing genital wart identifier or nongenital anatomic location. Both items 1 and 2 above were defined as genital warts.
Consistent with previously published literature,5,16 we defined an incident case as a genital wart diagnosis that occurred during the observation period (between July 1, 2000, and July 1, 2005) and was preceded by 12 months with no genital wart diagnosis. Given that most of episodes of care for incident genital warts are 5 months,16 we elected to use a 12-month disease-free interval. We also calculated the number of visits for genital warts that occurred after an incident case and defined a repeat health care visit for genital warts as any outpatient, emergency, or urgent care visit with a genital wart diagnosis that followed an incident case. We defined a genital wart recurrence as a diagnosis of genital warts that occurred at least 6 months after a previous genital wart diagnosis. Recurrent cases could therefore occur between January 1, 2001, and July 1, 2005. We based the definition of recurrence on previously published data describing the natural course of genital warts, which usually take 3 to 6 months to clear.17,18
For calculation of the incidence rate, person-time began accumulating when enrollees were age eligible (i.e. 11 years) and ended when there was a diagnosis of genital warts after a 12-month disease-free interval, with censoring at age 30 years or the end of the study period. We calculated sex- and age-specific incidence rates and incidence rate ratios comparing females vs. males stratified by age group at the time of diagnosis. We compared categorical variables with χ2 tests and distributions of continuous variables with Wilcoxon rank sum tests for nonparametric data. We used SAS 9.2 (Cary, NC) for all analyses.
The study population included 181,264 individuals (53.4% female), with a median age of 21 years. Initially, a total of 2148 individuals were identified as having a potential genital wart (ICD-9-CM code 078.11, 078.10, or 078.19; Fig. 1). Of these, we identified 1682 (78%) individuals with incident genital warts based on an ICD-9-CM code of 078.11 or of 078.10 or 078.19, with a genital wart identifier. Female participants accounted for 73.7% (n = 1240) of the incident genital wart diagnoses. Genital wart diagnoses were assigned by obstetrician/gynecologist providers in 92.7% of women; male participants received the diagnoses predominantly from dermatologists (49.5%) and internists (44.1%; data not shown).
Incidence of Genital Warts
The incidence of genital warts was highest among women aged 20 to 24 years (6.3/1000 person-years) and lowest among boys aged 11 to 14 years (0.04/1000 person-years) (Table 1). In all age groups, the incidence rate was higher in female than in male participants; the female/male incidence rate ratio was highest among persons aged 15 to 19 years (8.6; 95% confidence interval [CI], 5.8–12.6) and lowest among those aged 25 to 29 years (1.4; 95% CI, 1.2–1.7).
Anatomic Location of Incident Genital Warts
Of the 1682 incident genital warts, most (69.8%) had an anatomic site specified, including anus, rectum, urethra, penis, vulva, vagina, or cervix (Table 2). There was a genital wart identifier in 92.7% of female participants and only 8.4% of male participants (Table 2). Most female participants had genital warts on the vulva (63.4%), cervix (21.0%), or vagina (6.5%). The most common identifiable specific location for male incident genital warts was the urethra/penis (5.7%).
Health Care Visits for Genital Warts
Among persons with incident genital warts, 47.9% (n = 808) had more than 1 visit for genital warts. Overall, the number of health care visits ranged from 1 to 22 (Table 3). There were no significant differences in the number of visits between females and males and across age groups. Among all incident genital warts with an identifiable anatomic location, genital warts that presented on the vulva were associated with the greatest number of visits compared with genital warts at any other location (P < 0.001).
Recurrence of Genital Warts
Most people with an incident genital wart diagnosis (87.2%) did not have a recurrence of genital warts during the observation period (Table 3). Of the 1682 people with incident genital wart diagnoses, 10.9% had a single recurrence and 1.8% had 2 to 4 recurrences of genital warts during the observation window. A larger proportion of young adults had recurrent genital warts; 0% of 11- to 14-year-olds had a recurrence and 14.1% of 25- to 29-year-olds had a recurrence.
We describe genital wart incidence and recurrence in a cohort of young persons in a large integrated health care delivery system before HPV vaccine use. In this study, we used a unique and specific method for identifying cases of genital warts and found an overall incidence rate of 2.3/1000 person-years among females and males aged 11–29 years. Similar to other studies,5,10 we found the incidence rate of genital warts to be higher in females than in males.
Previous studies have reported on the epidemiology of genital warts among distinct populations such as university students,6 and few have examined larger populations in general health care settings in the United States.5,10,16 One of the largest studies in the United States to date has been an analysis of the Medstat MarketScan database, which found the incidence of genital warts before HPV vaccination was highest among 20- to 24-year-old women (6.3 cases/1000 person-years) and 25- to 29-year-old men (5.0 cases/1000 person-years). We similarly found that the incidence was highest among 20- to 24-year-old women (6.3/1000 person-years) but, in contrast, found that incidence rates in males also peaked among those aged 20 to 24 years (2.7/1000 person-years). This difference may have been caused by our different method for identifying genital warts, which may underestimate male genital warts because of lack of anatomic recording or fewer visits by men for routine health care, specifically a genital examination. In addition, females had higher incidence rates than did males across all age groups, which may be explained by sexual partner mixing patterns (i.e., young women may have older male partners),19 in addition to differences in health care use.
We found that the vulva was the most common location for genital warts among women. A study of 600 patients presenting with genital warts in Germany found that the warts most commonly occurred on the perineum, followed by the vagina and the vulva.20 Northern California Kaiser Permanente did not have a location qualifier for the “perineum,” and it is possible that these warts may have been coded as vulvar warts. Although we were unable to classify the anatomic location of most warts presenting in males, similar to previous literature,21,22 we found that the penile warts were the most common among the genital warts we could classify.
We found that only 47.9% of enrollees had more than 1 health care visit for genital warts, and 12.8% of enrollees had at least 1 recurrence of genital warts after a 6-month period without a visit for genital warts. Males and young adults had a higher proportion of recurrent genital warts. Existing knowledge about repeat visits and recurrence comes from large administrative claims databases as well as randomized controlled trials of treatment of genital warts.23 One study evaluating claims data, which defined recurrence to occur after a 12-month period without a visit for genital warts, described an average of 3.1 repeat physician visits for each individual episode of care for genital warts.5 Treatment studies, with varying lengths of follow-up, have reported recurrence of genital warts after clinical clearance of disease in 4% to 77% of patients receiving treatment of genital warts.23 We found lower repeat health care visits for genital warts, as well as lower recurrence of genital warts 6 months after their last visit. The reasons for this difference are unclear but could be caused by differences in the definition of recurrence, differences in management of genital warts in this setting, or other reasons. The burden of recurrent genital warts is important because it contributes to increased health care costs and psychosocial impact.
Emerging data suggest that HPV vaccination will have a large impact on the burden of genital warts. For example, in Australia, the proportion of people presenting with genital warts to sexual health clinics rapidly declined24 soon after the 2007 national HPV vaccination program for females aged 12 to 27 years.25,26 Similarly, in the United States, a preliminary analysis of genital warts claims from a large family planning program indicates that the rates of genital warts claims have decreased between 2007 and 2010.27 Future studies will be able to compare postvaccination incidence estimates to our existing data.
This study has several limitations. Our data focus on individuals in a single health care delivery system and therefore may not be generalizable to all populations, such as those with intermittent insurance coverage, public insurance, or no insurance. We were only able to identify genital warts from adolescents and young adults who presented for medical care and therefore may have underestimated the true incidence of disease because some people may choose to forego care or choose to have care elsewhere. An international survey of patients with genital warts found that up to one third of individuals with genital warts did not seek immediate treatment.28 Adolescents and young adults may be more likely than other groups to seek care outside their primary health plan.29,30 We were unable to identify the anatomic location of genital warts presenting in males, perhaps because of differences in specific coding practices across specialties. In addition, the description of the anatomic location of genital warts may be affected by ascertainment bias; in some cases, the physician may have performed a limited clinical examination. As a result of these methods, not every individual in the sample had the same period of observation. We may have underestimated recurrent cases, especially among incident cases that occurred later in the observation period, due to censoring of the data in 2005. Lastly, we did not validate the codes with chart review.
Our study focused on a large cohort of individuals with excellent access to health care, which decreased the likelihood that they would forego medical care. Unlike many previous studies in the United States that used a combination of ICD-9-CM codes, procedure codes, and pharmacy data, which may be nonspecific for genital warts,5,10 we were able to identify genital wart diagnoses using physician-recorded anatomic locations. This novel method for the identification of genital warts allowed us both to have a high level of confidence that our identified cases represented genital warts (rather than nonspecific wart located elsewhere) and to describe the specific anatomic location of genital warts.
These data have important implications for public health practice and clinical care. We found a substantial burden of disease in 20- to 24-year-olds, with a greater incidence rate in women than in men, similar to other studies. This information on genital warts before HPV vaccine introduction provides baseline data that can be used in future evaluations to measure vaccine impact.
1. Scarbrough Lefebvre CD, Van Kriekinge G, Goncalves MA, et al. Appraisal of the burden of genital warts from a healthcare and individual patient perspective. Public health 2011; 125: 464–475.
2. Jeynes C, Chung MC, Challenor R. ‘Shame on you’—the psychosocial impact of genital warts. Int J STD AIDS 2009; 20: 557–560.
3. Wang KL, Jeng CJ, Yang YC, et al. The psychological impact of illness among women experiencing human papillomavirus–related illness or screening interventions. J Psychosom Obstet Gynaecol 2010; 31: 16–23.
4. Chesson HW, Blandford JM, Gift TL, et al. The estimated direct medical cost of sexuality transmitted diseases among American Youth, 2000. Perspect Sex Reprod Health 2004; 36: 11–19.
5. Insinga RP, Dasbach EJ, Myers ER. The health and economic burden of genital warts in a set of private health plans in the United States. Clin Infect Dis 2003; 36: 1397–1403.
6. Partridge JM, Hughes JP, Feng Q, et al. Genital human papillomavirus infection in men: Incidence and risk factors in a cohort of university students. J Infect Dis 2007; 196: 1128–1136.
7. Mao C, Hughes JP, Kiviat N, et al. Clinical findings among young women with genital human papillomavirus infection. Am J Obstet Gynecol 2003; 188: 677–684.
8. Giuliano AR, Lu B, Nielson CM, et al. Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men. J Infect Dis 2008; 198: 827–835.
9. Nielson CM, Harris RB, Dunne EF, et al. Risk factors for anogenital human papillomavirus infection in men. J Infect Dis 2007; 196: 1137–1145.
10. Koshiol JE, Laurent SA, Pimenta JM. Rate and predictors of new genital warts claims and genital warts–related healthcare utilization among privately insured patients in the United States. Sex Transm Dis 2004; 31: 748–752.
11. Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human papillomavirus vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007; 56 (RR-2): 1–24.
12. CDC. Recommendations on the use of quadrivalent human papillomavirus vaccine in males—Advisory Committee on Immunization Practices (ACIP), 2011. MMWR. Morb Mortal Wkly Rep 2011; 60: 1705–1708.
13. 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.
14. 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.
15. 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.
16. Hoy T, Singhal PK, Willey VJ, et al. Assessing incidence and economic burden of genital warts with data from a US commercially insured population. Curr Med Res Opin 2009; 25: 2343–2351.
17. Oriel JD. Natural history of genital warts. Br J Vener Dis 1971; 47: 1–13.
18. 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.
19. Aral SO, Hughes JP, Stoner B, et al. Sexual mixing patterns in the spread of gonococcal and chlamydial infections. Am J Public Health 1999; 89: 825–833.
20. Hillemanns P, Gabrielle Breugelmans J, Gieseking F, et al. Estimation of the incidence of genital warts and the cost of illness in Germany: A cross-sectional study. BMC Infect Dis 2008; 8: 76.
21. Fleischer AB Jr, Parrish CA, Glenn R, et al. Condylomata acuminata (genital warts): Patient demographics and treating physicians. Sex Transm Dis 2001; 28: 643–647.
22. Chuang TY, Perry HO, Kurland LT, et al. Condyloma acuminatum in Rochester, Minn., 1950–1978. I. Epidemiology and clinical features. Arch Dermatol 1984; 120: 469–475.
23. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: Diagnosis, treatment, and prevention. Clin Infect Dis 2002; 35 (suppl 2): S210–S224.
24. Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: Analysis of national sentinel surveillance data. Lancet Infect Dis 2011; 11: 39–44.
25. Garland SM, Skinner SR, Brotherton JM. Adolescent and young adult HPV vaccination in Australia: Achievements and challenges. Prev Med 2011; 53 (suppl 1): S29–S35.
26. Read TRH, 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.
27. 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.
28. Maw RD, Reitano M, Roy M. An international survey of patients with genital warts: Perceptions regarding treatment and impact on lifestyle. Int J STD AIDS 1998; 9: 571–578.
29. Brackbill RM, Sternberg MR, Fishbein M. Where do people go for treatment of sexually transmitted diseases? Fam Plan Perspect 1999; 31: 10–15.
30. Civic D, Scholes D, Grothaus L, et al. Adolescent HMO enrollees’ utilization of out of plan services. J Adolesc Health 2001; 28: 491–496.