Systematic review of the incidence and prevalence of genital warts

Anogenital human papillomavirus (HPV) is the most frequent sexually transmitted viral infection in the world, which can result in malignant cancers or benign skin and mucosal tumors, including anogenital warts (AGWs) [1]. AGWs are categorized as a clinical anogenital HPV infection because they manifest as visible lesions, namely as single or multiple papules on the vulva, perineum, perianal area, vagina, cervix, penis, anus, scrotum and urethra [1]. Clinical symptoms may include pruritus, burning, vaginal discharge and bleeding [2]. Four distinct sub-types of AGWs have been described: condylomata acuminata (pointed warts), flat / macular lesions, papular, and keratotic lesions [1]. The first two sub-types are mainly found on moist, non-keratinized epithelia, while the latter two usually present on keratinized epidermis [1]. AGWs are also often referred to as genital warts, condylomata acuminata or genital verruca, although strictly speaking the first two terms are subsets of the AGW category.

HPV 6 and 11 account for the majority of AGW cases [1, 3–5]. AGWs are highly infectious; approximately 65% of individuals with an infected partner develop AGWs within 3 weeks and 8 months [6]. In rare cases, AGWs can be associated with malignant lesions, namely Buschke-Lowenstein tumors [5]. Recent prospective studies reported that the median time between infection with HPV types 6 or 11 and the development of AGWs was 11 to 12 months among males [7, 8] and 5 to 6 months among young females [9]. Although there are no severe health implications or mortality associated with AGWs, there are significant psychosocial issues which often ensue [10, 11].

Treatment options include patient-applied (home-based) chemical treatments (podofilox, imiquimod), physician-applied (office-based) chemical treatments (podophyllin, trichloracetic acid, interferon, green tea extract [12]) and ablative treatments (cryotherapy, surgical removal, laser treatment) [13–16]. The main limitation of current therapies is the high recurrence rate after initial remission [15, 17, 18]. The quadrivalent HPV vaccine demonstrated high efficacy in preventing the onset of HPV 6/11-related AGWs in both males [19] and females [20].

Although AGWs rank among the most frequent sexually transmitted diseases (STD) [21, 22] the epidemiology of AGWs is not well characterized. A recent review by Scarbrough and colleagues reported the epidemiology of AGWs only in the USA, UK and France [23]. Syrjanen and colleagues evaluated the clinical burden of HPV 6 and 11 infections in Finland, including AGWs [24]. Other reviews summarized the epidemiology associated with HPV infections in general (including genital warts, oropharyngeal cancer and ano-genital cancers such as vulvar, vaginal, anal and penile cancers) [5, 25, 26]. Although providing important data, the primary focus of these reviews was not AGWs. Given the lack of systematic reviews focusing on the epidemiology of AGWs in the literature, the objective of this study was to review the recent published literature on the global epidemiology (incidence and prevalence) of AGWs in the general adult population.

AGWs are a common manifestation of an HPV infection, particularly among young men and women. Reported annual incidence rates typically range between 100 and 200 new cases per 100,000 general adult population based on retrospective administrative databases, medical chart reviews and prospectively collected physician reports. AGW prevalence estimates typically range between 0.13% and 0.20% among these studies. There were also no marked regional differences observed in the incidence and prevalence of AGWs. These methodological approaches cover large populations; however, they can only capture AGW cases among patients seeking care in their respective healthcare systems. Studies which are based on genital examination of general population samples are less dependent on healthcare seeking behavior and tend to report comparatively higher prevalence estimates (ranging from 1% to 5%). However, prevalence data for males based on genital examinations of asymptomatic individuals are quite limited because, unlike females who routinely visit their gynecologists, males usually seek consultation with a reproductive specialist (i.e. urologists) if they present symptoms. Given these data limitations, our review includes a Mexican study of males seeking vasectomies in public clinics [45] and a prospective HPV epidemiology study of heterosexual males [8], populations, although not strictly general, may approximate the general male population.

The specialty of the physicians most frequently performing the initial diagnosis of AGWs varies depending on the healthcare system of individual countries, which could contribute to the differences in reported AGW incidence rates across studies. According to national database studies in both the US [36] and Germany [34], most females visited their gynecologists, while males consulted primarily dermatologists. In the United Kingdom, both males and females were most frequently diagnosed in genitourinary clinics [38, 40]. In the Netherlands, individuals with AGWs are usually diagnosed by general practitioners [39].

Patients who contract AGWs may have a limited capacity to recognize them or be unwilling or unable to seek treatment. This may be due to a variety of psychological and social reasons, both of which could explain why prevalence estimates tend to be higher among studies based on genital examination. The Multicenter AIDS Cohort Study, including men both with and without HIV infection, found that, of men with external AGWs diagnosed by a trained clinician, only 38% reported having genital warts [62]. Similarly, one study among heterosexual men who denied a history of genital warts reported that on clinical examination, 4.1% of them had visible warts on genital sites [44]. With respect to healthcare seeking behavior, one survey among males and females with AGWs across Canada, France, Germany, the UK, and the USA observed that one third of respondents delayed seeking healthcare hoping that the warts would clear without treatment or thinking that the problem was not serious [11]. Spontaneous remission of AGWs is possible, but the reported proportions of individuals who actually experience spontaneous clearance vary widely from 0% to 50% [13, 18]. Furthermore, there is a lack of a published systematic analysis of this issue. A Canadian study reported that the median delay between the time patients first noticed they had AGWs and their first visit to a healthcare provider was 76 days for men and 30 days for women [63]. Obviously, all individuals participating in these studies eventually contacted the healthcare system for their condition [11]. Thus, the true number of individuals being aware of having AGWs but never seeking healthcare would be difficult to estimate. In this context it is interesting to note that in studies based on medical or administrative records, AGW incidence rates tend to be higher among males than females; however, in population-based surveys, consistently more females than males disclose a history of AGWs [53, 55–57].

Potential changes in treatment-seeking behavior could explain recent increases in AGW incidence, observed by several European and North American studies [31, 32, 36, 39, 54]. However, to our knowledge, there is little evidence that such changes occurred in the time periods analyzed. According to one study, younger women in Denmark, Sweden, Norway and Iceland tended to report higher numbers of sex partners than older birth cohorts, and lifetime number of sex-partners was a strong correlate of self-reported AGW history [54]. Thus, changes in sexual behavior may potentially contribute to increased AGW diagnoses reported in some studies.

The epidemiological data consistently confirms that AGW incidence peaks in young males and females, corresponding to the age of peak rate of new partner acquisition [64]. The earlier peak among females than males could be related to sexual mixing patterns, as younger females tend to have older male sex partners [64, 65], or, possibly, to shorter incubation times in females [7–9], although directly comparative data is currently not available. A UK study reported that among AGW patients, the loss of quality of life was greatest for women in the youngest age group (16-19 years) [66].

The annual incidence of recurrent AGWs ranged between 47 and 163 cases per 100,000 males and between 23 and 110 per 100,000 females in population-based studies [28, 29, 37, 38, 43]. Although some of the variation may be due to differences in case definitions, particularly with respect to the length of symptom-free interval for an episode to be counted as recurrent, this finding nevertheless highlights the high burden of recurrent disease. Recurrence rates observed in clinical trials of AGW therapies range widely among studies and treatments, from 9% to 80% [13, 14, 16, 18]. One retrospective analysis including 289 patients attending an STD clinic in Copenhagen, Denmark, reported that 65% of the patients had at least one recurrent AGW episode [67].

The high incidence of AGWs and the substantial economic and psychosocial burden of this condition and its treatment [68] indicate that it would be more beneficial to prevent rather than treat AGWs. The Centers for Disease Control and Prevention (CDC) recommend several options to reduce the risk of contracting AGWs including the correct and consistent use of condoms and altering sexual behavior by limiting the number of sexual partners [69]. The CDC also recommends the currently licensed quadrivalent HPV vaccine [69], which has shown high prophylactic efficacy against HPV 6/11-related genital warts in females [70] and males [19].

There are limitations to our study. One of them is our focus on peer-reviewed literature published in the last 10 years. This limitation was a consequence of the large scope of this review that intended to comprehensively capture the epidemiology of the disease, while being global in nature and rigorous in data extraction and analysis. Other limitations stem from gaps in the literature. Despite the substantial literature available on the epidemiology of AGWs, they are a notifiable disease in the UK only, which provides extensive incidence data [10]. However, there is limited epidemiological data for certain European countries, particularly Eastern Europe and little data from other regions of the world, such as Africa, Latin America and Southern Asia.

Further, some incidence rates have to be interpreted with caution because of variations in the methodologies and age ranges of study populations across the studies included. Some studies included AGW patients of all ages, whereas others only evaluated an age range that represented a more sexually active population (e.g., age 14 to 64). The latter can overestimate the reported incidence rate as is demonstrated by the data of Hillemanns and colleagues [37]. In this study, the incidence of any AGWs was 149 per 100,000 women aged 14 to 65 years compared to 99 for the entire female population [37]. Furthermore, Kraut and colleagues noted that in Germany the incidence was highest in the city states of Hamburg, Bremen and Berlin compared to other, less urbanized German regions [34]. If the same were true for Asia, the incidence reported from Hong Kong [30] and from the six largest metropolitan centers in South Korea may not be applicable country-wide [46]. An Italian study [41] reported AGW incidence rates in males and females that where substantially below the ranges reported by other studies, possibly because it only captured AGWs diagnosed by GPs excluding AGWs diagnosed by specialists (e.g., gynecologists, dermatologists). Similarly, a Quebec study reporting AGW incidence among individuals covered by the public drug plan may overrepresent the elderly population and underestimate this rate among the younger, working population, which is usually covered by private drug plans [31]. Nevertheless, this review provides a comprehensive description of the epidemiology of AGWs based on the available published literature.

AGWs are common in both males and females across the world but data is limited, partially because, in contrast to some other STDs, their reporting is not mandatory. Further population-based studies are required to arrive at a more accurate representation of the global epidemiology of AGWs, to help policy makers make informative decisions about adopting effective treatment and preventative practices.