Review
Prevention strategies against human papillomavirus in males

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Abstract

Sexually transmitted human papillomavirus (HPV) infection is very common in men and women. Oncogenic HPV is strongly associated with cancers and high-grade dysplasias of the anogenital tract, including the anus, penis, and also a proportion of oropharyngeal cancers. In reducing male disease burden, some consider screening and treatment for high-grade anal dysplasia (AIN) to prevent anal cancer in high-risk populations. Such strategies have wide implications for the workforce, and require more evidence for the optimal management of AIN.

Male sexual behavior, with consequent HPV infection and disease contribute to considerable disease burden in females. Hence, inclusion of males in prophylactic HPV vaccination programs should prevent HPV-related disease in males as well as substantially reducing disease burden in females. Clinical trial data in males 16–26 years for the quadrivalent vaccine show it is well tolerated, induces a strong type-specific immunological response comparable to that of females, and reduced vaccine HPV-type-related genital infection, as well as disease. Cost–benefit analyses and mathematical modeling show that the most cost-effective strategy involves routine administration of this vaccine to 12-year-old females, with catch-up vaccination of 12- to 24-year-olds, with the most effective strategy in disease reduction including men and/or boys in the program. Such a vaccination strategy including 12-year-old boys is projected by 2050 to reduce HPV 16 infection by 88–94% in females and 68–82% in males, plus the aforementioned male HPV- related cancers by 22–27%. Therefore, inclusion of males in an HPV vaccination program is likely to have significant health and economic benefits over and above those observed from current female-only programs. However, comprehensive cost–benefit analyses are needed to determine the efficacy of these programs in the overall population. Such analyses will be crucial for the design, acceptance, and implementation of these vaccination programs into clinical practice globally.

Introduction

In men, as in women, sexually transmitted human papillomavirus (HPV) infections are very common. In contrast to women however, less is known about the natural history of genital HPV infection and associated lesions in males. The ongoing HPV in Men (HIM) study provides the most current data on HPV infection and lesion development in males [1], [2]. In a sample of 1160 men from Brazil, Mexico, and the United States, aged 18–70 years, from whom swabs were collected from the coronal sulcus, glans penis, penile shaft, and scrotum and tested for HPV DNA detection then genotyping by Roche Linear Array, the overall HPV prevalence was 65.2%, with no significant difference in overall prevalence by age regardless of country examined. Overall of those positive 12% were oncogenic types only, 20.7% non-oncogenic types only, while 17.8% both oncogenic and non-oncogenic. Multiple infections were common, being detected in 25.7%. The most common oncogenic subtype was HPV 16 (overall 6.5%), while of the non-oncogenic genotypes, HPV 6 (6.6%) was more common than HPV 11 (1.5%) [1]. Moreover in a prospective cohort study of 290 men 18 to 44 years with a mean follow-up of 15.5 months, and samples collected every 6 months, infection was common with relatively rapid rates of acquisition and clearance. The 12 month cumulative risk of acquiring a new HPV infection was 29.2%, with a median time to clearance of any infection being 5.9 months [2]. In a further analysis of 2607 men from the HIM study, the overall incidence for development of warts and other genital lesions was 2.5 and 0.6 per 1000 person-months, respectively [3].

While much is known about oncogenic HPVs being the etiological agents of cervical cancer in women, evidence is gathering to show that oncogenic HPVs, particularly type 16, are strongly associated with some anogenital cancers in men. Specifically, HPV has been linked with 90% of anal cancers, approximately 40% of penile cancers, and around 12% of oropharyngeal cancers [4]. In contrast to cervical cancer, these cancers are less common, with penile cancer being rare and constituting less than 1% of all male cancers, and with an incidence rate recorded in Danish men over a 20-year period in the order of 1 per 100,000 [5]. HPV is associated with a proportion of the precancerous high-grade dysplastic lesions of penile and anal intraepithelial neoplasias (PIN and AIN respectively).

To date, economic data have primarily focused on the more common HPV-related cervical cancer and its precursor lesions, as well as the benign, very common condition of genital warts, caused primarily by HPV 6 and 11 [6]. While data on non-cervical HPV disease and other HPV-related conditions are less comprehensive [7], available data indicate that HPV-related disease is associated with a significant economic burden in males [7], [8]. A US-based study of 15- to 24-year olds, conducted in 2000, determined that among the sexually transmitted infections, human immunodeficiency virus (HIV) and HPV accounted for 90% of the total economic burden [8]. Specifically, in men, the total direct cost of HPV infection acquired through to age 24 years was estimated at US$62 million per annum; the comparable figure for women being US$2.8 billion [8]. The more recent study, using an incidence-based approach to evaluate the direct medical costs of non-cervical HPV-related conditions in both sexes, confirmed that non-cervical HPV infection carries a substantial disease burden [7]. Lifetime cost per case estimates (expressed in 2003 values) were calculated using available secondary data. In HPV-related conditions affecting males, the highest total lifetime costs associated with all new cases occurring over a 1-year period were attributed to anogenital warts (US$171 million, Table 1), followed by anal cancer (US$92 million, Table 1), juvenile onset recurrent respiratory papillomatosis (US$82.2 million, Table 1), mouth/oropharyngeal cancer (US$38 million, Table 1), and penile cancer (US$4.4 million, Table 1).

Prior to the introduction of the prophylactic quadrivalent HPV vaccination program in Australia, a retrospective audit of Australian sexual health clinics demonstrated that in individuals aged 18–45 years, the diagnosis and treatment of external genital warts constituted a significant economic burden in these specialist clinics [9]. The median age at presentation was 26.8 years for men and 23.2 years for women. In addition, a quarter of the patients had another sexually transmitted infection at presentation.

Yet, in Australia, only 17% of patients seek treatment from sexual health clinics. However in a recent analysis of incidence and health-care resource utilization associated with genital warts treatment within the primary care sector, using data from a nationally representative general practice database, the true burden of disease associated with genital warts has been described in Australia prior to the HPV vaccination program [10]. This report describes an annual incidence of 2.19 cases of genital warts per 1000 Australians (95% confidence interval [CI], 1.88–2.49), with a peak incidence in women aged 20–24 years at 8.61 cases per 1000 and in men aged 25–29 years at 7.40 cases per 1000. The annual cost of management of genital warts was estimated at over A$14 million, with an estimated cost per treated case of A$251 for men and A$386 for women, showing that genital warts impose a large health and cost burden on Australians [10]. A cross-sectional study conducted in Germany reported that considerable costs are associated with the treatment of genital warts [11]. In men, the mean annual total direct cost of genital warts was EUR 315.46 per patient for new cases and EUR 115.57 per patient for recurrent cases.

Studies on the psychosocial effects of HPV-related disease in males are lacking. However, there is a significant psychosocial burden reported in women being screened for, or diagnosed, with HPV-related disease [12], [13]. In one study in Australia, women diagnosed with external genital warts had a comparable burden to women receiving ablative therapy for high-grade cervical intraepithelial neoplasia [12].

Thus, there is increasing evidence that HPV infection and HPV-related disease sequelae in males are associated with a considerable burden of disease. This is apart from the male's role in sexual transmission of HPV to females. The inclusion of males in an HPV vaccination program is therefore likely to produce significant health and economic benefits over and above those observed from current female-only vaccination programs.

In developed countries with high-quality cervical cytological screening programs, with high coverage of the appropriate target population, prevention of cervical cancer has been very effective, as shown by the reductions in incidence as well as in mortality. Even then, as cervical cytology has a low sensitivity, the success of the programs has been due to the frequency of repeated Papanicolaou (Pap) smears plus the length of time it takes for precancerous lesions to progress to cancer (often several decades). Furthermore, in countries where Pap screening cytology is of poor quality, rates of cervical cancer remain high [14]. Therefore, once prophylactic HPV vaccines achieve high coverage, there will be a notable reduction in precancerous lesions, with a concomitant reduction in the positive predictive value of cytology and the need of a more sensitive assay for cellular abnormalities such as HPV DNA detection.

For male HPV-related disease, there is no counterpart to cancer of the cervix, whereby 100% of a particular cancer is caused by a virus. Moreover, penile cancer is rare, and screening for PIN is not warranted.

Given the greater risk and incidence of anal cancer, and the recognition of progression of high-grade anal intraepithelial neoplasia (AIN 2/3) to anal squamous cell carcinoma in HIV-positive men who have sex with men (MSM) [15], [16], some clinicians are recommending screening for AIN in HIV-positive MSM and possibly HIV-positive women (and possibly those with other immunocompromised states such as transplant recipients) [17] using anal cytology, high-resolution anoscopy (HRA), with directed HRA biopsy for definitive diagnosis.

A recent study in a small community-based sample of MSM who had a high prevalence of HPV infection and precancerous anal lesions, confirmed that cytological screening may be the best approach to identifying AIN in an at-risk population [18]. The cost effectiveness of anal cancer screening is only now being considered; in a recent report of HIV-positive MSM, the direct use of HRA was the most cost-effective strategy for detecting AIN 2/3, as compared with no screening, abnormal anal cytology followed by HRA, or a positive oncogenic HPV test followed by HRA [19].

However, implementing such screening strategies requires cytologists trained in anal cytology, clinicians trained in HRA, as well as appropriate treatment and follow-up of AIN 2/3. In addition, some ablate AIN 2/3 when it is diagnosed, while others keep it under careful surveillance. [15], [16], [20] As there are divergent views with respect to screening for and management of AIN 2/3, appropriate guidelines for care are required.

If male vaccination were to become routine, the effect of such a vaccination strategy would need to be confirmed by monitoring of ongoing registries (vaccine, cervical cytology, various cancer registries for HPV-related diseases). A first long-term national surveillance in Australia studying the effects of the national HPV vaccination program (government funded and targeting girls 12 to 13 years of age with an initial 2-year capture program to 26 years of age) on the incidence of genital warts in the population is currently ongoing (N. Franklin, personal communication). The interim Australian estimates of the coverage of an Australian school-based vaccination program with the quadrivalent vaccine that was started in April 2007 revealed that, in the first year, the coverage was 75–80% (three doses) [21]. By the end of 2008, the bivalent vaccine had also been approved for use in this program. By May 2009, over 5 million doses of the quadrivalent vaccine had already been distributed in Australia. Recently published is the retrospective review of new cases of genital warts being seen in the Melbourne Sexual Health Clinic, whereby since the introduction of the national program for young women, irrespective of their vaccination status, the proportion of women under 28 years with warts diagnosed decreased by 25.1% (95% CI 30.5% to 19.3%) per quarter in 2008, but not in women over 28 years of age. Of note, since 2008 there has been a significant decline in genital warts in heterosexual men suggesting a herd immunity effect [22].

There is significant debate surrounding the issue of whether male circumcision is an effective method for HPV prevention in males. In 2002, Castellsagué et al. demonstrated that circumcision is associated not only with a reduced risk of penile HPV infection, but also a significant reduction in the risk of invasive cervical cancer in women whose partners are circumcised [23]. Pooled data from 1913 couples indicated that rates of penile HPV infection were 5.5% in circumcised versus 19.6% in uncircumcised males. Monogamous females whose circumcised male partners had at least six sexual partners, had a 58% lower risk of cervical cancer than women with uncircumcised partners [23].

More recent studies lend weight to the increasing body of literature indicating that there is a significantly reduced prevalence of HPV in circumcised males [24], [25]. In over 5500 males aged between 14 and 49 years, the prevalence of high-risk HPV genotypes was 18% in circumcised males versus 27.9% in non-circumcised males (p = 0.009) [24]. These findings were confirmed by an analysis of 1158 men aged 18–70 years enrolled in the HIM study, which determined that circumcision was associated with reduced risk of HPV detection across all categories of HPV evaluated [25]. Circumcision was associated with a 30% and 37% reduction in the risk of oncogenic and non-oncogenic infection, respectively [25]. On the basis of available data, Giuliano et al. speculated that circumcision may influence HPV DNA detection by altering the rates of HPV persistence or the duration of HPV infection [25].

However, a 2007 meta-analysis examining the relationship between circumcision and HPV infection concluded that the medical literature does not support the claim that circumcision reduces the risk of genital HPV infection [26]. Sixteen articles contained data on circumcision status in patients with and without HPV infections; eight of these studies used accurate diagnostic methods. Only three articles satisfied the strict inclusion criteria. In these three studies, there was no significant association between circumcision status and HPV infection (odds ratio, 1.20; 95% CI, 0.80–1.79). If the eight studies using accurate diagnostic methods were adjusted for the method of determining circumcision status and failure to sample the penile shaft using meta-regression, the summary effects odds ratio is 1.25 (95% CI, 0.95–1.67).

A possible explanation for these contradictory findings is the sampling methods used in these studies [27]. Specifically, the evaluation of multiple sites increases the likelihood of HPV DNA detection, particularly among circumcised men. The penile shaft appears to be of particular importance; failure to obtain samples from sites such as the penile shaft and scrotum may markedly reduce the number of HPV infections detected amongst circumcised men [27].

A very recent systematic review and meta-analysis of 18 studies involving a total of 6778 circumcised and 5181 uncircumcised men found that male circumcision was not only associated with a statistically significant risk of detecting penile HPV, but also of HPV-related lesions [28]. This meta-analysis showed a consistent and robust inverse association between being circumcised and the detection of penile HPV, suggesting a protective effect of circumcision on HPV infection, with an overall odds ratio of 0.62 (95% CI, 0.47–0.81) [28]. Furthermore, in another study of a longitudinal cohort of 445 men, where 2-monthly samples and questionnaires were obtained, while there was no difference in acquisition of HPV infection by circumcision status, there was a significant increased risk of HPV persistence, particularly in the glans of uncircumcised men. Persistent HPV infection in men who are uncircumcised may increase the risk of transmission to their sexual partners as well as the risk of development of HPV-related disease in them is selves [29].

Section snippets

Vaccine efficacy in males

An established body of data demonstrates that male HPV infection significantly contributes to infection and cervical disease in women [30], [31], [32], [33]. These findings have led to the question of whether young males should also receive prophylactic HPV vaccination. In addition to preventing HPV-related disease in men, vaccination of males is expected to substantially reduce the disease burden in women.

In 270 healthy young males, aged between 10 and 18 years, a phase I/II study utilizing

Conflict of interest statement

SMG has received advisory board fees and grant support from Commonwealth Serum Laboratories and GlaxoSmithKline, and lecture and consultancy fees from Merck and Co. SMG reports having previously owned stock in Commonwealth Serum Laboratories. SMG has received grant support through her institution from Merck and Co and GlaxoSmithKline [GSK] to do clinical trials for HPV/cervical cancer vaccines.

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