Question no. 1: What is the impact of HPV-related diseases in males?

A) Prevalence of the infection [3] – Grading = 2++

In a systematic review by Dunne et al. on prevalence of HPV in men [3] it was found to be as high as 72.9%; and the median probability of transmission per sex act was around 40%;. Table 2 reports the results of prevalence studies in which the polymerase chain reaction (PCR) was used to detect the presence of the virus in multiple samples collected from different anatomical sites that were deemed to be most suitable for the purpose (e.g. the glans, sulcus and scrotum). The study populations varied, and included the general population (workers, students), patients attending STD clinics, healthy participants, and the partners of women with HPV-related diseases (CIN1+). Studies that didn’t took into consideration partners HPV positivity and which included university students, military recruits, and healthy, sexually active males, prevalence ranged between 6%;–45%;. The mean prevalence of positive tests in the partners of women with cervical intraepithelial neoplasia (CIN) lesions was higher (50–70%;), whereas among males recruited at clinics for sexually transmitted diseases (STDs), the prevalence of positive tests was around 45%;. One of the most recent and significant studies, in terms of population sampled, conducted by Giuliano et al. [6] included 1.160 men in three countries, reporting a total prevalence of 65.2%; HPV positivity. Although not a review, this study alone, adds more subjects than all previous studies placed together, making it one of the most statistical significant studies on the subject.

B) The prevalence of infection by age [6] – Grading = 2+

Table 2 Main prevalence studies conducted using the PCR method Full size table

In males, the prevalence of HPV does not differ significantly among age group as it does in females [6]. Indeed, prevalence in males remains high (50–70%;) throughout their lifetime, without any substantial decline with age. In contrast, in women, the prevalence curve is consistently bimodal (with some geographical variability): there is a peak after first sexual intercourse up to the age of 25–30 years, followed by a decline up to the perimenopausal age, when a second peak is often observed [24]. This pattern has been observed in Italy too, according to an epidemiological study conducted in Turin [25]. In the Turin study, the first peak of HPV prevalence corresponded to 13–14%; (with a manifestation occurring up to the age of 39 years), after which the prevalence decreased to 5%; at the age of 45 years and then increased to 8%; during the perimenopausal period. Another important difference between males and females is the probability of acquiring an HPV genotype that is associated with a high risk (HR) or a low risk (LR) of oncogenicity (HR-HPV and LR-HPV, respectively). Women seem to have a higher probability of acquiring an HR-HPV [26], whereas the probability of acquiring the two types of HPV appears to be similar in males (the 24-month cumulative incidence was 47.9%; for HR vs 46.6%; for LR) [27].

C) Incidence and clearance of the infection [27] – Grading = 2+

The natural course of the disease has not been investigated properly in males from an epidemiological point of view, namely, by establishing rates of acquisition and time to clearance of HPV infection. A few prospective studies have estimated the probability of acquiring the infection for heterosexual males. In a population of 290 male participants aged between 18 and 44 years (of whom 88%; claimed to be heterosexual), who were followed up for a mean period of 15.5 months [27], the overall prevalence of HPV infection (any genotype) was 30%;, the period prevalence (positive test at any time in the study) was 52.8%;, and the incidence of infection amounted to 29.4 per 1,000 person–months. The incidence of new infections, as measured in males with a negative HPV test at recruitment, was 42.3 per 1,000 person–months. Using Kaplan–Meier survival curves, it was estimated that the rate of acquisition of new infections was 29.2%; over 12 months (19%; for HR-HPV vs 16%; for LR-HPV), and the rate of acquisition of the HR genotypes 16 and 18 (5.1%; of new infections) was higher than that of LR genotypes 6 and 11 (3.4%; of new infections). The mean clearance time (defined as the time to elimination of 50%; of all infections) was estimated to be 5.9 months (95%; CI: 5.7–6.1). HPV DNA was no longer detectable in 75%; of infected subjects 12 months from onset of the infection, without any differences between HR-HPV and LR-HPV, after 5.9 months [27].

The study by Partridge [27], which was conducted in a population of 240 male university students aged 18–23 years, yielded a prevalence of 25.8%; and estimated a cumulative incidence at 24 months of 62.4%; (95%; CI: 52.6–72.2) for all HPV genotypes. The incidence of HR-HPV and LR-HPV genotypes was similar (approximately 48%;). The glans, the shaft of the penis, and the scrotum had the same probability of being infected (44%;); whereas the positive test rate of urinary samples was much lower (7–8%;) [27].

D) HPV-related diseases in males

The HPV-related diseases that occur in males are genital warts and cancers of the penis, anus, oral cavity, and oropharynx (carcinomas of the head and neck).

➣ Anogenital warts [7, 28, 29] (grading = 2–, 3, 2+, respectively)

In most cases (90%;), anogenital warts are caused by HPV genotypes 6 and 11 [7]. In Italy, the HPV infection and genital warts is not subject to mandatory reporting, according to an investigation at 12 STD centres attended by a high-risk population, genital warts were diagnosed in 33%; of subjects, 73%; of whom were male. The mean age and standard deviation (SD) of the male population was 33.6 (±11.0) years, whereas the mean age (SD) of the female population was 30.9 (±10.9). The distribution by age bracket showed that the proportion of anogenital warts was higher in the 14–25-year age group than in the older age brackets, in both males and females. In Italy, genital warts in STD clinics showed that in males, 89.9%; of anogenital warts were diagnosed in self declared heterosexual men and 10.1%; in self declared bisexuals or homosexuals [28]. Data showed that in Italy through STD clinics, genital HPV infections is the most diagnosed STI in Italy, this study is important as it is the only study on genital warts incidence as it is not a reportable disease. Genital warts show a high spread among young people both in males and females.

Having ≥ 2 sexual partners in the last 6 months (reported by 50.3%; of males) and the presence of other concomitant STDs (recorded in 17.1%; of males) were risk factors [28]. In a study conducted in Italy in 2008, it was estimated that the number of cases of anogenital warts per year in women aged between 14 and 64 years was approximately 120,000 (with a prevalence that corresponded to 0.6%;) [28, 29].

➣ Cancer of the penis [30–32] (grading = 2–, 2–, 2–, respectively)

Cancer of the penis is a rare tumor in Western countries. It has been estimated that around 1,000 cases of HPV-related cancer of the penis occur in Europe every year. HPV DNA is detected in approximately 40–50%; of all cases of cancer of the penis, and seroepidemiological studies have shown that the main genotypes involved are HPV 16 and 18 [30–32]. No studies are available in Italy.

➣ Cancer of the anus [33, 34] (grading = 2–, 2–, respectively)

The HPV virus is detected in 80%; of cancerous lesions of the anus, and genotype 16 is the subtype that is involved most commonly (87%;). In the USA, the incidence of cancer of the anus increased considerably between 1970 and 2000. Its incidence is particularly high in homosexual males and the risk is increased even further in the presence of human immunodeficiency virus (HIV) infection. It has been estimated that, in Europe, something like 2,000 cases of cancer of the anus occur in males every year [33, 34].

➣ Carcinomas of the head and neck [16] (grading = 2–)

The overall prevalence of HPV DNA in carcinomas of the head and neck is approximately 26%; and it reaches a peak of 36%; in cancer of the oropharynx. HPV-16 is the genotype involved most commonly (60–80%;). Furthermore, a significant association has been found between HPV in the oral cavity and sexual habits [16].

E) HPV and fertility [35–38] – Grading = 3, 3, 2–, and 3, respectively

Preliminary studies show not only that HPV is present in semen, but that it might reduce sperm motility probably causing reduced fertility in males. Moreover, the virus might interfere with the development of the embryo in animal models according to some studies [35–38]. HPV might be a cause of infertility, even so, further studies are needed in order to clarify its relationship with fertility.

F) Diagnosis of HPV in males [39–41] – Grading = 2+, 2++, 2–, respectively

At the moment, there is no generally accepted and validated test for screening HPV in males in the clinical practice. However, there is a general consensus on when diagnostic testing should be performed, which may be summarized as follows [39–41]:

1. When the patient has a partner who is HPV positive or has an HPV-related disease; 2. When HPV-related clinical manifestations are present; 3. When the patient has sex with men.

At present, molecular methods are used most commonly, both to detect infection and to identify the virus genotype. The tests are based on amplification methods (PCR) with hybridization [42]. Cell samples for the HPV test may be collected from multiple sites (penis shaft; balano-preputial sulcus; glans; navicular fossa of the urethra; scrotum; the pubic, perianal, and anal areas; the oral cavity; the oropharynx; and the larynx), possibly from suspicious lesions [31, 43].

For males, a test that identifies not only HR-HPV but also LR-HPV and genotypes associated with intermediate risk or that have not been classified yet would be useful, because it may enable differential diagnoses to be made between benign and malignant lesions and those related or not related to HPV (e.g. molluscum contagiosum) [44–46].

G) Follow-up of male patients with HPV-related diseases [47, 48] – Grading = 4, and 1 (according to the Guidelines of the Italian Society of Virology)

The following investigations are suggested for the follow-up of HPV-related diseases:

➣ According to the site involved, benign lesions should be checked clinically with genitoscopy and/or anoscopy every 4?months for the first year, as appropriate. Molecular analysis to screen for HPV should be carried out with the same frequency;

➣ In subjects at risk (those with neoplastic lesions or with a history of HPV-related neoplasias), testing for HPV DNA should be carried out every 4 to 6?months;

➣ In subjects with a greater risk of infection and disease development (immunodepressed, HIV-positive and/or homosexual subjects), testing for HPV should be carried out every 8 to 12?months;

➣ In asymptomatic HPV-positive subjects, laboratory follow-up is recommended after 8 to 12?months to assess the persistence or clearance of the infection and to check whether any lesions have developed.

Question conclusions

According to the answers given by the SC, Impact of HPV-related diseases seem to be high in males. Not the same burden as in women for high risk HPV types related lesions but more when taking into account only low grade HPV related lesions such as genital warts. Prevalence seems to be higher than in women irrespective of age and no standardized HPV test guidelines are recommended as in women. Preliminary fertility studies in men seem to show that HPV might have an important role, more studies and data need to be done in order to prove HPV relation with fertility.

Conclusive considerations of the consensus panel

➣ More prevalence studies in males should be conducted. In Italy, notification of HPV related diseases such as genital warts are not mandatory, more epidemiological data is needed in order to evaluate disease impact.

➣ More scientific studies should be made about data on the standardized collection of biological samples and method of testing used for HPV detection in males in order to implement in the future standard recognized sampling and diagnostic tests in eventual prevention and screening programs.

➣ Further research on the issue of HPV and fertility worldwide is required in order to fully understand if it is related and affected by HPV and in what measures HPV vaccination might reduce this.

Question no. 2: What role does a positive test for HPV infection in a partner play in the problems associated with HPV-related diseases?

A) Transmission potential of the virus [1, 2, 27, 49] – Grading = 2++, 2++, 2++, and 2+, respectively

HPV is a highly contagious virus that is widespread in the environment. It is transmitted mainly through sexual contact. However, indirect secondary modes of transmission also exist (contact of skin with skin, hetero-inoculation mediated by the hands, contact with underwear or inanimate objects) [1, 2, 27, 49]. To assess the role that males might have in the transmission of HPV to female partners, studies on couples appear to be more relevant than population studies. Interestingly enough, most studies are focused on long term relationship, or relationships on which the female partner is affected of an HPV lesion such as CIN, little is known about recently established relations at an early age, that can help understand HPV dynamics, natural history and transmission models in young couples. HPV concordance data is variable throughout different studies. In Studies conducted in couples that had a mean duration time of 10 years of relationship, concordance of at least one HPV type in couples that were both positive for HPV was of 57.8%; [21] which is more prevalent than expected by chance, other studies conducted in Italian couples, demonstrate also high HPV concordance in infected couples of around 45%; [50]. Both studies show high HPV infection rates irrespective of HPV type, especially when the female partner is already infected, concordance rates might be important to understand transmission dynamics that are important for persistent infections and development of lesions. In recently established couples, according to Burchell et al., the rate of HPV infections was around 64%;, of which concordance was found in 41%; of the heterosexual couples [51], even in a young recently made couple (aged 18–24) HPV infection and concordance was higher than expected by chance. In time new most newly made couples will probably clear infection, even so high prevalence and concordance with time, like in long term relationships, might explain persistent infection dynamics and explain in part increased lesion development risks. Genotype concordance in couples could depend on several variables: behavioural variables (frequency, type, duration of sexual contact and protection measures), biological variables (different susceptibilities and clearance abilities of tissues in the two genders), and probably others that have not yet been identified.

B) Transmission dynamics [50, 52–54] – Grading = 2–, 2++, 2++, and 2+, respectively

Transmission of the virus from one partner to another varies also according to sexual practices. Many male partners may be classified as «healthy carriers» who unknowingly serve as an asymptomatic reservoir and could contribute to the development of HPV-related diseases in women [52–54].

C) Risk factors and monitoring [27, 55–58] – Grading = 2++, 2–, 2–, 2+, and 4, respectively

In males, age does not appear to be related clearly to the acquisition of the infection. In general, sexual habits (duration of sexual activity and number of recent partners) correlate with the presence of infection, in both males and females. Individual factors (age at first sexual intercourse, number of partners while sexually active, smoking habits, and alcohol consumption) or factors related to the female partner (anal sex, partner with a history of STD) are not related consistently and significantly to the acquisition of infection and its presence in males [3, 4, 27]. In addition, a state of immunodeficiency (due to HIV infection) is a risk factor for infection of HPV [55–57]. Every male sexual partner of a woman affected by anogenital warts should be examined to detect and, if necessary, treat any esophytic HPV-related lesions. It is important to extend monitoring beyond the mean incubation period (3 months) [58]. At present, testing for HPV (through PCR) in asymptomatic males with a negative examination of the penis (penoscopy) is not recommended, even when the female partner has had a positive cytological examination [58].

Question conclusions

Based on the previous statements and data, HPV DNA sero status seem to play a fundamental role in HPV transmission and diseases development between partners. In males, there are several risk factors that play a fundamental role in HPV infection and development of the disease such as immunodeficiency disease.

Conclusive considerations of the consensus panel

➣ Awareness campaigns should be implemented not only for anogenital warts but for HPV-related diseases in general, through all institutional channels, in order to increase HPV knowledge and reduce, when possible, HPV transmissibility at a population level.

➣ Subjects with an immunodeficiency status, such as HIV, have a greater risk of HPV infection; prevention strategies should also target high risk populations.

Question no. 3: What method of prevention of HPV-related diseases could significantly reduce their impact on the male population?

A) Primary Prevention [59–68] – Grading = 1++, 1++, 1++, 1++, 1++, 1++, 1++, 1+, 1++, and 2+, respectively.

Primary prevention through vaccination has proved to be very effective in preventing precancerous lesions and cancers of the cervix, vulva, and vagina, as well as anogenital warts, in women up to the age of 45 years [59–66]. The quadrivalent vaccine is effective against HPV genotypes 6, 11, 16, and 18. In Europe, the vaccine is indicated for the prevention of cervical cancer, precancerous lesions of the cervix, vulva, and vagina, and also for genital warts in women aged between 9 and 45 years [69].

Clinical trials have shown that the quadrivalent vaccine is effective in preventing external genital lesions (anogenital warts, as well as penile and perineal lesions) in males aged between 16 and 26 years in 90.4%; (95%; CI: 69.2–98.1) of cases [67]. On the basis of these results, in October 2009, the US Food and Drug Administration (FDA) approved the extension of the indications for the quadrivalent vaccine to males up to the age of 26 years, for the prevention of anogenital warts. In addition to the USA, another seven countries have approved the extension of the indications for the quadrivalent vaccine to males up to the age of 26 years for the prevention of anogenital warts [70].

At present, efficacy data on the quadrivalent vaccine with respect to the prevention of external genital and anal precancerous lesions are available (Table 3). In a subpopulation of homosexual males aged between 16 and 26 years, population at a higher risk of anal precancerous lesions, the quadrivalent vaccine was effective in 77.5%; (95%; CI: 39.6–93.3) of cases in preventing precancerous anal lesions (per-protocol analysis); furthermore, in a post-hoc analysis, the efficacy rate was 91.7%; (95%; CI: 44.6–99.8) [71, 72] specifically from HPV types 16 and 18.

Table 3 Efficacy of the quadrivalent vaccine in preventing external genital lesions and AIN (per-protocol population) Full size table

Notes of importance after the consensus:

In accordance to the importance and recommendations already stated by the CC document about HPV in males, in late 2010 and 2011, on the basis of vaccine efficacy data against HPV-related anal precancerous lesions, in December 2010, the FDA approved the extension of the indications for the quadrivalent vaccine to the prevention of anal cancer and anal intraepithelial lesions in males and females aged between 9 and 26 years [73]. In addition, the results for efficacy related to the prevention of anal cancer and anogenital warts in males aged 16–26 were taken into consideration by the European Medicines Agency and resulted in the extension of indication of the quadrivalent vaccine in males 9–26 years of age for the prevention of genital warts.

B) Condoms [74, 75] – Grading = 1+, and 2+, respectively

The use of a condom reduces, albeit not completely, the risk of transmission of HPV infection between heterosexual partners. Moreover, correct and consistent use of a condom reduces the risk of transmission by approximately 50%; and appears to promote clearance of the infection as seen on a randomized trial conducted in women diagnosed with CIN lesions and their partners, in the group that used condom, correct usage seemed to promote regression of CIN lesions and clearance of HPV infection on both [74]. Condom usage also reduces the risk of HPV infection in males from female infected partners [75].

Question conclusion

Vaccination on males, according to recent data, seems to be effective with the quadrivalent vaccine as it is in women. Vaccination is the most effective measure to reduce HPV related diseases impact in males with efficacy rates around 90%;. Condom usage seems to be also effective in reducing at least in 50%; the risk of transmission when used correctly.

Conclusive considerations of the consensus panel

➣ An awareness campaign should be implemented about available vaccines, the importance of vaccination and its high efficacy in males. Also about other prevention measures such as condom usage, through all institutional channels.

➣ The quadrivalent HPV vaccine has proven to be effective in protecting males against genital warts and HPV related precancerous anal lesions. Based on vaccine efficacy results, male vaccination should be recommended as in females as they can benefit too from vaccination.

Question no. 4: Could primary prevention of HPV-related diseases in men reduce HPV-related diseases in their partners?

A) Vaccination [76] – Grading = 2–

Little data is still available about vaccination effect on a population level. Only on the years to come data will become more available and valid. Only one ecological study, obtained from vaccination programs carried out in women in Australia, were vaccination coverage is high on women, although still early have shown that vaccination induces also some herd immunity in men i.e. there is a partial reduction in the occurrence of anogenital warts in heterosexual males compared to vaccinated women. In Australia, the quadrivalent vaccine has been administered to schoolgirls aged between 12 and 18 years and to women younger than 26 years since 2007. The coverage rate in the area where the study was conducted ranged from 65%; to 75%;. One year after the implementation of the mass vaccination program, comparison of the rates of diagnosis of anogenital warts before and after the introduction of vaccination showed a 48%; reduction in the diagnosis of anogenital warts in women younger than 28 years, but no corresponding reduction was obtained in women older than 28 years and in the males who have sex with males population [76].

Over the same period, a 17%; reduction in the diagnosis of genital warts among heterosexual males was recorded. This reduction was not observed in homosexual males, a finding that suggests some herd immunity effect. In other words, use of the vaccine confers indirect protection on the unvaccinated population as a result of the reduction in the total number of infected subjects, which in turn decreases the number of potentially infectious contacts.

B) Reduction in HPV-related events [77, 78] – Grading = Publications could not be assessed, because they are abstracts or other types of communication

In view that natural history in males, although explained, still lacks further research as today we know that although similar, it does not behave as in females and because of the paucity of established epidemiological data, it is impossible (at the moment) to provide details on the impact of a primary prevention strategy on the reduction of HPV-related disease in partners

The complexity of the scenario produced by the implementation of primary prevention in males is due to a number of general considerations: 1) there is limited information on the natural history of HPV infection in males, that behaves differently than females (incidence, prevalence, seroprevalence and burden of disease is different), information is still scarce and more studies are still needed; 2) the inconsistencies of epidemiological data and rates of concordance of genotypes among couples (which are in turn modulated by differences in sexual behavior, age, relationship time and by the diagnostic method adopted among other factors); 3) The lack of a reliable and validated monitoring and diagnosis system (in the long and short term) for males.

Given that HPV infection is a sexually transmitted disease, interventions for primary prevention in one partner will evidently have a positive effect in terms of reducing HPV-related disease in the other partner. Mathematical models indicate that the cost–effectiveness ratio for the vaccination of males becomes favorable in the presence of a low coverage rate for females, because it can contribute towards the containment of infection in the community [77, 78], some even state that it becomes more cost effective to vaccinate males rather than hard to reach women [79]. As a result, herd immunity from vaccinating only women is likely to be insufficient to eradicate HPV infection, in fact, on the other hand, a single sex HPV vaccination campaign may also increase the psychological burden on women [80], and this sex inequality could amount to an additional healthcare burden. As a disease that affects both men and women, social fairness needs to be taken into consideration as both individually can benefit from the vaccine. There’s also the matter of males who have sex with males, to whom no benefit is gained from female vaccination only as shown in early ecological studies [76]. In addition, lessons learned from history, seem to show that single gender vaccination campaigns, such as the one against rubella in 1996, that although both diseases differ significantly, there are several potential pitfalls in single sex vaccine programs [81]. From this perspective, it remains to be seen whether the current objective of the vaccination program in Italy will be achieved, namely 95%; coverage with three doses of vaccine within 5 years from the start of the program. The available data for the 1997 born cohort (updated to 31 December 2009) indicate that the coverage rate at 3 vaccine doses is only 53.1%; [82].

Question conclusions

Although herd immunity exist, primary vaccination exclusively of males or females doesn’t seem to be effective when coverage rates are less than high in reducing HPV related disease on partners in a significant way. In Italy coverage rates are not high, only 53%; of 12 years old females have been vaccinated with 3 doses. Social equity right to get the vaccine in males and higher risk groups, as well as social burden (including psychological burden) should be taken into consideration as they seem relevant.

Conclusive considerations of the consensus panel