Human papillomavirus infection and disease in men: Impact of HIV
1 Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa
2
London School of Hygiene and Tropical
Medicine, London, United Kingdom
Corresponding
author:
S Delany-Moretlwe
([email protected])
There is growing evidence of a significant
burden of human papillomavirus (HPV) infection and associated
disease in men. High rates of HPV infection have been observed
in men from sub-Saharan Africa where HIV prevalence is high. HIV
infection increases HPV prevalence, incidence and persistence
and is strongly associated with the development of anogenital
warts and anal, penile and head and neck cancers in men. Despite
increasing access to antiretroviral therapy, there appears to be
little benefit in preventing the development of these cancers in
HIV-positive men, making prevention of infection a priority. New
prevention options that are being introduced in many African
countries include male circumcision and HPV vaccination.
However, more data are needed on the burden of HPV disease in
men before boys are included in HPV vaccination programmes.
S Afr J HIV Med 2013;14(4):183-188. DOI:10.7196/SAJHIVMED.1002
Human papillomavirus (HPV) is
a common sexually transmitted infection (STI) affecting both
men and women.1 HPV infections can be
classified as either low- (LR) or high-risk (HR).
2
HR-HPV infections have been associated with cancer of the
anogenital and oropharyngeal tissues. While the
majority of HPV infections are transient and clear
spontaneously, persistent infection with HR-HPV is associated
with the development of pre-neoplastic and neoplastic lesions
in these areas (Fig. 1). While much is known about the natural
history of HPV infection in cervical cancer in women, less is
known about the development of HPV-associated disease in men.
Emerging evidence points to a significant role for HIV
infection in promoting HPV prevalence, incidence and
persistence. This review provides an update on
current evidence regarding the epidemiology of HPV infection
and disease in men, the effects of HIV on HPV infection and
disease in men in sub-Saharan Africa (SSA), and the prospects
for prevention in this setting.
Global burden of HPV
HPV infection is ubiquitous in men. A systematic review of 62 studies using reliable methods of HPV DNA detection and conducted prior to 2009, representing 14 800 men in 23 countries, showed that anogenital HPV DNA prevalence is generally high in sexually active men. The review highlighted considerable variation in estimates by region, from 1% to 84% in LR men, to 2% to 93% in HR men.3 Compared with studies in women, peak prevalence spanned a wide range of ages, suggesting that men have the potential for longer-term persistence of infection or higher rates of re-infection.3 Type-specific HPV seroprevalence studies are better indicators of lifetime exposure to HPV infection, although they may underestimate cumulative HPV exposure, given that not all infections lead to seroconversion.4 Recent population-based studies have estimated the prevalence of antibodies to vaccine-preventable HPV types 6, 11, 16 and 18. Among men aged 14 - 59 years in the USA, 12.2% of men were seropositive for any vaccine type, with a peak prevalence of 18% among men aged 50 - 59 years.5 In a similar population-based study in Australia, peak prevalence of any vaccine type was 31.5% among men aged 40 - 49 years;6 and a study from the Netherlands estimated that the seroprevalence of any HR-HPV in men aged ≥14 years was 20%.7 There is some evidence that seroprevalence appears to be rising as a result of changes in sexual behaviour and earlier age of sexual debut. In a related study from the Netherlands comparing serosurveillance rates of HR-HPV in the periods 1995 - 1996 and 2006 - 2007, overall HR-HPV seroprevalence rates were significantly higher in the later survey, compared with the earlier survey across all age groups.8
Burden of infection in SSA
A recent global review of 117 studies worldwide suggests that the seroprevalence of HPV is even higher in SSA, although data on men in SSA are sparse.4 In a small study of Tanzanian genital ulcer disease (GUD) patients, pregnant women and male blood donors, the prevalence of antibodies to HR-HPV ranged from 77% in male GUD patients to 15% in male blood donors. In this study, the prevalence of antibodies to HPV types 16, 18, 51 and 52 was considerably higher in HIV-positive patients with GUD.9
Although data on anogenital HPV DNA prevalence in men in SSA are also limited,3 overall reported prevalences in men are high, ranging from 19% to 78%.10-15 In most, but not all studies, the most prevalent type was HPV-16.15 The observed heterogeneity in estimates can be attributed to differences in age distribution, sexual behaviour and HIV prevalence within the different populations. Emerging data suggest that the incidence of HR anogenital HPV infection in men is also high, ranging from 35.7/100 person years in South African men to 40/100 person-years in East African men participating in male circumcision (MC) trials.16-18 In both settings, the risk of HPV acquisition was doubled in HIV-positive men. These incidence rates are much higher than those previously observed elsewhere.19 , 20
Factors associated with HPV infection
HPV seroprevalence rates are consistently lower in men than in women,[6,21 ,22] with men also producing lower antibody titres than women. 23 There are several plausible biological explanations for differences in antibody responses between men and women. Men may experience a higher frequency of transient infections, a lower viral load, or produce less robust immunological responses than women. 24 It has been argued that the site of infection and/or type of epithelium influence antibody responses, with men experiencing a higher proportion of infections in more keratinised tissues (e.g. penile shaft) than women (e.g. anal canal or cervix). Thicker, more keratinised epithelium may present a barrier to infection, and if infected, may be less likely than mucosal surfaces to induce an immune response, given the relative distance from draining lymphatics and lymph nodes. 23 , 25 Recent data from a study comparing type-specific HPV antibody prevalence with the corresponding prevalence of HPV DNA detected in the external genitalia and anal canal in heterosexual men and men who have sex with men (MSM) support this notion. Higher HPV-6 and -16 seroprevalence rates were observed in men that had a same HPV-type infection in the anal canal, than in those with the same HPV-type infection in the external genitalia only. Higher seroprevalence rates were also observed in MSM compared with heterosexual men.26
The association between HPV infection and age is somewhat inconsistent, with fairly flat prevalence curves reported in populations where HIV prevalence is relatively low. 3 , 27 Data emerging from Africa, present a similarly mixed picture. A study among Kenyan fishermen showed a lower risk for HPV infection in older age groups,10 while data from Kenyan men participating in an MC trial showed little variation in prevalence with age.28 A more recent study in men from Tanzania demonstrated an association between increasing age and HPV prevalence, but that this association was driven by HIV-positive men.15 Two recent incidence studies confirmed that increasing age is associated with a lower risk for HPV infection.16 , 17 Combined, these data tend to suggest that the association between HPV infection and age in men in SSA is related to patterns of sexual activity, but confounded by HIV status, which may promote the persistence of HPV infection.
Sexual behaviour is an important risk factor for anogenital HPV infection. More recent publications have highlighted the importance of age of sexual debut,8 marital status,29 high number of lifetime sexual partners,5 , 30 , 31 number of recent sexual partners,30 longer history of sexual activity,30 route of exposure,26 , 30 , 32 and having sex with men32-34 as risk factors for anogenital HPV infection. Similar observations about sexual risk behaviour and an association with HPV have been made in studies of men in SSA.10 , 17 , 28 While the data on the protective effects of condoms are somewhat mixed,35 evidence from African studies in men show a reduced risk of genital HPV infection associated with condom use.10 , 28 , 36 , 37 Evidence from randomised controlled trials (RCTs) of MC has conclusively demonstrated the protective benefits of MC in reducing the risk of HPV prevalence and incidence.[17,36, 38,39] Related findings from the trial in Kenya have highlighted less frequent bathing as a risk factor for HPV infection, which may be associated with poor genital hygiene in uncircumcised men.18 , 28
STIs are independently associated with the risk of HPV infection, particularly chlamydia,19 , 30 herpes simplex virus (HSV)-2,34 and hepatitis B.40 While they may share a common mode of transmission, STIs are thought to increase the risk of HPV infection by facilitating access to the basal epithelium through micro-abrasions in the skin.35 Recent reports on male populations in Africa point to a higher risk of penile HPV in men co-infected with laboratory-diagnosed Chlamydia trachomatis or Neisseria gonorrhoeae, and those who are HSV-2-seropositive.28 Interestingly, HR-HPV clearance was recently shown to shown to be higher in HIV-negative men co-infected with syphilis or HSV-2, suggesting that other genital tract infections may also create an inflammatory cytokine milieu that may facilitate the clearance of HPV.17
HIV is a strong risk factor for HPV infection in men. While studies of anal HPV infection in MSM from Europe and the Americas first identified an increased risk for infection in HIV-positive men,24 there is now a growing body of evidence from studies of men in SSA that shows that prevalent and incident anogenital HPV infection is more common in HIV-positive men.[15,16, 37] Multiple infections, particularly with HR-HPV, are more common in HIV-positive men.13 , 41 Prevalence of infection increases with declining CD4+ count.42 Partner HIV status has also been shown to increase the risk of HPV detection in men.14 , 43
Anogenital warts
Anogenital warts (AGWs) are the most common clinical manifestation of HPV infection.44 Caused mainly by infection with HPV-6 and -11,45 they are highly infectious. An estimated 65% of people whose sexual partner has genital warts will develop warts themselves. 46 The estimated incubation period from HPV infection to genital wart development is 2 weeks - 8 months.47 While approximately 20 - 30% of genital warts will spontaneously regress,48 recurrence is common, resulting in significant psychological morbidity and high medical costs for repeated treatment. These costs are not insignificant when compared with costs for treatment of cervical cancer in women.49 Two recent reviews estimated the prevalence and incidence of AGWs in the general adult population worldwide45 and in SSA,50 respectively.. Worldwide, the overall prevalence of AGWs, based on genital examinations, ranged from 0.2% to 5.1%, with higher prevalence rates observed in males. Data suggest that prevalence has increased in recent decades, possibly as a result of changes in sexual behaviour.
Studies in male populations in SSA suggest much higher
prevalence rates than in high-income countries, possibly as a
result of higher HIV prevalence rates. Highest rates of 4.8 -
12.2% have been observed in HR men from Central and South
Africa, a region of high HIV prevalence. Lack of circumcision
and HIV infection have been identified as risk factors for
AGWs in men.12 Importantly, HIV-positive
men with AGWs may also be at risk for infection with HR-HPV.
In a small study in Johannesburg among HIV-positive men with
penile warts, 85% were found to have HR-HPV as well. HPV-16
and -18 were most frequently detected.41
These high rates of HR-HPV detection in men with HIV suggest
that they are at significant risk for the future
development of pre-neoplastic and neoplastic lesions,
emphasising the importance of targeting screening programmes
for HIV-positive men with AGWs.
Anal cancer
While relatively uncommon, the incidence of anal cancer in men appears to be rising.51 A systematic review examined these trends, and found that age-adjusted incidence rates for anal cancer have increased in several high-income countries, with HPV infection identified as the most important associated aetiological factor.52 Besides increasing age, smoking, receptive anal intercourse and HIV infection were the most important risk factors for anal cancer, with the highest incidence rates observed in HIV-positive MSM. While anal cancer incidence is highest in HIV-positive MSM, it should be noted that receptive anal intercourse is not a prerequisite for anal HPV infection, pre-cancer lesions or anal cancer. Piketty et al.53 demonstrated high rates of anal infection and squamous intraepithelial lesions in HIV-positive men with no previous history of anal intercourse – an observation made subsequently in other studies.54 In such instances, anal HPV infection is thought be transferred to the anal canal through transiently infected fingers or toys, as well as by shedding from other infected genital sites.
Anal cancer is considered to be biologically similar to cervical cancer. Like cervical cancer, it is thought to be preceded by a spectrum of intraepithelial changes and anal intraepithelial neoplasia (AIN), which can be graded similarly to cervical cancer. While there is strong supportive evidence that high-grade AIN is a precursor to invasive cancer, there is no consensus regarding the prevalence or significance of AIN, nor on the rate of AIN progression to cancer. Almost all of the natural history data come from studies in MSM, with few data on heterosexual, HIV-negative or African populations. A recent meta-analysis of anal HPV and associated lesions in MSM found that HIV-positive men were consistently more likely to be infected with HPV, to have associated lesions, and to have higher rates of anal cancer, although the excess in HIV-positive men was smallest for high-grade AIN, and was not statistically significant for that category. While there were no data on progression rates of AIN to cancer, estimates from this analysis suggest that rates of progression are significantly lower than those observed in cervical cancer.55 Despite significant heterogeneity in the data, and a lack of prospective data, it remains plausible that high-grade AIN lesions regress more frequently than high-grade cervical lesions. 56 While the prevention of anal cancers in high-risk HIV-positive men is a priority, these findings raise doubts about the utility of anal cancer screening programmes at present. Until further evidence of benefit for screening in terms of reductions in anal cancer incidence and mortality become available, anal cancer screening programmes for men are likely to be controversial.
Despite immune reconstitution associated with highly
active antiretroviral therapy (HAART), there appears to be
little evidence that this therapy has a preventive effect on
the development of anal cancer. The recent meta-analysis and
other analyses of temporal trends in anal cancer incidence
have highlighted the continuing high incidence of anal cancer,
despite the widespread introduction of HAART. 55
,
57
,
58
These data suggest that prolonged survival afforded by HAART
initiation may allow more time for AIN to progress to cancer,
thus leading to higher anal cancer rates.
Penile cancer
Penile cancers are relatively rare. In 2008, of the estimated 22 000 new penile cancer cases, half were attributable to HPV, with much higher rates observed in regions with a low human development index.59 Data from Zimbabwe suggest that southern Africa has higher incidence rates,60 and a recently published report of HPV detection in cancerous and pre-cancerous penile lesions from men in South Africa demonstrated multiple HPV infections, with high rates of HPV-16.61 Risk factors for penile cancer include: a lack of MC; phimosis and/or poor genital hygiene; AGWs; and HIV infection. HIV-positive men have an eight-fold increased risk of penile cancer, which may be associated with higher HPV infection rates.62 Other risk factors for penile cancer that have been reported include current smoking, early age of first sexual intercourse, high lifetime number of female sexual partners, lack of condom use, chronic inflammatory conditions including balanitis and lichen sclerosus, and treatment with ultraviolet photochemotherapy for psoriasis.63
Head and neck squamous cell carcinomas
Head and neck cancer commonly refers to squamous cell carcinomas (SCCs) arising in the upper aerodigestive tract (oral cavity, nasopharynx, hypopharynx and larynx). Traditionally, most head and neck cancers were associated with tobacco and alcohol exposures and presented after the age of 60 years. More recently, a shift in the epidemiology of oropharyngeal SCC has been observed, with a rising incidence, particularly in the palatine tonsils and base of the tongue, occurring in younger age groups and in people who have never smoked. 64 Like the cervix and anus, there is an epithelial transition zone within the oropharynx which is prone to HPV infection, dysplasia and the development of SCCs. In a systematic review of studies involving histological specimens of head and neck SCCs, in 36% HPV DNA was detected, and HPV-16 was the most common HPV type associated with head and neck SCC.65 HIV-infected individuals have a 1.5 - four-fold higher risk of oropharyngeal or tonsillar cancer than the general population. Although the proportion of oropharyngeal cancers is unknown, HIV-positive individuals appear to be at moderately increased risk of HPV-associated head and neck SCC compared with the general population.66 D’Souza et al.67 showed convincing evidence that oral cavity HPV DNA infection was related to sexual behaviour, including oral sex. There is evidence that HIV-positive individuals have a higher prevalence of oral HR-HPV, even after controlling for sexual behaviour,68 and that the risk for infection appears to be higher among those with a declining CD4+ count.69 While there are limited data on the natural history of oral HPV infection, the majority of infections clear within two years,70 although persistence appears to be associated with a CD4+ count <500 cells/μl.71 There do not appear to be benefits for HAART on either the persistence of HPV infection or the clearance of oral lesions, but more evidence is needed in this regard.66 Data on oral HPV and HPV-associated head and neck SCC in African populations is currently scarce, although one study from Senegal,72 which included 117 invasive head and neck cancer histology specimens, mainly from men with a mean age of 52 years, found only four cases to be positive for HPV DNA. The authors remarked that larger studies are needed to confirm these findings and explore other potential risk factors specific to the region.72
Prevention of HPV-associated infection and disease in men
Evidence for the benefit of several strategies to prevent HPV infection and subsequent disease in men has emerged in recent years. Studies have shown a greater protective effect of condoms in the prevention of HPV acquisition in men. Analysis of data from a multi-national cohort study in men showed a two-fold lower risk of HPV acquisition in men with no steady partner and who always used condoms. In addition, the probability of clearing an oncogenic infection was 30% higher in men who consistently used condoms with non-steady partners.73 Consistent condom use has also been associated with the regression of penile lesions in men.74 Recent RCTs in Africa provide strong evidence that MC is protective against HPV infection. In these trials, MC has been associated with reductions in the incidence, prevalence and persistence of HPV infection in men. In HIV-negative men, MC has also been shown to reduce HR-HPV transmission to female partners.75 Recent data suggests that decreased penile shedding of HR-HPV observed in HPV-infected circumcised men may help to explain the protective effects observed for female partners.38 MC has also been associated with a lower prevalence of flat penile lesions in men.39
Vaccines are the ideal form of primary prevention for
infectious diseases, and have been successful in the control
of many other infectious diseases. Having been shown to be
efficacious in women, HPV vaccine studies have
now demonstrated evidence of benefit in men. An RCT involving
4 065 men from 18 countries aged 16 - 26 years showed that the
quadrivalent vaccine was 90% effective in preventing infection
with vaccine-specific types in the per protocol analysis, and
89% effective in preventing AGWs in the same population.76 In
602 MSM aged 16 - 26 years, the quadrivalent
vaccine was 77.5% effective in preventing HPV-6-, -11-, -16-
and -18-associated AIN.77 The bivalent vaccine
is not currently registered for use in men. HPV vaccination
has been shown to be safe and highly immunogenic in HIV-1
infected men.78 Modelling studies
predict benefits of vaccination for boys, when high levels of
vaccine coverage are achieved in girls,79
and data emerging from countries where national vaccination
programmes have been introduced confirm this. Even though
vaccination was restricted to girls, in Australia, there has
been an 82% decline in AGWs in men aged <21 years since the
introduction of the vaccine.80 In Denmark, a 50%
decline in AGWs in young men aged <19 years was observed
only three years post vaccine introduction.
81 However,
these benefits may not translate to all men, particularly MSM
who may not benefit from herd immunity. Australia is the first
country to extend vaccination to men. While several countries
in Africa have recently introduced HPV vaccination programmes,
these school-based programmes do not include boys. Further
evidence is needed of the HPV-associated burden of disease in
men, and the potential effects of HIV on HPV-associated
disease in men before the vaccination of boys can be
considered in lower-resource settings.
Conclusion
HPV infection and associated disease are
common in men in SSA. While data on the burden of disease are
limited, studies suggest that infection with HPV is common,
particularly in the context of HIV. There is also growing
evidence to suggest that HIV infection enhances HPV persistence
– a precursor for the development of cancer. Given expanding
access to HAART in Africa, there is now potential for
significant morbidity and mortality from HPV-related cancers in
men in the future. While MC and HPV vaccination programmes are
being rolled out in many African countries where the burden of
HIV is high, more data are needed on the natural history and
burden of HPV-associated disease in men in Africa to inform the
development of prevention programmes.
References
1. International Agency for Research on Cancer. Monographs on the Evaluation of Carcinogenic Risks to Humans 2007;90.
2. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology 2004;324:17-27.
3. Smith JS, Gilbert PA, Melendy A, et al. Age-specific prevalence of human papillomavirus infection in males: A global review. J Adolesc Health 2011;48(6):540-552. [http://dx.doi.org/10.1016/j.jadohealth.2011.03.010]
4. Tiggelaar SM, Lin MJ, Viscidi RP, et al. Age-specific human papillomavirus antibody and deoxyribonucleic acid prevalence: A global review. J Adolesc Health 2012;50(2):110-131. [http://dx.doi.org/10.1016/j.jadohealth.2011.10.010]
5. Markowitz LE, Sternberg M, Dunne EF, et al. Seroprevalence of human papillomavirus types 6, 11, 16, and 18 in the United States: National Health and Nutrition Examination Survey 2003-2004. J Infect Dis 2009;200(7):1059-1067. [http://dx.doi.org/10.1086/604729]
6. Newall AT, Brotherton JM, Quinn HE, et al. Population seroprevalence of human papillomavirus types 6, 11, 16, and 18 in men, women, and children in Australia. Clin Infect Dis 2008;46:1647-1655. [http://dx.doi.org/10.1086/587895]
7. Scherpenisse M, Mollers M, Schepp RM, et al. Seroprevalence of seven high-risk HPV types in The Netherlands. Vaccine 2012;30(47):6686-6693. [http://dx.doi.org/10.1016/j.vaccine.2012.08.068]
8. Scherpenisse M, Mollers M, Schepp RM, et al. Changes in antibody seroprevalence of seven high-risk HPV types between nationwide surveillance studies from 1995-96 and 2006-07 in The Netherlands. PLoS One, 2012;7(11):e48807. [http://dx.doi.org/10.1371journal.pone.0048807]
9. Mbwana J, Viscidi R, Lyamuya E, et al. Prevalence of serum antibodies to human papilloma virus in patients with genital ulcer disease in an urban population of Tanzania. Sex Transm Infect 2007;83(1):64-65.
10. Ng'ayo MO, Bukusi E, Rowhani-Rahbar A, et al. Epidemiology of human papillomavirus infection among fishermen along Lake Victoria Shore in the Kisumu District, Kenya. Sex Transm Infect 2008;84(1):62-66.
11. Auvert B, Sobngwi-Tambekou J, Cutler E, et al. Effect of male circumcision on the prevalence of high-risk human papillomavirus in young men: Results of a randomized controlled trial conducted in Orange Farm, South Africa. J Infect Dis 2009;199(1):14-19.
12. Smith JS, Moses S, Hudgens MG, et al. Increased risk of HIV acquisition among Kenyan men with human papillomavirus infection. J Infect Dis 2010;201:1677-1685. [http://dx.doi.org/10.1086/652408]
13. Müller EE, Chirwa TF, Lewis DA. Human papillomavirus (HPV) infection in heterosexual South African men attending sexual health services: Associations between HPV and HIV serostatus. Sex Transm Infect 2010;86:175-180.
14. Veldhuijzen NJ, Dhont N, Vyankandondera J, et al. Prevalence and concordance of HPV, HIV, and HSV-2 in heterosexual couples in Kigali, Rwanda. Sex Transm Dis 2012;39(2):128-135. [http://dx.doi.org/10.1097/OLQ.0b013e3182367c4c]
15. Olesen TB, Iftner T, Mwaiselage J, et al. Prevalence and type distribution of human papillomavirus among 1813 men in Tanzania and the relationship to HIV status. Sex Transm Dis 2013;40(7):592-598. [http://dx.doi.org/10.1097/OLQ.0b013e31828fcf57]
16. Mbulawa ZZ, Marais DJ, Johnson LF, et al. Impact of human immunodeficiency virus on the natural history of human papillomavirus genital infection in South African men and women. J Infect Dis 2012;206:15-27. [http://dx.doi.org/10.1093/infdis/jis299]
17. Tobian AA, Kigozi G, Gravitt PE, et al. Human papillomavirus incidence and clearance among HIV-positive and HIV-negative men in sub-Saharan Africa. AIDS 2012;26(12):1555-1565. [http://dx.doi.org/10.1097/QAD.0b013e328353b83c]
18. Backes DM, Snijders PJ, Hudgens MG, et al. Sexual behaviour and less frequent bathing are associated with higher human papillomavirus incidence in a cohort study of uncircumcised Kenyan men. Sex Transm Infect 2013;89(2):148-155. [http://dx.doi.org/10.1136/sextrans-2012-050532]
19. Kjaer SK, Munk C, Winther JF, et al. Acquisition and persistence of human papillomavirus infection in younger men: A prospective follow-up study among Danish soldiers. Cancer Epidemiol Biomarkers Prev 2005;14:1528-1533.
20. 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(9769):932-940. [http://dx.doi.org/10.1016/S0140-6736(10)62342-2]
21. Stone KM, Karem KL, Sternberg MR, et al. Seroprevalence of human papillomavirus type 16 infection in the United States. J Infect Dis 2002;186:1396-1402.
22. Thompson DL, Douglas JM Jr, Foster M, et al. Seroepidemiology of infection with human papillomavirus 16, in men and women attending sexually transmitted disease clinics in the United States. J Infect Dis 2004:190:1563-1574.
23. Slavinsky J, Kissinger P, Burger L, et al. Seroepidemiology of low and high oncogenic risk types of human papillomavirus in a predominantly male cohort of STD clinic patients. Int J STD AIDS 2001;12:516-523.
24. Partridge JM, Koutsky LA. Genital human papillomavirus infection in men. Lancet Infect Dis 2006;6(1):21-31.
25. Edelstein ZR, Carter JJ, Garg R, et al. Serum antibody response following genital α9 human papillomavirus infection in young men. J Infect Dis 2011;204:209-216. [http://dx.doi.org/10.1093/infdis/jir242]
26. Lu B, Viscidi RP, Wu Y, et al. Seroprevalence of human papillomavirus (HPV) type 6 and 16 vary by anatomic site of HPV infection in men. Cancer Epidemiol Biomarkers Prev 2012;21(9):1542-1546. [http://dx.doi.org/10.1158/1055-9965.EPI-12-0483]
27. Giuliano AR, Lazcano-Ponce E, Villa LL, et al. The human papillomavirus infection in men study: Human papillomavirus prevalence and type distribution among men residing in Brazil, Mexico, and the United States. Cancer Epidemiol Biomarkers Prev 2008;17:2036-2043. [http://dx.doi.org/10.1158/1055-9965.EPI-08-0151]
28. Smith JS, Backes DM, Hudgens MG, et al. Prevalence and risk factors of human papillomavirus infection by penile site in uncircumcised Kenyan men. Int J Cancer 2010;126(2):572-577. [http://dx.doi.org/10.1002/ijc.24770]
29. Lu B, Hagensee ME, Lee JH, et al. Epidemiologic factors associated with seropositivity to human papillomavirus type 16 and 18 virus-like particles and risk of subsequent infection in men. Cancer Epidemiol Biomarkers Prev 2010;19(2):511-516. [http://dx.doi.org/10.1158/1055-9965.EPI-09-0790]
30. Poynten IM, Waterboer T, Jin F, et al. Human papillomavirus types 6 and 11 seropositivity: Risk factors and association with ano-genital warts among homosexual men. J Infect 2013;66(6):503-511. [http://dx.doi.org/10.1016/j.jinf.2013.03.005]
31. Mooij SH, van der Klis FR, van der Sande MA, et al. Seroepidemiology of high-risk HPV in HIV-negative and HIV-infected MSM: The H2M study. Cancer Epidemiol Biomarkers Prev 2013;22(10):1698-1708. [http://dx.doi.org/10.1158/1055-9965.EPI-13-0460]
32. Heiligenberg M, Alberts CJ, Waterboer T, et al. Route of sexual exposure is independently associated with seropositivity to HPV-16 and HPV-18 among clients of an STI clinic in the Netherlands. J Infect Dis 2013;208(7):1081-1085.
33. Lu B, Viscidi RP, Lee JH, et al. Human papillomavirus (HPV) 6, 11, 16, and 18 seroprevalence is associated with sexual practice and age: Results from the multinational HPV Infection in Men Study (HIM Study). Cancer Epidemiol Biomarkers Prev 2011;20(5):990-1002. [http://dx.doi.org/10.1158/1055-9965.EPI-10-1160]
34. Heiligenberg M, Michael KM, Kramer MA, et al. Seroprevalence and determinants of eight high-risk human papillomavirus types in homosexual men, heterosexual men, and women: A population-based study in Amsterdam. Sex Transm Dis 2010;37(11):672-680. [http://dx.doi.org/10.1097/OLQ.0b013e3181e71069]
35. Veldhuijzen NJ, Snijders PJ, Reiss P, et al. Factors affecting transmission of mucosal human papillomavirus. Lancet Infect Dis 2010;10:862-874. [http://dx.doi.org/10.1016/S1473-3099(10)70190-0]
36. Tarnaud C, Lissouba P, Cutler E, et al. Association of low-risk human papillomavirus infection with male circumcision in young men: Results from a longitudinal study conducted in Orange Farm (South Africa). Infect Dis Obstet Gynecol 2011;2011:567408. [http://dx.doi.org/10.1155/2011/567408]
37. Tobian AA, Grabowski MK, Kigozi G, et al. High-risk human papillomavirus prevalence is associated with HIV infection among heterosexual men in Rakai, Uganda. Sex Transm Infect 2013;89(2):122-127. [http://dx.doi.org/10.1136/sextrans-2012-050524]
38. Wilson LE, Gravitt P, Tobian AA, et al. Male circumcision reduces penile high-risk human papillomavirus viral load in a randomised clinical trial in Rakai, Uganda. Sex Transm Infect 2013;89(3):262-266. [http://dx.doi.org/10.1136/sextrans-2012-050633]
39. Backes DM, Bleeker MC, Meijer CJ, et al. Male circumcision is associated with a lower prevalence of human papillomavirus-associated penile lesions among Kenyan men. Int J Cancer 2012;130(8):1888-1897. [http://dx.doi.org/10.1002/ijc.26196]
40. Nyitray A, Nielson CM, Harris RB, et al. Prevalence of and risk factors for anal human papillomavirus infection in heterosexual men. J Infect Dis 2008;197:1676-1684. [http://dx.doi.org/10.1086/588145]
41. Firnhaber C, Sello M, Maskew M, et al. Human papillomavirus types in HIV seropositive men with penile warts in Johannesburg, South Africa. Int J STD AIDS 2011;22(2):107-109. [http://dx.doi.org/10.1258/ijsa.2010.010306]
42. Mbulawa ZZ, Marais DJ, Johnson LF, et al. Influence of human immunodeficiency virus and CD4 count on the prevalence of human papillomavirus in heterosexual couples. J Gen Virol 2010;91:3023-3031. [http://dx.doi.org/10.1099/vir.0.020669-0]
43. Mbulawa ZZ, Marais DJ, Johnson LF, et al. Influence of human immunodeficiency virus and CD4 count on the prevalence of human papillomavirus in heterosexual couples. J Gen Virol 2010 91(Suppl 12):3023-3031.
44. Scheurer ME, Tortolero-Luna G, Adler-Storthz K. Human papillomavirus infection: Biology, epidemiology, and prevention. Int J Gynecol Cancer 2005:15:727-774.
45. Patel H, Wagner M, Singhal P, Kothari S. Systematic review of the incidence and prevalence of genital warts. BMC Infect Dis 2013;13:39. [http://dx.doi.org/10.1186/1471-2334-13-39]
46. Lacey CJ. Therapy for genital human papillomavirus-related disease. J Clin Virol 2005;32:S82-S90.
47. Oriel JD. Natural history of genital warts. Br J Vener Dis 1971;47:1-13.
48. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: Diagnosis, treatment, and prevention. Clin Infect Dis 2002;35:S210-S224.
49. Raymakers AJ, Sadatsafavi M, Marra F, et al. Economic and humanistic burden of external genital warts. Pharmacoeconomics 2012;30(1):1-16. [http://dx.doi.org/10.2165/11591170-000000000-00000]
50. Banura C, Mirembe FM, Orem J, et al. Prevalence, incidence and risk factors for anogenital warts in Sub Saharan Africa: A systematic review and meta analysis. Infect Agent Cancer 2013;8(1):27. [http://dx.doi.org/10.1186/1750-9378-8-27]
51. Kurdgelashvili G, Dores GM, Srour SA, et al. Incidence of potentially human papillomavirus-related neoplasms in the United States, 1978 to 2007. Cancer 2013;119(12):2291-2299. [http://dx.doi.org/10.1002/cncr.27989]
52. van der Zee RP, Richel O, de Vries HJ, Prins JM. The increasing incidence of anal cancer: Can it be explained by trends in risk groups? Neth J Med 2013;71(8):401-411.
53. Piketty C, Darragh TM, Da Costa M, et al. High prevalence of anal human papillomavirus infection and anal cancer precursors among HIV-infected persons in the absence of anal intercourse. Ann Intern Med 2003;183:453-459.
54. Abramowitz L, Benabderrahmane D, Ravaud P, et al. Anal squamous intraepithelial lesions and condyloma in HIV-infected heterosexual men, homosexual men and women: Prevalence and associated factors. AIDS 2007;21:1457-1465.
55. Machalek DA, Poynten M, Jin F, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: A systematic review and meta-analysis. Lancet Oncol 2012;13(5):487-500.
56. Stanley MA, Winder DM, Sterling JC, Goon PK. HPV infection, anal intra-epithelial neoplasia (AIN) and anal cancer: Current issues. BMC Cancer 2012;12:398. [http://dx.doi.org/10.1186/1471-2407-12-398]
57. Chiao EY, Hartman CM, El-Serag HB, Giordano TP. The impact of HIV viral control on the incidence of HIV-associated anal cancer. J Acquir Immune Defic Syndr 2013;63:631-663. [http://dx.doi.org/10.1097/QAI.0b013e3182968fa7]
58. Piketty C, Selinger-Leneman H, Bouvier AM, et al. Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: Results from the french hospital database on HIV. J Clin Oncol 2012;30(35):4360-4366. [http://dx.doi.org/10.1200/JCO.2012.44.5486]
59. Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases. Vaccine 2012;30(Suppl 5):F12-F23. [http://dx.doi.org/10.1016/j.vaccine.2012.07.055]
60. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030-3044.
61. Lebelo RL, Boulet G, Nkosi CM, et al. Diversity of HPV types in cancerous and pre-cancerous penile lesions of South African men: Implications for future HPV vaccination strategies. J Med Virol 2013 (in press). [http://dx.doi.org/10.1002/jmv.23730]
62. Spiess PE, Horenblas S, Pagliaro LC, et al. Current concepts in penile cancer. J Natl Compr Canc Netw 2013;11(5):617-624.
63. Anic GM, Giuliano AR. Genital HPV infection and related lesions in men. Prev Med 2011;53(Suppl 1):S36-S41.
64. Habbous S, Chu KP, Qiu X, et al. The changing incidence of human papillomavirus-associated oropharyngeal cancer using multiple imputation from 2000 to 2010 at a Comprehensive Cancer Centre. Cancer Epidemiol 2013 (in press). [http://dx.doi.org/10.1016/j.canep.2013.09.011]
65. Kreimer AR, Clifford GM, Boyle P, Franceschi S, et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467-475.
66. Beachler DC, D'Souza G. Oral human papillomavirus infection and head and neck cancers in HIV-infected individuals. Curr Opin Oncol 2013;25(5):503-510. [http://dx.doi.org/10.1097/CCO.0b013e32836242b4]
67. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356:1944-1956.
68. Beachler DC, Weber KM, Margolick JB, et al. Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults. Cancer Epidemiol Biomarkers Prev 2012;21(1):122-133. [http://dx.doi.org/10.1158/1055-9965.EPI-11-0734]
69. Kreimer AR, Alberg AJ, Daniel R, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 2004;189:686-698.
70. Videla S, Darwich L, Cañadas MP, et al. Natural history of human papillomavirus infections involving anal, penile, and oral sites among HIV-positive men. Sex Transm Dis 2013;40(1):3-10. [http://dx.doi.org/10.1097/OLQ.0b013e31827e87bd]
71. D'Souza G, Fakhry C, Sugar EA, et al. Six-month natural history of oral versus cervical human papillomavirus infection. Int J Cancer 2007;121(1):143-150.
72. Ndiaye C, Alemany L, Diop Y, et al. The role of human papillomavirus in head and neck cancer in Senegal. Infect Agent Cancer 2013;8(1):14. [http://dx.doi.org/10.1186/1750-9378-8-14]
73. Pierce Campbell CM, Lin HY, Fulp W, et al. Consistent condom use reduces the genital human papillomavirus burden among high-risk men: The HPV infection in men study. J Infect Dis 2013;208(3):373-384. [http://dx.doi.org/10.1093/infdis/jit191]
74. Bleeker MC, Hogewoning CJ, Voorhorst FJ, et al. HPV-associated flat penile lesions in men of a non-STD hospital population: Less frequent and smaller in size than in male sexual partners of women with CIN. Int J Cancer 2005;113:36-41.
75. Tobian AA, Gray RH. Male foreskin and oncogenic human papillomavirus infection in men and their female partners. Future Microbiol 2011;6(7):739-745. [http://dx.doi.org/10.2217/fmb.11.59]
76. Giuliano AR, Goldstone S, Moreira ED, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl H Med 2011;364:401-411.
77. Moscicki AB, Palefsky JM. HPV in men: An update. J Low Genit Tract Dis 2012;15:231-234. [http://dx.doi.org/10.1097/LGT.0b013e318203ae61]
78. Wilkin T, Lee JY, Lensing SY, et al. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. J Infect Dis 2010;202(8):1246-1253. [http://dx.doi.org/10.1086/656320]
79. Brisson M, van de Velde N, Boily MC. Economic evaluation of human papillomavirus vaccination in developed countries. Public Health Genomics 2009;12:343-351. [http://dx.doi.org/10.1159/000214924]
80. 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. [http://dx.doi.org/10.1136/bmj.f2032]
81. Sandø N, Kofoed K, Zachariae C, Fouchard J, et al. A reduced national incidence of anogenital warts in young Danish men and women after introduction of a national quadrivalent human papillomavirus vaccination programme for young women – an ecological study. Acta Derm Venereol 2013 (in press). [http://dx.doi.org/10.2340/00015555-1721]
82. Stanley M. Immune responses to human papillomavirus. Vaccine 2006;24(Suppl 1):S16-S22.