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Prevalence of Genital Human Papillomavirus among Men in Europe: Systematic Review and Meta-Analysis Julie B. Hebnes, MD,* Tina B. Olesen, MSc,* Anne Katrine Duun-Henriksen, PhD,† Christian Munk, MD, PhD,* Bodil Norrild, DSc,‡ and Susanne K. Kjaer, MD, DMSc*§ *Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; †Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark; ‡Department of Cellular and Molecular Medicine (ICCM), University of Copenhagen, Copenhagen, Denmark; §Gynecological Clinic, Juliane Marie Centre, Copenhagen University Hospital, Copenhagen, Denmark DOI: 10.1111/jsm.12652

ABSTRACT

Introduction. Human papillomavirus (HPV) is the commonest sexually transmitted infection worldwide and causes substantial morbidity in both sexes. Most European countries offer HPV vaccination for girls, but vaccine recommendations for boys are warranted. Aims. The aims of this study were to investigate the prevalence of genital HPV, identify parameters that affect the prevalence, and describe the type-specific prevalence among men in Europe. Methods. A systematic review and meta-analysis of the published literature in PubMed and Embase. Main Outcome Measures. Genital HPV prevalence and factors influencing prevalence in general and high-risk male populations in Europe. Results. We included 31 articles that gave the prevalence of genital HPV DNA among men in northern, southern and western Europe; no studies from eastern Europe were identified. The pooled HPV prevalence among 1,863 men representing the general population (nine studies) was 12.4%, with large heterogeneity between studies (I2 = 96.3%, P < 0.0001). The pooled HPV prevalence among 6,428 men in the high-risk population (22 studies) was 30.9%, also with substantial heterogeneity (I2 = 95.6%, P < 0.0001). In unadjusted meta-regression analysis, the HPV prevalence in the general population was significantly higher in studies published after 2000 (28.5%) than in earlier studies (8.8%) (P = 0.0179). In the meta-regression analysis adjusted by publication year, the heterogeneity in the two population groups could not be explained by geographical region, anatomical sampling site, or HPV detection method. HPV16 was the most prevalent high-risk type in both populations. Conclusions. HPV prevalence differs in male general and high-risk populations, but HPV16 and HPV18 are among the most common HPV types detected in both groups. Our findings contribute knowledge that may be useful as a baseline measure before the introduction of HPV vaccination for boys in Europe, and add to understanding of the epidemiology of HPV infection in men. Hebnes JB, Olesen TB, Duun-Henriksen AK, Munk C, Norrild B, and Kjaer SK. Prevalence of genital human papillomavirus among men in Europe: Systematic review and meta-analysis. J Sex Med **;**:**–**. Key Words. Human Papillomavirus; Genital; Men; Europe; Systematic Review; Meta-Analysis

Introduction

H

uman papillomavirus (HPV) is one of the commonest sexually transmitted infections worldwide and plays an important role in the etiology of cancers at various sites. Since HPV was © 2014 International Society for Sexual Medicine

established as the necessary cause of cervical cancer [1], extensive research has been conducted on the natural history of HPV, especially in women [2]. Persistent infection with some highrisk (HR) HPV types is related to cancers of the vulva, vagina, and cervix in women, penile cancer J Sex Med **;**:**–**

2 and anal cancer in men, and certain types of head and neck cancers in both men and women [2–6]. Infection with some low-risk (LR) HPV types (HPV6 and 11) is associated with anogenital warts, which give rise to substantial morbidity both among men and women [7–9]. Furthermore, HPV infection can cause significant psychosexual dysfunction due to embarrassment, stress, and concern about transmitting the virus to sexual partners [10,11]. The prevalence of genital HPV infection in men has been found to vary substantially between different populations [12], and several factors have been suggested to influence the prevalence including sampling sites and techniques [12–14]. Most studies have investigated HPV prevalence among men at high risk of acquiring HPV infection (e.g., attendees at sexually transmitted disease [STD] clinics and sexual partners of HPV-infected women) [12,15]. The HPV prevalence among men in the general population has been less well studied. A quadrivalent vaccine targeting HPV6, 11, 16, and 18 and a bivalent vaccine targeting HPV16 and 18 are currently available [16–18]. In addition, a nine-valent vaccine targeting HPV6, 11, 16, 18, 31, 33, 45, 52, and 58 is now in clinical trial [19,20]. Routine HPV vaccination for girls has been implemented in 19 of the 29 countries of the European Union, but none of the countries vaccinate boys against HPV. The only European country currently recommending vaccination for boys is Austria [21,22]. Aims

We undertook a systematic review and metaanalysis to assess the prevalence of genital HPV DNA among men in both high-risk and the general population in Europe and the factors that might explain differences in prevalence. We also describe the prevalence of selected HPV types covered by the available vaccines. Methods

Search Strategy The study was conducted in accordance with the PRISMA guidelines [23]. We searched PubMed and Embase up to June 18, 2013 using the search terms “papillomavirus,” “human,” “men,” “genital,” and “prevalence” (see supporting information Appendix S1 for full search strategy). The J Sex Med **;**:**–**

Hebnes et al. search was restricted to publications in English, with no restriction on publication date. After removal of duplicates of relevant abstracts, the abstracts and full texts of potentially relevant articles were reviewed independently by two authors ( J.B. Hebnes and T.B. Olesen). Additional articles were identified from the reference lists of relevant articles. We contacted the authors of articles with possibly overlapping study populations to decide which article to include. Missing information on the nationality of study populations was also obtained from authors.

Eligibility We included peer-reviewed publications that reported the prevalence of genital HPV DNA among men in Europe. The eligible populations were males aged ≥ 15 years. The required minimum sample size was 20 participants with an adequate HPV DNA result. HPV DNA had to be detected by polymerase chain reaction (PCR) or by non-PCR, e.g., Hybrid Capture 2™, Southern blot, or filter hybridization (in situ hybridization, dot blot, and slot blot). Eligible samples were scrape or swab specimens from the male genital area, including the urethra, glans, shaft, scrotum, and perineum. We excluded studies that reported anal HPV prevalence only, HPV DNA detected in semen or urine, and studies based on serological HPV tests. If it was not clear whether anal and penile HPV estimates were presented separately, the article was dismissed. Studies reporting HPV prevalence in scrape or swab specimens from men with genital warts were included, but those based only on biopsy material from genital warts were excluded. Reports of HPV prevalence in penile cancers and precursor lesions were also excluded. Data Extraction Data were extracted independently by two authors (J.B. Hebnes and T.B. Olesen), and all inconsistencies were evaluated and discussed until consensus was reached. The data extracted were first author, publication year, country, year of study, description of study population, sample size, age, HIV and circumcision status, anatomical site sampled, sampling method, HPV DNA detection method, prevalence of any HR and LR HPV. Data on typespecific HPV prevalence were extracted when available and were restricted to types included in the nine-valent vaccine only. Prevalence was estimated from figures when presented only graphically. If prevalence estimates were reported separately from the urethra and other penile sites,

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HPV among Men in Europe the latter were used in the analysis because HPV prevalence estimates from the urethra are found to be lower [14,24]. If an article reported HPV prevalence estimates separately from different sampling sites (e.g., glans, shaft, perianal area, and urethra), the estimate based on most samples adequate for HPV DNA testing was used in the analysis. When prevalence was estimated by more than one HPV detection method, only the results with the most sensitive method were used in the analysis [25]. STD clinic attendees, HIV-positive males, and male sexual partners of women with HPV infection or abnormal cytology were defined as “high-risk populations”; all others were defined as the “general population.” When more than one publication described the same population or presented overlapping results, data from the article with the most detailed information were used.

sive cervical cancer; and (ii) STD clinic attendees to see whether it was appropriate to lump these studies. We considered publication year as the most important confounder and we estimated the parameters of unadjusted models and models adjusted for publication year. Adjusted models were compared with P values from likelihood ratio tests and unadjusted models were evaluated by P values from tests of moderator. Publication bias was determined from funnel plots and Egger’s test for all studies combined. For all analyses, values of P < 0.05 were considered statistically significant. We report weighted estimates of prevalence with 95% CIs. The statistical software R [27] was used with the packages “meta” [28] and “metafor” [29] for all analysis.

Statistical Analysis All analyses were performed separately for studies of the general and high-risk populations. The overall prevalence was estimated by applying an arcsine transformation to raw proportions. The estimate was based on a random effects model, in which the between-study variance was determined with the DerSimonian–Laird estimator. Forest plots are presented of the study-specific and pooled prevalence of any HPV and 95% confidence intervals (CIs) sorted by publication year. The prevalence in individual studies is given with exact binomial 95% CIs. The overall heterogeneity across studies was evaluated with the I2 statistic as the percentage of variation due to heterogeneity. The significance of the heterogeneity was determined with Cochrane’s Q test. In cases of significant heterogeneity, meta-regression analysis was performed to determine whether it could be explained by one or more of the following study variables defined a priori: publication year, geographical region, anatomical sampling site, and HPV detection method. Geographical regions were grouped into eastern, northern, southern, and western Europe according to the United Nations Geoscheme for Europe [26]. Anatomical sampling site was divided into urethra only and other penile sites (+/− the urethra), and HPV detection method was grouped into PCR and non-PCR methods. In the initial meta-analysis model related to the high-risk population, we included a variable describing the “source population,” grouped into: (i) sexual partners of women with HPV, cervical intraepithelial neoplasia (CIN), carcinoma in situ (CIS), or inva-

Main Outcome Measures

The main outcome measures were the prevalence of genital HPV in general and high-risk male populations in Europe and factors that influence the prevalence. Results

We identified 2,234 abstracts in the database search, 1,155 from PubMed and 1,079 from Embase. After removal of 800 duplicates, 1,434 abstracts were reviewed. After full-text review of 120 potentially relevant articles, 93 were excluded. A total of 31 articles were included in the metaanalysis, of which 27 were identified by full-text review and another 4 from the reference lists of relevant articles. Figure 1 summarizes the study selection. The characteristics of the studies and HPV prevalence estimates for men in the general population and high-risk populations are presented in Table 1A, B. We included two case-control studies with healthy controls representing the general population and the case groups representing highrisk populations [32,36].

General Population Data for the general population were reported in 10 articles covering 2,217 men in 8 countries (Table 1A): 6 in northern Europe [31–34,37,38], 2 in southern Europe [35,36], and 1 in western Europe [30]; 1 study included men from both northern and western Europe (Norway and Germany) [39]. No studies in eastern Europe were found. Most studies were conducted among J Sex Med **;**:**–**

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Hebnes et al. 1155 abstracts identified in PubMed

1079 abstracts identified in Embase

2234 abstracts identified in database search

800 duplicates removed

1434 abstracts reviewed

1314 abstracts excluded

120 full-text articles assessed for eligibility 93 full-text articles excluded because of: 27 relevant papers

-

4 additional papers identified from reference lists

-

-

-

31 papers included in the meta-analysis

Figure 1 Flowchart of study selection.

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overlapping study population (n=14) no data on men (n=2) no individual data (n=2) size of study population (n=7) HPV detected in semen /urine (n=7) biopsy material (n=22) not European country (n=2) no HPV DNA testing (n=6) anal HPV detected (n=7) anal/penile HPV prevalence not presented separately (n=4) no relevant information (n=13) data on men and women not presented separately (n=3) biopsy/swab material not presented separately (n=3) swab material from genital warts (n=1)

Male sexual partners of women in the general population

Denmark, 1987–1988

Finland, 1992–1992

Croatia, 1990–1993

Spain, 1985–1987

Denmark, 1998

Finland, N/A

Germany, Norway, 2004–2008

Hippelainen et al. [34]

Grce et al. [35]

Castellsague et al. [36]

Kjaer et al. [37]

Kero et al. [38]

Vardas et al. [39]

Healthy men with no history of or current genital warts or anogenital lesions, 1–5 lifetime sexual female partners

Sexual partners of pregnant women

Military conscripts

Husbands of women with normal epithelium or inflammation

Family planning clinic attendees

Military conscripts

Military conscripts

354

128

337

171

79

285

(16–24)

Mean 28 (19–46)

Mean 20.3 (18–29)

Mean 45.4

N/A

Mean 19.8 ± 1.1

Mean 21 (20–23)

(20–49)

90

138

(18–23)

105

(16–79)

PCR. General primers (GP5 + /6+) followed by enzyme immunoassay Nested PCR. General primers for L1 (MY09/ 11, GP5 + /6+) RT-PCR. Primers in L1, E6, E7

Filter hybridization (slot-blot, specific probes) PCR. General primers for L1 (MY09/11) followed by dot blot

PCR. Type-specific primers followed by dot blot (type-specific probe) PCR. General primers for L1 (MY09/11)

PCR. Type-specific primers Filter hybridization RNA/ DNA

Filter hybridization DNA/ DNA (F-ISH)

Urethra. Sample with Cytobrush Penile, scrotal, perineal, perianal areas. Smear with Dacron swab

6, 11, 16, 18, 31, 33

Coronal sulcus, glans, urethra. Smear with wet cotton-tipped swab Coronal sulcus, glans. Smear with cotton-tipped swab

Coronal sulcus, glans, prepuce, urethral meatus. Smear with Accellon brush Urethra. Smear with cotton swab

Coronal sulcus, glans, urethral meatus. Smear with cotton-tipped swab Urethra. Sample with Accellon brush

Coronal sulcus, glans. Smear with cotton-tipped swab Urethra. Urobrush®

20 types (14 HR)

36 types (14 HR)

25 types

6, 11, 16, 18

1, 6, 11, 16, 18, 31, 33

6, 11, 16, 18, 31, 33, 35

6, 11, 16, 18, 33 6, 11, 16, 18, 31, 33, 35

6, 11, 16, 18

Sites sampled and sampling method

F-ISH, filter in situ hybridization; HPV = human papillomavirus; HR = high risk; LR = low risk; N/A = not available; PCR = polymerase chain reaction; RT = real-time

Sweden, 1991

Forslund et al. [33]

Sweden, N/A

530

Blood donors or patients from department of dermatology Military conscripts

HPV types detected

Germany, N/A

Assay

GrussendorfConen et al. [30] Kataoka et al. [31] Kjaer et al. [32]

Age, years (range)

Number of adequate samples

Country and year of study

Study (reference)

Description of study population

Study characteristics and HPV prevalence estimates among men representing the general population

Table 1A

N/A

22.7

33.8

3.5

26.6

16.5

8.7

0.0

17.1

5.8

Any HPV

Prevalence (%)

N/A

N/A

N/A

2.3

N/A

N/A

N/A

N/A

N/A

N/A

HR HPV

N/A

N/A

N/A

1.2

N/A

N/A

N/A

N/A

N/A

N/A

LR HPV

HPV among Men in Europe 5

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United Kingdom, N/A

Germany, 1984–1987

Denmark, 1987–1988

Sweden, N/A

United Kingdom, 1990

Sweden, 1991–1992

Netherlands, 1988–1990

Spain, 1985–1987

Italy, N/A

Sweden, N/A

Denmark, 1993

Netherlands, 2000–2001 Netherlands, 1995–2002

Study (reference)

Campion et al. [40]

Schneider et al. [41]

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Kjaer et al. [32]

Wikström et al. [42]

Hillman et al. [43]

Strand et al. [44]

van Doornum et al. [45]

Castellsague et al. [36]

Chiarini et al. [46]

Wikstörm et al. [47]

Svare et al. [48]

van der Snoek et al. [49] Bleeker et al. [50]

MSM STD clinic attendees Sexual partners of women with mild dyskaryosis or worse and/or CIN

STD clinic attendees

Men with symptoms of nongonococcal urethritis STD clinic attendees, reasons not related to HPV

Husbands of women with CIN3 or CIS

STD clinic attendees

Genitourinary clinic attendees with genital warts, gonorrhea, or genital dermatosis STD clinic attendees

Sexual partners of women with HPV associated lesions of the cervix Sexual partners of women with CIS or invasive cervical cancer STD clinic attendees

Sexual partners of women with CIN3 or chlamydial cervicitis

Description of study population

(19–76) Mean 37.6 (22.5–57.7)

181

(18–40+)

Mean 27.1 (18–54)

N/A

Mean 44.7

Mean 37 (SD 10)

PCR. Type-specific primers and LiPA PCR. General primers (GP5 + /6+) followed by reverse line blot

PCR. General (GP5/6) and type-specific primers for typing

PCR. General primers (GP5 + /6+) followed by reverse dot blot

PCR. Generic primers in E1

PCR. Type-specific primers followed by dot blot PCR. General primers for L1 (MY09/11) followed by dot blot

Nested PCR. General primers for L1 (MY09/ 11, GP5 + /6+)

PCR. General primers (GP5/6) followed by Southern blot

Mean 26.7 (17–55,6)†

Median 25 (20–53)

PCR. Type-specific primers followed by dot blot

Filter hybridization RNA/DNA

Filter hybridization DNA/DNA

Filter hybridization DNA/DNA

Assay

Mean 28 (17–58)

(25–49)

Mean 36.5

Median 27.5*/26 (21–38)*/(19–32)

Age, years (range)

258

198

235

247

183

85

65

169

228

41

156

75

Number of adequate samples

Study characteristics and HPV prevalence estimates among men from high-risk populations

Country and year of study

Table 1B

45 types (18 HR)

25 types

6, 11, 16, 18, 31, 33, 35, 40, 42, 45, 54, 56, 62, 66, 67, 70, 73, L11353, CP8304 >27 types

6, 11, 16, 18, 31, 33

25 types

6, 11, 16, 18, 33

21 types (13 HR)

6, 11, 16, 18, 31, 33

6, 16

6, 11, 16, 18, 31, 33, 35

6, 11, 16, 18

6, 16

HPV types detected

Coronal sulcus, glans, shaft, scrotum, perianal region. Smear with wet cotton-tipped swab Coronal sulcus. Smear with dry swab Coronal sulcus, glans, prepuce. Scrape with Cervex brush

Prepuce, glans, coronal sulcus. Smear with cytobrush

Sulcus, glans, prepuce, urethra, shaft. Smear with Cytobrush, plastic probe (urethra) Coronal sulcus, urethra. Smear with cottontipped swab Coronal sulcus, glans, urethra. Smear with wet cotton-tipped swab Urethra. Swab

Glans, urethra, prepuce, shaft. Scrape with plastic spatula and Cytobrush (urethra) Glans, prepuce, fossa navicularis, shaft. Smear with cotton-tipped swab Coronal sulcus, glans, urethral meatus. Smear with cottontipped swab Coronal sulcus, inner part of the prepuce, urethra. Smear with Cytobrush, cottontipped swab (urethra) Urethra. Sample with cotton-tipped swab

Sites sampled and sampling method

72.9

16.3

44.9

13.2

31.2

17.5

25.9

29.2

20.7

53.9

4.9

39.1

26.7

Any HPV

Prevalence (%)

58.6

8.5

N/A

N/A

N/A

15.4

N/A

N/A

16.6

N/A

N/A

N/A

N/A

HR HPV

27.0

N/A

N/A

N/A

N/A

2.2

N/A

N/A

N/A

N/A

N/A

N/A

N/A

LR HPV

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Greece, N/A

United Kingdom, 2003

Italy, 2004–2006

Italy, 2006–2008

United Kingdom, N/A

United Kingdom, N/A

Spain, 2002–2011

Spain, 2005–2009

Netherlands 2009–2011

Hadjivassiliou et al. [52]

Jalal et al. [53]

Benevolo et al. [54]

Barzon et al. [55]

Bisset et al. [56]

Cuschieri et al. [57]

Álvarez-Argüelles et al. [58]

Videla et al. [59]

Vriend et al. [60]

STI clinic attendees

HIV + men attending an outpatient HIV clinic

Sexual partners of women affected previously or presently by CIN or with HPV DNA in cervicovaginal brushings Men referred for HPV testing. Indications for testing: STD screening, HPV suspected lesions, HPV-positive partners Genitourinary clinic attendees with multiple sexual partners or diagnosis of genital warts within 6 months Drop-in sexual health service attendees Men attending an STD service

STD clinic attendees without genital warts and sexual partners of women with genital warts Genitourinary clinic attendees

Sexual partners of HPV-positive women

1,095

648

1,318

117

87

510

71

437

64

47

(16–24)

Median 41 (36–47)

Mean 35.8, (±11.38) (17–87)

(16–25)

N/A

Median 34 (20–72)

Mean 37.6 (20–61)

Median 26 (15–77)

Mean 32.2 SD 11.5 (15–65)

Mean 36.7 (23–58)

27 types (20 HR)

16, 18, 31, 33, 45, 52, 58

15 types (13 HR)

6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 66, 68

INNO-LiPATM PCR. General primers in L1 (MY09/11, GP5 + /6+), PCR with type-specific primers in E6/E7 for typing PCR. Type-specific primers in E6/E7 F-HPVTM typing (Molgentix SL, Spain) PCR. (SPF10 primers) followed by immunoassay

20 types (17 HR)

21 types (13 HR)

22 types (17 HR)

27 types (14 HR)

8 types (13 HR)

34 types (15 HR)

PCR. General primers (GP5 + /6+), Bio-Plex array technology for typing

Nested PCR. General primers for L1 (MY09/ 11, GP5 + /6+)

Nested PCR. General primers for L1 (MY09/ 11, GP5 + /6+) and reverse line hybridization PCR. General primers in L1 followed by reverse line blot

Hybrid Capture 2™

INNO-LiPATM

Coronal sulcus, glans, prepuce, shaft. Self-sampling with penile swab

24.5

25.6

36.9

Coronal sulcus, glans, urethra, shaft. Dacron swab

29.1

Shaft. Smear with swab

N/A

43.3

35.2

20.8

20.3

68.1

Paraurethra‡

Glans, prepuce, shaft, scrotum. Smear with swab

Glans, corona. Sterilized brush or Dacron swab§

Coronal sulcus, glans, prepuce, urethra, shaft. Cytobrush

Urethra. Swab

Coronal sulcus, glans, prepuce, shaft‡. Smear with dry cotton-tipped swab and wet Cytobrush Urethra. Sample with Cytobrush

N/A

19.3

N/A

N/A

49.4

N/A

31.0

12.6

4.7

23.4

N/A

10.3

N/A

N/A

N/A

N/A

4.2

N/A

12.5

12.8

*Fifty sexual partners of women with CIN3 †One hundred men with gonorrhea ‡Also sampled from the urethra § Also sampled from the shaft, perianal area, and urethra CIN = cervical intraepithelial neoplasia; CIS = carcinoma in situ; HPV = human papillomavirus; HR = high risk; LR = low risk; MSM = men who have sex with men; N/A = not available; PCR = polymerase chain reaction; SD = standard deviation; STD = sexually transmitted disease; STI = sexually transmitted infection

Italy, 2003–2005

Giovannelli et al. [51]

HPV among Men in Europe 7

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8 military conscripts [31,33,34,37]. The general population studies also included e.g., male partners of pregnant women [38] and of women in the general population [32] and family planning clinic attendees [35]. The number of samples adequate for HPV testing ranged from 79 to 530. Most articles were published before 1999 [30–36] and, in most, samples were collected from more than one site, including the glans, prepuce, sulcus, urethra, and scrotal and perineal areas [30,32,34,36,37,39], whereas in four studies only the urethra was sampled [31,33,35,38]. PCR was the most commonly used method for detecting HPV DNA [31,33,34,36–39]; filter hybridization was used in three studies [30,32,35]. No studies provided information on HIV status. Circumcision status was reported in one article where 1/40 (2.5%) was circumcised [32]. Prevalence estimates of any HPV were reported in all but one article [39]; HR and LR HPV prevalences were estimated in one article (Table 1A) [36]. The study-specific and pooled HPV prevalences from the nine studies of the general population reporting an estimate of any HPV are presented in Figure 2A. The pooled prevalence of any HPV was 12.4% (95% CI, 5.6–21.5), but the HPV prevalence in individual studies varied widely, from 0% (95% CI, 0.0–4.0) in a small, early study using filter hybridization [32] to 33.8% (95% CI, 28.8–39.2) in a larger study using PCR [37]. Wide statistical heterogeneity was therefore found between studies (I2 = 96.3%, P < 0.0001). We examined the pooled HPV prevalence in relation to publication year, geographical region, anatomical sampling site, and HPV detection method to identify factors that could explain the between-study variation (Table 2A). The pooled HPV prevalence of 8.8% (95% CI, 3.8–15.8) in studies published during 1987–1999 was much lower than in recent studies (28.5%; 95% CI, 18.3–40.0) and the variable was statistically significant in the univariable metaregression analysis (P = 0.0179). Although the HPV prevalence in northern (13.7%; 95% CI, 5.0– 26.0) and southern Europe (12.6%; 95% CI, 0.0– 42.4) was higher than in western Europe (5.9%; 95% CI, 4.0–8.0), the difference was not statistically significant (P = 0.8186). The HPV prevalence was generally higher in studies with PCR-based detection (15.8%; 95% CI, 7.5–26.5) than with non-PCR based detection (6.7%; 95% CI, 0.0– 23.1), but the difference was not statistically significant (P = 0.2362). Moreover, we found no statistically significant difference when we looked separately at studies in which PCR with typeJ Sex Med **;**:**–**

Hebnes et al. specific, general, or mixed primers was used (data not shown). With respect to anatomical site sampled, an unexpectedly higher HPV prevalence was observed in urethral samples only (18.0%; 95% CI, 10.6–26.8) than in samples from other penile sites (8.6%; 95% CI, 1.2–21.7), however, with this difference not being statistically significant (P = 0.2742). In the meta-regression analysis adjusted by publication year, the heterogeneity could not be explained by geographical region (P = 0.9644), anatomical site (P = 0.1836), or HPV DNA detection method (P = 0.4977). We also performed the analysis restricted to include only the studies based on the PCR detection method. This gave a pooled HPV prevalence estimate of 15.8% (95% CI, 7.5–26.5), and we observed a similar picture for the other factors as in the full analysis (data not shown). Estimates of the prevalence of HPV6, 11, 16, 18, 31, 33, 45, 52, and 58 were reported in seven articles [30,31,33,35,36,38,39]. The HPV types tested for differed between the studies but most determined the prevalence of HPV6/11, 6, 16, and 33 [31,33,36,38,39]. In studies investigating more than one HPV type, HPV16 tended to be among the most common (prevalence 0.6–3.9%) (data not shown).

High-Risk Population High-risk populations were studied in 23 articles, with results for 6,515 men (Table 1B). Northern Europe was represented in most publications (n = 10) [32,40,42–44,47,48,53,56,57]; eight studies were conducted in southern Europe [36,46,51,52,54,55,58,59] and five in western Europe [41,45,49,50,60]. No studies were conducted in eastern Europe. Fourteen articles were published after 1999 [47–60]. Most studies were conducted among STD clinic attendees [42– 49,53,55–57,59,60], some of whom had genital warts [43,52]. The high-risk population also included HIV-positive men attending an outpatient HIV clinic [59] and men with symptoms of nongonococcal urethritis recruited at an outpatient urological department [46]. The remaining studies were conducted among male sexual partners of women with HPV, CIN, CIS, or invasive cervical cancer [32,36,41,50,51,54]. In one case-control study, the control group consisted of sexual partners of women with chlamydial cervicitis and the case group comprised partners of women with CIN3 [40]. Two studies were based on samples collected from the coronal sulcus and from the shaft only [49,57]; the urethra was the sampling site used

HPV among Men in Europe

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Figure 2A Forest plot of the study-specific and pooled prevalence of any human papillomavirus (HPV) and 95% confidence intervals (CIs) in the general population.

in four studies [43,46,52,53], but most studies were based on samples from other penile sites [32,36,40– 42,44,45,47,48,50,51,54–56,58–60]. PCR was used for HPV detection in most studies [36,42–51,53– 60], filter hybridization in three [32,40,41], and Hybrid Capture 2™ in one [52]. Information on HIV status was provided in five studies

[48,49,52,59,60], in two of which no men tested HIV-positive [52,60]. In the remaining three studies, 3/198 (1.5%) [48], 17/258 (6.6%) [49], and 648/648 (100%) [59] were HIV-positive. HPV prevalence estimates among HIV-positive men were presented separately in only two articles [49,59]. Circumcision status was reported in five

Figure 2B Forest plot of the study-specific and pooled prevalence of any human papillomavirus (HPV) and 95% confidence intervals (CIs) in high-risk populations.

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Table 2A Pooled prevalence of any HPV among men in the general population by publication year, geographical region, anatomical sampling site, and HPV detection method Variable Total Publication year 1987–1999 2000–2013 Geographical region Northern Europe Southern Europe Western Europe Anatomical sampling site Urethra Other penile sites† HPV detection method PCR Non-PCR‡

No. of studies

Sample size

Pooled HPV prevalence, %

9

1,863

12.4

95% CI

P for unadjusted test of moderator

P for adjusted test of moderator*

0.0179

N/A

5.6–21.5

7 2

1,398 465

8.8 28.5

3.8–15.8 18.3–40.0

6 2 1

1,083 250 530

13.7 12.6 5.9

5.0–26.0 0.0–42.4 4.0–8.0

4 5

450 1,413

18.0 8.6

10.6–26.8 1.2–21.7

6 3

1,164 699

15.8 6.7

7.5–26.5 0.0–23.1

I2 (%) 96.3 93.2 82.6

0.8186

0.9644 96.1 96.3 —

0.2742

0.1836 80.8 97.9

0.2362

0.4977 95.0 96.0

*Adjusted for publication year †Including the glans, coronal sulcus, preputium, shaft, scrotum, and perineum ‡ Hybrid capture 2, Southern blot, and filter hybridization (in situ hybridization, dot blot, and slot blot) CI = confidence interval; HPV = human papillomavirus; N/A = not available; PCR = polymerase chain reaction

articles [32,48,52,54,59]; none reported HPV prevalence among circumcised individuals separately. In two studies, there were no circumcised men [52,54], in the rest, 7/91 (7.7%) [32], 24/198 (12.1%) [48], and 166/733 (22.6%) were circumcised [59]. All but one article [56] presented the prevalence of any HPV; 10 studies had information on HR HPV prevalence [36,43,49–54,56,59], and six articles reported LR HPV prevalence estimates [36,50–52,54,59]. The number of samples adequate for HPV sampling ranged from 41 to 1,318. Figure 2B shows the study-specific and pooled prevalence of any HPV in the 22 HR studies

reporting an estimate of any HPV. The pooled prevalence was 30.9% (95% CI, 25.4–36.7), but the prevalence varied widely among studies from 4.9% (95% CI, 0.6–16.5) [32] to 72.9% (95% CI, 65.8– 79.3) [50], resulting in substantial between-study heterogeneity (I2 = 95.6%, P < 0.0001). Although not statistically significant, the pooled prevalence from the urethra (23.4%; 95% CI, 18.1–29.2) was lower than from other penile sites (32.7%; 95% CI, 26.2–39.6). Remarkably, the variables publication year, geographical region, anatomical sampling site, and HPV detection method, each assessed separately, had no significant effect on pooled HPV prevalence in the unadjusted analysis (Table 2B).

Table 2B Pooled prevalence of any HPV among men from high-risk populations by publication year, geographical region, anatomical sampling site, and HPV detection method Variable Total Publication year 1987–1999 2000–2013 Geographical region Northern Europe Southern Europe Western Europe Anatomical sampling site Urethra Other penile sites† HPV detection method PCR Non-PCR‡

No. of studies

Sample size

Pooled HPV prevalence, %

95% CI

22

6,428

30.9

25.4–36.7

9 13

1,249 5,179

27.0 33.7

18.4–36.7 26.2–41.3

9 8 5

1,565 3,088 1,775

26.1 33.5 35.0

16.75–36.7 26.5–40.9 18.3–53.8

4 18

917 5,511

23.4 32.7

18.1–29.2 26.2–39.6

18 4

6,092 336

32.8 21.8

26.7–38.3 9.3–37.7

P for unadjusted test of moderator

P for adjusted test of moderator*

0.2852

N/A

95.6 93.2 96.8 0.4378

0.3745 94.9 93.1 97.9

0.1892

0.2453 70.9 96.1

0.1491

*Adjusted for publication year †Including the glans, coronal sulcus, preputium, shaft, scrotum, and perineum ‡Hybrid capture 2, Southern blot, and filter hybridization (in situ hybridization, dot blot, and slot blot) CI = confidence interval; HPV = human papillomavirus; N/A = not available; PCR = polymerase chain reaction

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I2 (%)

0.2346 96.2 89.7

HPV among Men in Europe Moreover, we found no variation for the variable detection method when we looked at studies using PCR with type-specific, general, or mixed primers (data not shown). We also examined whether the source population (i) sexual partners of women with HPV, CIN, CIS, or cervical cancer, or (ii) STD clinic attendees had an impact on HPV prevalence. The pooled prevalence was 28.6% (95% CI, 23.4– 34.2) among STD clinic attendees and 36.1% (95% CI, 18.1–56.5) among sexual partners of women with HPV, CIN, CIS, or cervical cancer. Metaregression analysis showed no significant impact of this variable on HPV prevalence (P = 0.2139) (data not shown). In the adjusted meta-regression analysis, we found that none of the prespecified variables could explain the heterogeneity in the HPV prevalence: geographical region: (P = 0.3745); anatomical sampling site: (P = 0.2453), and HPV detection method (P = 0.2346). Type-specific prevalence estimates were reported in 19 articles [32,36,40–43,45– 48,50,51,53–57,59,60]. The types tested for varied between the studies; however, most reported prevalence estimates of HPV6, 16, 18, 31, and 33 [36,40,43,45–48,50,51,53–57,59,60]. In studies reporting prevalence estimates for more than one HPV type, the commonest HPV types detected were HPV6 (1.7–14.7%), HPV16 (2.9–34.8%), and HPV18 (0.4–25.4%) (data not shown).

Publication Bias Publication bias was tested by funnel plot of the standard error of the prevalence of any HPV reported in the 31 studies (data not shown). Using the Egger regression test, we found no evidence of publication bias (P = 0.7881). Discussion

In this systematic review and meta-analysis of studies examining HPV prevalence among men in Europe, we identified 31 studies, of which 10 reported prevalence estimates for the general population and 23 reported estimates for HR populations. One of the main findings of our study was the wide heterogeneity in HPV prevalence within both populations. As expected, the highest pooled HPV prevalence (30.9%) was observed among 6,428 men in high-risk populations. The pooled HPV prevalence was 12.4% in 2,217 men in the general population, among which we also observed the pooled prevalence to be significantly higher in studies published after 2000 (28.5%) than in earlier studies (8.8%). In the

11 meta-regression analysis adjusted for publication year, none of the a priori defined variables (geographical region, anatomical sampling site, or HPV detection method) explained the wide heterogeneity of results. HPV16 tended to be the most common HR HPV type in both populations; however, generally type-specific prevalence estimates were based on few samples. This is, to our knowledge, the first meta-analysis of HPV prevalence among men in Europe. Smith et al. [15] reviewed studies of the prevalence of genital HPV among men worldwide, including European low- and high-risk populations; however, they did not include all the studies that we used in our analysis. The review of Smith et al. included studies reporting HPV prevalence from biopsy material and anal and seminal samples, whereas we restricted our analysis to studies based on scrape or swab specimens from the urethra, the penis from glans to scrotum, and the perineal area. Prevalence estimates from seminal samples are lower than those from scrape and swab samples from the external genitalia [14], and estimates from anal samples depend on the population studied [61]. By restricting the analysis to studies based on scrape or swab specimens from penile sites, we have potentially reduced some of the heterogeneity between studies in the estimates of HPV prevalence. We evaluated a possible change in HPV prevalence over time due to changes in e.g., lifestyle habits and sexual behavior by examining the effect of publication year (as a proxy measure of time of HPV sampling). In the unadjusted metaregression analysis, the pooled HPV prevalence was significantly lower in seven studies published before 2000 than in the two most recent studies in the general population. PCR-based HPV detection methods, which are considered the most sensitive [25], were used in only four of the seven studies published before 2000. The lower pooled prevalence in earlier publications might therefore be due to the detection method used and potentially not to a change in HPV prevalence over time. It has been reported that the optimal sampling sites for detection of genital HPV DNA in men are the glans, corona, prepuce, and shaft of the penis, whereas the urethra is less favorable because it yields lower HPV prevalence estimates [14,24]. Few studies included in our analyses were based on urethral samples. As expected, in the high-risk population, the pooled prevalence based on urethral samples was lower than that based on other penile sites, whereas the converse was true for the J Sex Med **;**:**–**

12 general population. Nevertheless, when we investigated the influence of sampling site on HPV prevalence in a meta-regression analysis, no association was found. Urethral samples are difficult to obtain [14] and varying prevalence estimates from urethra have been reported [12], which could partly explain our finding that sampling site had no statistically significant influence on HPV prevalence. HPV prevalence among men varies both between and within geographical regions across the world [15,39]. Although the pooled prevalence in the general population was higher in some regions, we found no statistically significant association between geographical region and HPV prevalence. However, no studies in eastern Europe were found. In a recent meta-analysis of women with normal cytology, the prevalence of cervical HPV was higher in eastern Europe than in the rest of Europe [62]. Thus, the absence of studies from that region might be part of the explanation why we did not observe a geographical difference. It has been reported that nearly half of all penile cancers and most anal cancers among men are attributable to HPV [7]. The commonest types detected in penile and anal cancers are HPV16 and 18 [3,5,61]. We found that the type-specific prevalence varied widely in the high-risk population. Nevertheless, the most prevalent types among all men in the studied populations were HPV6, 16, and 18—types all covered by available vaccines. These were also the types most commonly investigated and reported. Hence, other less wellstudied HPV types could potentially be equally or more prevalent. However, type-specific data were consistently based on few samples, thus results should be interpreted with caution. HPV vaccination of girls will in theory also benefit the male population through herd immunity. However, vaccinating boys would reduce HPV-related disease in both sexes to a greater extent than herd immunity, which depends on high vaccination rates among females. Furthermore, men who have sex with men, who are particularly susceptible to HPV-related anal cancer, would benefit from vaccination programs for boys. In our analysis of heterogeneity between studies, none of the selected variables significantly affected HPV prevalence in the general population or in the high-risk population. Therefore, other factors such as age, lifetime number of sexual partners, HIV, and circumcision status might be an additional source of variance in HPV prevalence and should be considered. Age-specific prevalence curves among men [15,63] are flatter than those J Sex Med **;**:**–**

Hebnes et al. described for women [64,65], and results pointing toward an association between age and HPV infection in men have been inconsistent. Younger age is associated with more sexual risk-taking behavior and the risk for acquiring HPV infection increases with the number of recent and lifetime sexual partners [37,48,66–68]. Nevertheless, we had no information on lifetime number of sexual partners and age-specific prevalence estimates were available in very few studies. The prevalence of genital HPV is increased in HIV-positive men [69,70]. We included one study of HIV-positive men only [59]. Of the remaining four articles providing information on HIV status, three did not present HPV prevalence results separately for HIV-positive men. Thus, with the information available, we were not able to investigate the association between HIV status and HPV prevalence in our analysis. Circumcision status might also result in differences in HPV prevalence. It has been reported that circumcision reduces the acquisition and increases clearance of HPV [71,72]. However, details on circumcision status were only available in five studies [32,48,52,54,59] and since prevalence estimates were not reported separately for circumcised men, we were not able to include the results in the meta-analysis. Differences in lifestyle habits such as smoking and drinking might also partly explain the variation in prevalence estimates among men in Europe. A strength of our study is that the review and meta-analysis were based on a thorough literature search, with data extracted independently by two authors to minimize errors. We included studies of HPV prevalence estimates based on samples from penile sites only, which improved the comparability of the sampling methods. In addition, stratifying the studies by population type (general population vs. high-risk populations) might have reduced between-study heterogeneity. One limitation is that we included studies published from 1987 onward, when the detection methods used were often less sensitive than those used more recently. Thus, the pooled HPV prevalence in this study might be underestimated. Furthermore, we present cross-sectional prevalence estimates and cannot evaluate the persistence of HPV infection, which plays an important role in the cancer pathway. Conclusions

Assessing HPV prevalence in men and investigating the sources of variation are essential for understanding the epidemiology of HPV infection. It

13

HPV among Men in Europe forms a baseline estimate of HPV in men before the HPV vaccination has been introduced in boys, and the results could also be valuable in the decision on whether to implement vaccination programs for boys. HPV infection is highly prevalent in men in both the general and high-risk populations in Europe. Not surprisingly, we found substantial heterogeneity in HPV prevalence in subpopulations. This variation was associated with publication year, but in the adjusted metaregression analyses, the heterogeneity in the two types of population could not be explained by geographical region, anatomical sampling site, or HPV DNA detection method. The variation in HPV prevalence might be due to differences in e.g., sexual behavior and the age-distribution of populations. HPV16 was the most commonly detected HR HPV type. Future research should include more studies on HPV prevalence in the general male population, studies on age-specific prevalence, and studies in eastern Europe. Corresponding Author: Susanne K. Kjaer, MD, DMSc, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Tel: +45-3525-7663; Fax: +45-3527-1811; E-mail: [email protected] Conflict of Interest: Susanne K. Kjaer received lecture fees, advisory board fees, and unrestricted grants through her institution from Merck and Sanofi Pasteur MSD. Christian Munk received lecture fees and support for conference participation from Sanofi Pasteur MSD. Julie B. Hebnes, Tina B. Olesen, Anne Katrine DuunHenriksen, and Bodil Norrild declared no conflicts of interest. Statement of Authorship

Category 1 (a) Conception and Design Julie B. Hebnes; Tina B. Olesen; Susanne K. Kjaer (b) Acquisition of Data Julie B. Hebnes; Tina B. Olesen; Bodil Norrild (c) Analysis and Interpretation of Data Julie B. Hebnes; Tina B. Olesen; Anne Katrine Duun-Henriksen; Christian Munk; Bodil Norrild; Susanne K. Kjaer

Category 2 (a) Drafting the Article Julie B. Hebnes; Tina B. Olesen; Susanne K. Kjaer (b) Revising It for Intellectual Content Julie B. Hebnes; Tina B. Olesen; Anne Katrine Duun-Henriksen; Christian Munk; Bodil Norrild; Susanne K. Kjaer

Category 3 (a) Final Approval of the Completed Article Julie B. Hebnes; Tina B. Olesen; Anne Katrine Duun-Henriksen; Christian Munk; Bodil Norrild; Susanne K. Kjaer

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Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s website: Appendix S1 Search terms used in PubMed.

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