MAJOR ARTICLE
Early Acquisition of Anogenital Human Papillomavirus Among Teenage Men Who Have Sex With Men Huachun Zou,1 Sepehr N. Tabrizi,2,3,4 Andrew E. Grulich,5 Suzanne M. Garland,2,3,4 Jane S. Hocking,6 Catriona S. Bradshaw,1,7,8 Andrea Morrow,7 Garrett Prestage,5,9 Alyssa M. Cornall,3,4 Christopher K. Fairley,1,7,9,a and Marcus Y. Chen1,7,9,a 1
(See the editorial commentary by Cranston on pages 635–8.)
Background. Anogenital human papillomavirus (HPV) is common among men who have sex with men (MSM) and causes anal cancer. This study examined the determinants of initial anogenital HPV infection among teenage MSM. Methods. Two hundred MSM aged 16 to 20 years were recruited via community and other sources. Men were tested for HPV DNA from the anus and penis. Results. The proportion of men with anal HPV of any type increased from 10.0% in men reporting no prior receptive anal sex to 47.3% in men reporting ≥4 receptive anal sex partners (P < .001).A similar pattern was also seen with HPV type 16 (P = .044). The proportion of men with penile HPV increased from 3.7% in men reporting no prior insertive anal sex to 14.8% in men reporting ≥4 insertive anal sex partners (P = .014). Overall, 39.0% (95% confidence interval (CI), 32.2%−46.1%) of men had at least 1 HPV type: 23.0% (95% CI, 17.4%−29.5%) had a vaccine-preventable type (6, 11, 16 or 18). Conclusions. Early and high per partner transmission of HPV occurred between men soon after their first sexual experiences. HPV vaccination needs to commence early for maximal prevention of HPV among MSM. Keywords. human papillomavirus; HPV; men who have sex with men; vaccination; sexually transmitted infections.
The human papillomavirus (HPV) is the most prevalent viral sexually transmitted infection (STI) worldwide and is the cause of genital warts and HPV-associated neoplasia [1]. Men who have sex with men (MSM) are a major risk group for STIs including HIV and they have a high prevalence of anogenital HPV infection and HPV-
Received 13 September 2013; accepted 2 October 2013; electronically published 21 November 2013. a Joint last authors. Correspondence: Associate Professor Marcus Y. Chen, 580 Swanston Street, Carlton, Victoria, Australia, 3055 ([email protected]). The Journal of Infectious Diseases 2014;209:642–51 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/infdis/jit626
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related lesions including anogenital warts, anal intraepithelial neoplasia, and anal cancer [2–4]. Data indicate that the incidence of anal cancer among MSM is high, with the highest rates among HIV-positive MSM [2, 5]. In a metaanalysis of published studies, overall, 63% of HIV-negative and 92% of HIV-positive MSM were infected with anal HPV. The overall prevalence of HPV 16, the HPV type most commonly associated with anal cancer, among HIV-negative and HIV-positive MSM was 12% and 35%, respectively [6]. The quadrivalent HPV vaccine is effective in preventing infection with HPV types 6, 11, 16, and 18; in preventing the development of genital warts in males [7]; and in protecting against anal intraepithelial neoplasia in MSM [8]. Mathematical modeling suggests that HPV vaccination of MSM is likely to be cost effective [9].
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School of Population and Global Health, University of Melbourne, Melbourne, Australia; 2Department of Obstetrics and Gynaecology, University of Melbourne; 3Department of Microbiology and Infectious Diseases, Royal Women’s Hospital, Melbourne, Australia; 4Murdoch Children’s Research Institute, Melbourne, Australia; 5Kirby Institute, University of New South Wales, Sydney, Melbourne, Australia; 6Centre for Women’s Health, Gender and Society, University of Melbourne, Melbourne, Australia; 7Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia; 8Central Clinical School, Monash University, Melbourne, Australia; and 9Australian Research Centre in Sex, Health and Society, La Trobe University, Melbourne, Australia
Studies have shown a high incidence of low- and high-risk genital HPV infection associated with new sexual partners among teenage females [10]. Such studies have underscored the need for HPV vaccination prior to the onset of sexual activity. No previous studies have been designed to examine factors associated with HPV infection among teenage MSM when initial infection with HPV would be expected to occur [11]. Such data would help to inform the development of policies that govern HPV vaccination of MSM. In this study, we sought to elucidate the determinants of initial anogenital HPV infection among teenage MSM and the proportion infected with HPV.
Men used a single-use paper emery board to gently exfoliate the epidermis over the entire penile shaft and glans penis and, if uncircumcised, the inner and outer aspects of the foreskin. Men then rolled a saline-moistened swab firmly over these areas. Swabs were placed in RNA (Ambion). A physician verified anal or penile warts. Blood for HPV serology was collected in 10-mL serum collection tubes (Greiner Bio One International AG) and centrifuged at 4800 × g for 10 minutes to separate cells from serum. Serum samples were aliquoted and stored at −80°C until testing. Laboratory Methods
METHODS Subjects and Recruitment
Specimen Collection
Specimens were obtained from men for HPV DNA testing in the following order: an oral rinse, an anal canal swab, a perianal swab, and a penile swab. The oral rinse and penile swab were self-collected by men after watching a video that demonstrated how to self-collect these specimens [12]. The study nurse collected the anal and perianal swabs using a technique that prevents cross-contamination of HPV DNA between the 2 sites. For the oral rinse men, rinsed and gargled 10 mL of saline for 20 seconds. The anal swab was obtained using a salinemoistened, flocked swab (Copan Flock Technologies) that was inserted 3 cm into the anal canal and rotated 6 times. The nurse then used a single-use paper emery board to gently exfoliate the epidermis of the perianal area within 5 cm of the anus. A saline-moistened swab was then rolled over the abraded area.
HPV Serology Serum samples were tested at PPD Vaccines and Biologics Lab. Antibodies against HPV types 6, 11, 16, and 18 were measured using a Luminex competitive immunoassay as previously described [16]. STI Testing Men were screened for pharyngeal and rectal Neisseria gonorrhoeae using modified Thayer-Martin media. First-void urine and a rectal swab were tested for Chlamydia trachomatis by strand HPV infection among teenage MSM
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To be eligible for the Human Papillomavirus in Young People Epidemiological Research (HYPER) Study, participants had to be males aged 16 to 20 years who self-identified as being samesex attracted. Men were not required to have engaged in sex with other males. Men were recruited between October 2010 and September 2012 via a number of avenues that focus on gay teenage males. These included community organizations that support gay teenagers with study promotion at social events such as dance parties; gay clubs at 6 Melbourne universities; gay community events including the Midsumma Festival; gay media including radio and magazine; the study Web site; and social networking Web sites including Facebook, Twitter, and Grindr. Recruitment also took place through 3 sexual health services in Melbourne. The study nurse assessed men at a baseline visit and then 3, 6, and 12 months later. On each occasion, specimens were obtained for HPV DNA testing, blood was obtained for HPV serology, and men completed a questionnaire regarding their sexual experiences. Men were also examined for the presence of anogenital warts. The results from the baseline visit are presented here. Men were offered vaccination with Gardasil (Merck, NJ) free of charge after completing the 12- month visit.
HPV DNA Detection and Genotyping Swab and oral rinse samples were tested at the regional HPV Labnet Reference Laboratory, Molecular Microbiology Department, Royal Women’s Hospital, Melbourne. Cellular material from oral rinses was pelleted by centrifugation at 5000 × g for 15 minutes and resuspended in 400 µL of phosphate buffered saline. Total DNA was extracted from 200 μL of each swab and oral rinse sample on 1 of 2 automated extraction platforms with equal performance and using magnetic bead capture of nucleic acids, either the VERSANT kPCR Molecular System SP (Siemens) or the MagNA Pure 96 using the MagNA Pure 96 DNA and Viral NA small volume kit (Roche Diagnostics GmbH). Extracted DNA was prescreened to assess its integrity by quantitative polymerase chain reaction (PCR) amplification of a 260 base-pair product of the human beta-globin gene [13]. Samples were subsequently amplified for the HPV L1 gene using consensus primers PGMY09–PGMY11[14], and amplicons were detected using PCR enzyme-linked immunosorbent assay (ELISA; Roche Diagnostics GmbH) as described previously [15]. Briefly, a generic probe for detection of the presence of any HPV sequences in the sample was employed using biotin-labeled probes able to detect all mucosal HPV types [13, 15]. Samples that were positive by ELISA were further genotyped by HPV linear array genotyping assay (Roche Molecular Systems), which involved PCR amplification of target DNA followed by nucleic acid hybridization and detection of 37 HPV genotypes (6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51–56, 58, 59, 61, 62, 64, 66–73, 81–84, 82v, and 89). DNA samples that were negative for both beta-globin and HPV were considered unassessable and excluded from the analysis.
Table 1. Demographic Characteristics and Sexual Behaviors Among Teenage Men Who Have Sex With Men
Table 1 continued. Participant Characteristic
Participant Characteristic
No./Median (IQR)
%
%
100 10
50.3 5.0
Age of sexual partners
Demographic
Mostly older partners Mostly younger partners
Age at recruitment (year) 16
No./Median (IQR)
6.5
22
11.0
18 19
37 62
18.5 31.0
20
66
33.0
Education level Less than final year of secondary school
Ever had vaginal sex Time since first vaginal sex (years)
34
17.5
No. of females with vaginal sex over lifetime
2 (1–4)
Final year of secondary school
137
70.6
23
11.9
Condom use always with all vaginal sex partners over lifetime
14
Tertiary or university qualification Route of recruitment Universities or gay community organizations Word of mouth
49
24.7
Sexual health clinics Circumcised Yes No
127
64.1
d
Partner’s penis in participant’s anus.
29
14.5
171
85.5 18.5
No. of cigarettes smoked per day Sex with males
5 (3–15)
No. of males kissed over lifetime
15 (7–29)
Ever had insertive oral sexa Time since first insertive oral sex (years)a
191 2.7 (1.4–4.0)
No. of males with insertive oral sex over lifetimea Ever had receptive oral sexb
9 (4–15) 195
Time since first receptive oral sex (years)b
2.6 (1.3–3.8)
No. of males with receptive oral sex over lifetimeb
8 (4–15) 173
95.5
97.5
86.5
1.8 (1.0–3.1) 4 (1–8)
Condom use always with all insertive anal sex partners over lifetimec Ever had receptive anal sexd
60
34.7
170
85.0
1.9 (0.8–3.0) 4 (2–8) 65
38.2
Insertive mainly
54
27.0
Receptive mainly Insertive and receptive
71 58
35.5 29.0
Never had any anal sex Unsure
15 2
7.5 1.0
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21.6 23.1
85
42.5
39 2.8 (1.6–3.9)
19.5
36.8
displacement assay (Becton Dickinson ProbeTec ET). In addition, men were screened for syphilis using enzyme immunoassay (EIA) and rapid plasma reagin and tested for HIV using EIA. The Alfred Hospital Research Ethics Committee ( project number 174/10) and the University of Melbourne Ethics Committee ( project ID 1034462) approved this study. Written informed consent was obtained from each participant. HYPER is registered on the Australia New Zealand Clinical Trials Registry (ACTRN12611000857909) and by the National Institutes of Health (NCT01422356). Participants gave informed consent for data sharing. Statistical Analyses
Time since first insertive anal sex (years)c No. of males with insertive anal sex over lifetimec
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Partner’s penis in participant’s mouth. Participant’s penis in partner’s anus.
81.5
•
43 46
Participant’s penis in partner’s mouth.
b c
37
644
a
11.1
163
Condom use always with all receptive anal sex partners over lifetimed Predominant role in anal sex
Ever had a female partner
22
No
Time since first receptive anal sex (years)d No. of males with receptive anal sex over lifetimed
Various ages Sex with females
Abbreviations: IQR, interquartile range.
Smoker Yes
Ever had insertive anal sexc
Mostly of a similar age
A sample size of 200 men was required to provide acceptable 95% confidence intervals (CIs) around the expected proportion of men with HPV. Proportions were used for categorical variables. Median and interquartile ranges were used for continuous variables. CIs for proportions were calculated using exact methods. Univariate and multivariate logistic regression models were used to calculate odds ratios to estimate the association between potential risk factors and HPV infection. The χ2 test with a P statistic was used to assess the significance of trends in HPV prevalence with number of lifetime sexual partners and with time since first sex. Concordance between HPV 6, 11, 16, and 18 DNA and antibody results were measured using kappa scores with 95% CIs. Statistical analyses were conducted using SPSS 19.0. RESULTS Participant Characteristics
Two hundred males aged 16 to 20 years were recruited into the study. The characteristics of men including circumcision status
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Table 2.
Human Papillomavirus DNA Detection and Seropositivity Among Teenage Men Who Have Sex With Men A. DNA Positivitya and Seropositivityb HPV DNA Positivity, n (%)c Anal N = 198
HPV Type d
Any type tested
High-risk typese Any high-risk types
Perianal N = 196
Penile N = 199
Any Site N = 200
Seropositivity N = 200c
n
%
n
%
n
%
n
%
n
%
61
30.8
60
30.6
19
9.5
78
39.0
...
...
21.7
47
24.0
15
7.5
62
31.0
...
...
10
5.1
9
4.6
3
1.5
13
6.5
7
3.5
HPV 18 HPV 26
4 0
2.0 0
3 0
1.5 0
2 0
1.0 0
6 0
3.0 0
6 ...
3.0 ...
HPV 31
0
0
0
0
0
0
0
0
...
...
HPV 33 HPV 35
0 1
0 0.5
0 1
0 0.5
0 1
0 0.5
0 2
0 1.0
... ...
... ...
HPV 39
2
1.0
2
1.0
1
0.5
4
2.0
...
...
HPV 45 HPV 51
7 7
3.5 3.5
7 11
3.6 5.6
2 2
1.0 1.0
9 12
4.5 6.0
... ...
... ...
HPV 52
0
0
0
0
0
0
0
0
...
...
HPV 53 HPV 56
7 1
3.5 0.5
6 1
3.1 0.5
1 0
0.5 0
9 1
4.5 0.5
... ...
... ...
HPV 58
1
0.5
2
1.0
0
0
2
1.0
...
...
HPV 59 HPV 66
8 8
4.0 4.0
8 8
4.0 4.0
2 6
1.0 3.0
10 14
5.0 7.0
... ...
... ...
HPV 67
3
1.5
4
2.0
1
0.5
6
3.0
...
...
HPV 68 HPV 69
2 1
1.0 0.5
0 1
0 0.5
0 0
0 0
2 1
1.0 0.5
... ...
... ...
HPV 70
1
0.5
1
0.5
0
0
1
0.5
...
...
HPV 73 HPV 82
3 3
1.5 1.5
4 7
2.0 3.6
2 1
1.0 0.5
7 7
3.5 3.5
... ...
... ...
Any low-risk type HPV 6
47 22
23.7 11.1
45 16
23.0 8.2
13 3
6.5 1.5
61 25
30.5 12.5
25
12.5
HPV 11
14
7.1
15
7.5
4
2.0
19
9.5
14
7.0
HPV 40 HPV 42
1 4
0.5 2.0
2 3
1.0 1.5
1 3
0.5 1.5
3 7
1.5 3.5
... ...
... ...
HPV 54
2
1.0
3
1.5
0
0
4
2.0
...
...
HPV 55 HPV 61
0 0
0 0
0 0
0 0
0 0
0 0
1 0
0.5 0
... ...
... ...
HPV 62
2
1.0
2
1.0
1
0.5
1
0.5
...
...
HPV 64 HPV 71
0 0
0 0
0 0
0 0
0 0
0 0
0 0
0 0
... ...
... ...
HPV 72
0
0
1
0.5
0
0
1
0.5
...
...
HPV 81 HPV 83
3 0
1.5 0
3 1
1.5 0.5
1 1
0.5 0.5
4 2
2.0 1.0
... ...
... ...
HPV 84
7
3.5
7
3.6
2
1.0
11
5.5
...
...
HPV 82v HPV 89
1 7
0.5 3.5
1 7
0.5 3.6
0 5
0 2.5
1 11
0.5 5.5
... ...
... ...
HPV 6/11/16/18 HPV 6/11
39 33
19.7 16.7
35 29
17.9 14.8
9 6
4.5 3.0
46 39
23.0 19.5
39 33
19.5 16.5
HPV 16/18
14
7.1
12
6.1
5
2.5
19
9.5
11
5.5
Low-risk typese
Vaccine-preventable typesf
HPV infection among teenage MSM
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HPV16
Table 2 continued. B. Detection of Multiple HPV Types HPV DNA Positivity, n (%) Anal N = 198 No. HPV Type Detected
n
Perianal N = 196 %
Any type Range
n
Penile N = 199 %
0–7
n
Any Site N = 200 %
0–6
n
0–5
Seropositivity N = 200 %
n
%
...
...
0–9
...
0
137
69.2
136
69.4
180
90.5
122
61.0
...
...
1 2
25 16
12.6 8.1
22 18
11.2 9.2
7 5
3.5 2.5
24 22
12.0 11.0
... ...
... ...
3
13
6.6
9
4.6
2
1.0
15
7.5
...
...
7
3.5
11
5.6
5
2.5
17
8.5
...
...
4+ Vaccine-preventable types
0–2
0–2
0–3
0–3
0–3
0 1
159 28
80.3 14.1
161 27
82.1 13.8
190 7
95.5 3.5
154 30
77.0 15.0
161 29
80.5 14.5
2 3
11 0
5.6 0
8 0
4.1 0
1 1
0.5 0.5
15 1
7.5 0.5
7 3
3.5 1.5
Abbreviations: HPV, human papillomavirus. a
HPV DNA includes swabs from the anus, perianal area, and penis and oral rinse. Four men tested positive for HPV DNA from the oral rinse: data not shown in table.
b
Seropositivity was determined for HPV types 6, 11, 16, and 18.
c
Eight samples for HPV DNA were excluded from the analysis due to insufficient sample.
d
Any of the 37 HPV types tested.
e
Classification based on Schiffman et al [1]. High risk types: HPV 16, 18, 26, 31, 33, 35, 39, 45, 51–53, 56, 58, 59, 66–70, 73, or 82. Low risk types: HPV 6, 11, 40, 42, 54, 55, 61, 62, 64, 71, 72, 81, 83, 84, 82v, or 89. f
Quadrivalent vaccine types refer to HPV types 6, 11, 16, and 18.
and lifetime sexual experience are shown in Table 1. The median age was 19 years. Most men had previously engaged in insertive (86.5%) and receptive anal sex (85.0%) with men; 19.5% reported past vaginal sex with women. Men reported a median duration of 1.9 years since first receptive anal sex with a man. Thirty-six percent of men were recruited from gay community sources, universities, or by word of mouth and 64% were recruited from sexual health clinics. Anal warts were present in 7.0% of men and penile warts were present in 1.0% of men. The proportion with pharyngeal gonorrhea, rectal gonorrhea, urethral chlamydia, rectal chlamydia, and early latent syphilis at baseline was 3.0%, 5.5%, 3.0%, 4.0%, and 1.0%, respectively. All men were HIV negative. HPV DNA Detection and Genotypes
One anal swab sample and 1 perianal sample that was unavailable as well as 3 perianal samples and 1 penile swab sample that were beta-globin negative were excluded from the analysis. The proportion of men with each of the 37 HPV types detected by PCR is shown in Table 2A by anatomical site. Overall, 39.0% (95% CI, 32.2%–46.1%) of men had at least 1 of the 37 HPV types detected at any of the anatomical sites tested, with 23.0% (95% CI, 17.4%–29.5%) having at least 1 of the quadrivalent 646
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vaccine-preventable types (HPV 6, 11, 16, and 18) present. The prevalence of HPV of any type was significantly higher in the anal canal (30.8%; 95% CI, 24.5%–37.7%) than the penis (9.5%; 95% CI, 5.8%–14.5%; P < .001) and oral rinse (2.0%; 95% CI, .6%–5.1%; P < .001). The proportion of men who had at least 1 of the quadrivalent vaccine–preventable HPV types was higher in the anal canal (19.7%; 95% CI, 14.4%–25.9%) than the penis (4.5%; 95% CI, 2.1%–8.4%; P < .001) and oral rinse (0.5%; 95% CI, 0%–2.8%; P < .001). There was high concordance between HPV types detected from the anal canal and perianal swabs (kappa = 0.80; 95% CI, .71–.89). At least 1 high-risk HPV type was found at any site in 31.0% (95% CI, 24.7%–38.0%) of men. Anal HPV type 16 DNA was found in 5.1% (95% CI, 2.4%–9.1%) of men. Multiple HPV DNA types were commonly found on the penis and in the anal canal. Infection with ≥2 HPV types was present in 11.0% of men (Table 2B). Anal HPV was absent in 27 of the 30 men who reported no prior receptive anal sex. HPV Seropositivity
The proportion of men who were seropositive for HPV types 6, 11, 16, and 18 was 12.5% (95% CI, 8.3%–17.9%), 7.0% (95% CI, 3.9%–11.5%), 3.5% (95% CI, 1.4%–7.1%), and 3.0% (95% CI,
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Range
Table 3.
Concordance Between Human PapillomavirusDNA and Serology Results
HPV DNA HPV 6 DNA
HPV 6 Antibody Detected Not detected
Detected
Not detected
14 11
11 164
Agreement Kappa, 95% CI 0.50 (.30, .70)
HPV 11 Antibody HPV 11 DNA
Detected
Not detected
Detected
7
12
Not detected
7
174
Detected
Detected 3
Not detected 10
Not detected
4
183
Detected
Detected 1
Not detected 5
Not detected
5
189
0.37 (.11, .64)
HPV 16 Antibody HPV 16 DNA
0.27 (−.10, .64)
HPV 18 Antibody 0.14 (−.38, .66)
Abbreviation: CI, confidence interval; HPV,human papillomavirus.
1.1%–6.4%), respectively. Five percent (95% CI, 2.4%–9.0%) were seropositive for 2 or more HPV types. Concordance between HPV DNA and antibody results ranged from low to moderate (kappa scores, 0.14–0.50) between the 4 HPV types (Table 3). Factors Associated With Anal and Penile HPV DNA Detection
The factors associated with detection of HPV DNA of any type in the anal canal and penis are shown in Table 4A and 4B, respectively. In the multivariate model, smoking (adjusted odds ratio [AOR] = 2.30; 95% CI, 1.04–5.28) and having 4 or more receptive anal sex partners in the prior 12 months (AOR = 3.74; 95% CI, 1.64–8.50) were significantly associated with anal HPV. A history of vaginal sex was significantly associated with detection of penile HPV DNA in the multivariate model (AOR = 4.50; 95% CI, 1.70–12.10). Nineteen (11.1%) of the 171 uncircumcised men but none of the 29 circumcised men had penile HPV detected (P = .059). Trends in the proportion of men with anal and penile HPV and numbers of lifetime anal/vaginal sex partners are shown in Figure 1A, C, E, and G. The proportion of men with anal HPV DNA of any type increased significantly from 10.0% in men who reported no prior receptive anal sex to 47.3% in men who reported 4 or more receptive anal sex partners (P < .001). Similarly, the proportion of men with anal HPV DNA of any type increased significantly, with increasing numbers of receptive anal sex partners with whom condoms were used inconsistently, with HPV among 52.0% among men who had 2 or more such partners (P = .002). The proportion of men with HPV type 16 DNA increased significantly from 0% in men who reported no prior receptive anal sex to 7.9% in men who reported
4 or more receptive anal sex partners (P = .044). Among the 30 men who had never had receptive anal sex, 70% reported being fingered anally and 83% reported receiving penile contact with their anus without penetration. The proportion of men with penile HPV DNA of any type increased significantly from 3.7% in men who reported no prior insertive anal sex to 14.8% in men who reported 4 or more insertive anal sex partners (P = .014). The proportion of men with penile HPV DNA of any type increased significantly from 6.2% in men who reported no prior vaginal sex to 57.1% in men who reported 4 or more vaginal sex partners (P < .001). Trends in the proportion of men with anal and penile HPV DNA and time since first anal or vaginal sex are shown in Figure 1B, D, F, and H. The proportion of men with anal HPV DNA of any type, anal HPV 16 DNA specifically, and penile HPV DNA of any type increased significantly with time since first anal sex with another man. The proportion of men with penile HPV DNA of any type increased significantly with time since first vaginal sex with a woman. When asked at the first study visit if they would be willing to disclose their sexuality to a doctor if the HPV vaccine was available free of charge, 85.5% indicated they would; 96.0% of men accepted HPV vaccination following completion of the study. Of the 173 men who had a doctor who provided care, 55.5% had already disclosed their sexuality for other reasons. DISCUSSION In this study, the proportion of men infected with HPV increased with each additional reported sex partner. These data HPV infection among teenage MSM
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HPV 18 DNA
Table 4. Men
Factors Associated With Anal and Penile Human Papillomavirus DNA Detection Among Teenage Men Who Have Sex With
Risk Factor
% (no. with HPV/no. men)
Crude OR (95% CI)
Adjusted OR (95% CI)
A. Anal HPV of Any Type Age difference with male sex partners Similar age
1
1
Mostly older
35.0 (35/100)
16.3 (7/43)
2.77 (1.12–6.87)
1.82 (.67–4.97)
Mostly younger Both older and younger
10.0 (1/10) 39.1 (18/46)
0.57 (.06–5.26) 3.31 (1.21–9.01)
0.90 (.09–8.71) 1.73 (.57–5.24)
Mainly insertive Mainly receptive
20.4 (11/54) 40.8 (29/71)
1 2.70 (1.20–6.09)
1 1.29 (.48–3.52)
Insertive and receptive
32.8 (19/58)
1.90 (.81–4.50)
1.32 (.49–3.55)
Role in anal sex with males
Current smoker No No. receptive anal sex partners in the past 12 moa ≤3 ≥4
27.0 (44/163)
1
1
45.9 (17/37)
2.30 (1.10–4.79)
2.30 (1.04–5.28)
19.6 (27/138)
1
1
54.8 (34/62)
5.00 (2.60–9.60)
3.74 (1.64–8.50)
Condom use in receptive anal sex during the past 12 moa No receptive anal sex in past 12 mo 10.0 (3/30) Inconsistent condom use Condom always B. Penile HPV of Any Type
1
1
38.8 (33/85)
5.7 (1.60–20.34)
1.35 (.23–7.77)
29.4 (25/85)
3.8 (1.04–13.50)
1.20 (.22–6.62)
6.7 (11/163) 21.6 (8/37)
1 3.81 (1.41–10.30)
1 2.72 (.94–7.87)
5.0 (6/121) 16.5 (13/79)
1 3.78 (1.37–10.40)
1 2.77 (.88–8.77)
Current smoker No Yes No. of insertive anal sex partners in the past 12 mob ≤2 ≥3
Condom use with insertive anal sex during the past 12 mob No insertive anal sex in past 12 mo Inconsistent condom use
3.7 (1/27) 10.5 (10/95)
1 3.06 (.37–25.03)
1 1.13 (.11–11.44)
Condom always
10.3 (8/78)
2.97 (.35–24.93)
1.42 (.15–13.50)
Ever had vaginal sex with a woman No Yes
6.2 (10/161) 23.1 (9/39)
1
1
4.50(1.70–12.10)
3.52 (1.26–9.82)
Abbreviations: CI, confidence interval; HPV, human papillomavirus; OR, odds ratio. a
Partner’s penis in participant’s anus.
b
Participant’s penis in partner’s anus.
suggest early and high per partner transmission of HPV among MSM soon after their first sexual experience. These data indicate that HPV vaccination needs to commence early for maximal prevention of HPV among MSM. While there have been previous studies of anal HPV among MSM, most of these cases have been in older men, most of whom have already had high numbers of sexual partners and who, in many cases, are HIV positive. These studies have shown that most adult MSM have anal HPV infection [6]. In contrast, data from this study suggest a greater prevalence of anal HPV among teenage MSM, from men with limited sexual 648
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experience to those who have accrued an increasing number of receptive anal sex partners. This applies to anal HPV 16 specifically, the HPV type most commonly found in anal cancers; HPV 16 increased in prevalence with increasing numbers of receptive anal sex partners. Approximately 10% of men who reported never receiving anal sex had anal HPV detected, possibly reflecting transmission via sexual behaviors other than receptive anal sex. Our study is unique in that it is one of the first to specifically focus on initial HPV infection among teenage MSM, with men recruited from a variety of sources. Data on HPV infection in
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Yes
teenage MSM are scarce. In a systematic review, there were only 6 studies that combined provided data on anal HPV for a total of 698 MSM aged ≤25 years, most of whom were aged >20 years. Previous studies have had potential biases, for example, sole recruitment from clinics including STD clinics; selection criteria that are potentially biased toward higher-risk or lower-
risk men; and studies where teenage MSM only comprised a small subset of men [11]. Most data are from a study that was designed to determine HPV vaccine efficacy among MSM rather than HPV prevalence. In that study, MSM were aged 17 to 27 years, with a median age of 22 years, and reported fewer than 5 lifetime sexual partners [17]. In another study, the HPV infection among teenage MSM
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Figure 1. Proportion of men with anal and penile human papillomavirus (HPV) and number of lifetime anal or vaginal sex partners or time since first anal or vaginal sex. Proportion of men with (A) anal HPV of any type and number of lifetime receptive anal sex partners; (B) anal HPV of any type and years since first receptive anal sex; (C) anal HPV type 16 and number of lifetime receptive anal sex partners; (D) anal HPV type 16 and years since first receptive anal sex; (E) penile HPV of any type and number of lifetime insertive anal sex partners; (F ) penile HPV of any type and years since first insertive anal sex; (G) proportion with penile HPV of any type and number of lifetime vaginal sex partners; and (H) proportion with penile HPV of any type and years since first vaginal sex.
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would be greater. Second, the data on HPV presented here are cross-sectional, with detection of HPV at 1 time point. Studies suggest that detection of HPV DNA at a single time point may represent contamination from very recent sexual contact as opposed to established HPV infection, which has generally been defined by the presence of the same HPV type at 2 separate time points [29]. In this study, the overall proportion of men with anal HPV was 3 times higher than for penile HPV. This may suggest that the anal mucosa is more susceptible to HPV infection than the keratinized, squamous epithelium of the penis or that the duration of anal HPV infection is longer, or it may reflect more receptive anal sex. Longitudinal studies have verified the persistence of HPV infection in the anus among MSM, particularly those who are HIV positive [30, 31]. In Australia, starting in 2013, free universal HPV vaccination was rolled out among males aged 12 to 13 years with a catch-up program in 2013 and 2014 for males aged 14 to 15 years. This will be part of an existing national school-based vaccination program that targets girls aged 12 to 13 years. Of interest will be the effect that male vaccination has on the prevalence of HPV-associated disease in males including MSM, though the benefits from cancer prevention may not be evident for years. The additional benefit to men and women that the 9-valent HPV vaccine, which also protects against HPV types 31, 33, 45, 52, and 58, warrants research. Notes Acknowledgments. We extend our thanks to the following organizations and individuals for their support: Minus18; Australian Life Styles Organisation (ALSO) Foundation; Youth Action Kommittee (YAK); the Action Centre; Family Planning Victoria; queer clubs at the University of Melbourne, Royal Melbourne Institute of Technology (RMIT), Monash University, Deakin University, Latrobe University, Victoria University; Joy FM; Melbourne Community Voice (MCV); Rainbow Network Victoria; Gay and Lesbian Health Victoria; Country Awareness Network (CAN) Resource Centre; Prahran Market Clinic; Tim Read; Lenka Vodstrcil; David Lee; Matiu Bush; Mark Chung; Helen Henzell; Helen Kent; Julie Silvers; Rabia Thomson; staff at the Melbourne Sexual Health Centre; Ed Yap; David Towl; Greg Adkins; Amanda Grattan and Merck Australia; TaNisha Evans; Sneha Kishnani; and Tania Tabone. Contributors. This study was conceived and designed by M. Y. C. and C. K. F. in consultation with the other authors. H. Z. designed the questionnaire and was responsible for data collection and analysis. S. N. T. and A. M. C. supervised HPV testing. All authors have contributed to interpretation of data and study findings. H. Z., C. K. F., and M. Y. C. drafted the manuscript with all authors critically reviewing the paper. Transparency declaration. The guarantor of this paper affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Data sharing statement. Participants gave informed consent for data sharing. Information in any publication arising from this study is provided in a way that participants cannot be identified. If chlamydia, gonorrhea, syphilis, or human immunodeficiency virus shows up on participants’ tests, infection would be reported to the Health Department as required by law, but without revealing participants’ identity.
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number of male receptive anal sex partners was also found to be significantly associated with anal infection, as in our study. However, the number of men in that study was much smaller than in our study and men were on average older and selected based on sexual behavior [18]. Among men in this study, the proportion with penile HPV also rose incrementally with increasing numbers of insertive anal sex partners but to an overall proportion that remained lower than for anal infection. Furthermore, among men who were also having sex with women, the prevalence of penile HPV rose with increasing number of vaginal sex partners. While there have been studies of early genital HPV acquisition in young females, which as in this study suggests a high rate of HPV transmission per partner [10], ours is the first study to examine early acquisition of penile HPV in any teenage male population. Although several studies have shown that male circumcision is protective against penile HPV infection, these are the first data to suggest there is also a protective effect of male circumcision against HPV among MSM, indicating that circumcision may be protective against the acquisition of penile HPV infection via insertive anal sex [19–21]. While receptive oral sex among men in this study was common, oral HPV was uncommon. The rapid rise in HPV prevalence seen in this population of young MSM underscores the need to vaccinate such men against HPV at the earliest possible time, ideally prior to the onset of sexual activity. The age of first anal sex among MSM in Australia has fallen over time. In one study, the median age of first anal sex among younger MSM was 18 [22], similar to age 17 years reported in this study. To date, while the number of countries with HPV vaccination programs targeting females increases, with evidence of falling HPV-related disease [23–26], no country, except for Australia, has implemented universal vaccination of schoolaged boys despite evidence for the potential additional benefit this might confer [27]. While universal vaccination of schoolaged boys would confer maximal prevention against HPV among MSM, in its absence, opportunistic vaccination of young MSM could still be beneficial. However, for targeted vaccination of MSM to achieve maximum HPV prevention, young MSM would need to be willing to disclose their sexuality in order to obtain the vaccine at a time when they are not already infected with HPV. The willingness to make such a disclosure may differ between different populations of MSM. In one study, MSM would only have disclosed their sexuality to obtain the HPV vaccine after a median of 15 male sex partners, a point at which many would already have been infected [28]. There are limitations to this study. First, the findings from this study may or may not extend to other populations of teenage MSM. A lower HPV prevalence would be expected among teenaged MSM who are less sexually experienced than those in this study. In such populations the potential benefit from opportunistic HPV vaccination targeting young MSM
References 1. Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer 2009; 4:8. 2. Chin-Hong PV, Vittinghoff E, Cranston RD, et al. Age-specific prevalence of anal human papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE study. J Infect Dis 2004; 190:2070–6. 3. Palefsky JM, Holly EA, Ralston ML, et al. Anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual and bisexual men: prevalence and risk factors. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17:320–6. 4. Palefsky JM, Holly EA, Ralston ML, Jay N. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis 1998; 177:361–7. 5. Grulich AE, Jin F, Conway EL, Stein AN, Hocking J. Cancers attributable to human papillomavirus infection. Sex Health 2010; 7: 244–52. 6. 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; 13:487–500. 7. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 2011; 364:401–11. 8. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 2011; 365:1576–85. 9. Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis. Lancet Infect Dis 2010; 10:845–52. 10. Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003; 157:218–26. 11. Zou H, Fairley C, Hocking J, Garland S, Grulich A, Chen M. The prevalence of anal human papillomavirus among young HIV negative men who have sex with men. BMC Infect Dis 2012; 12:341.
12. Read TR, Hocking JS, Vodstrcil LA, et al. Oral human papillomavirus in men having sex with men: risk-factors and sampling. PLoS One 2012; 7:e49324. 13. Resnick RM, Cornelissen MT, Wright DK, et al. Detection and typing of human papillomavirus in archival cervical cancer specimens by DNA amplification with consensus primers. J Natl Cancer Inst 1990; 82:1477–84. 14. Gravitt PE, Peyton CL, Alessi TQ, et al. Improved amplification of genital human papillomaviruses. J Clin Microbiol 2000; 38:357–61. 15. Layton-Henry J, Scurry J, Planner R, et al. Cervical adenoid basal carcinoma, five cases and literature review. Int J Gynecol Cancer 1996; 6:193–9. 16. Opalka D, Lachman CE, MacMullen SA, et al. Simultaneous quantitation of antibodies to neutralizing epitopes on virus-like particles for human papillomavirus types 6, 11, 16, and 18 by a multiplexed luminex assay. Clin Diagn Lab Immunol 2003; 10:108–15. 17. Goldstone S, Palefsky JM, Giuliano AR, et al. Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men. J Infect Dis 2011; 203:66–74. 18. Glick SN, Feng Q, Popov V, Koutsky LA, Golden MR. High rates of incident and prevalent anal human papillomavirus infection among young men who have sex with men. J Infect Dis 2014; 209: 369–76. 19. 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; 199:14–9. 20. Tobian AA, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009; 360:1298–309. 21. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002; 346:1105–12. 22. Lyons A, Pitts M, Grierson J, Smith A, McNally S, Couch M. Age at first anal sex and HIV/STI vulnerability among gay men in Australia. Sex Transm Infect 2012; 88:252–7. 23. Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet 2011; 377: 2085–92. 24. Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis 2011; 11:39–44. 25. Fairley CK, Hocking JS, Gurrin LC, Chen MY, Donovan B, Bradshaw CS. Rapid decline in presentations of genital warts after the implementation of a national quadrivalent human papillomavirus vaccination programme for young women. Sex Transm Infect 2009; 85:499–502. 26. Read TR, Hocking JS, Chen MY, Donovan B, Bradshaw CS, Fairley CK. The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination programme. Sex Transm Infect 2011; 87:544–7. 27. Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis 2007; 13:28–41. 28. Simatherai D, Bradshaw CS, Fairley CK, Bush M, Heley S, Chen MY. What men who have sex with men think about the human papillomavirus vaccine. Sex Transm Infect 2009; 85:148–9. 29. Widdice L, Ma Y, Jonte J, et al. Concordance and transmission of human papillomavirus within heterosexual couples observed over short intervals. J Infect Dis 2013; 207:1286–94. 30. Nyitray AG, Carvalho da Silva RJ, Baggio ML, et al. Age-specific prevalence of and risk factors for anal human papillomavirus (HPV) among men who have sex with women and men who have sex with men: the HPV in men (HIM) study. J Infect Dis 2011; 203:49–57. 31. de Pokomandy A, Rouleau D, Ghattas G, et al. Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study. J Infect Dis 2009; 199:965–73.
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Financial support. This work was supported, in part, by a research grant from the Investigator Initiated Studies Program of Merck Sharp Dohme (grant number 39379). This study was in part funded by an National Health and Medical Research Council (NHMRC) Program grant (568971). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp and Dohme or NHMRC. Potential conflicts of interest. This investigator-initiated study was funded by Merck. Merck had no input into the design, analysis, or reporting of the study. C. K. F. has received honoraria from CSL Biotherapies and Merck and research funding from CSL Biotherapies. C. K. F. owns shares in CSL Biotherapies, the manufacturer for Gardasil. J. S. H. has received an honorarium from CSL Biotherapies and is an investigator on an Australian Research Council–funded project (LP0883831) that includes CSL Biotherapies as a research partner. A. E. G. has received honoraria and untied research funding from CSL Biotherapies and has received honoraria from Merck. S. M. G. has received advisory board fees and grant support from CSL Biotherapies and GlaxoSmithKline and lecture fees from Merck, Glaxo Smith Kline (GSK), and Sanofi Pasteur; in addition, she has received funding through her institution to conduct HPV vaccine studies for Merck Sharp Dohme (MSD) and GlaxoSmithKline. S. M. G. is a member of the Merck Global Advisory Board as well as the Merck Scientific Advisory Committee for HPV. None of this relates to this specific work. M. Y. C. reported his institution received a grant from Merck Sharp Dohme that supported the conduct of the study. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Early Acquisition of Anogenital Human Papillomavirus Among Teenage Men Who Have Sex With Men Huachun Zou,1 Sepehr N. Tabrizi,2,3,4 Andrew E. Grulich,5 Suzanne M. Garland,2,3,4 Jane S. Hocking,6 Catriona S. Bradshaw,1,7,8 Andrea Morrow,7 Garrett Prestage,5,9 Alyssa M. Cornall,3,4 Christopher K. Fairley,1,7,9,a and Marcus Y. Chen1,7,9,a 1
(See the editorial commentary by Cranston on pages 635–8.)
Background. Anogenital human papillomavirus (HPV) is common among men who have sex with men (MSM) and causes anal cancer. This study examined the determinants of initial anogenital HPV infection among teenage MSM. Methods. Two hundred MSM aged 16 to 20 years were recruited via community and other sources. Men were tested for HPV DNA from the anus and penis. Results. The proportion of men with anal HPV of any type increased from 10.0% in men reporting no prior receptive anal sex to 47.3% in men reporting ≥4 receptive anal sex partners (P < .001).A similar pattern was also seen with HPV type 16 (P = .044). The proportion of men with penile HPV increased from 3.7% in men reporting no prior insertive anal sex to 14.8% in men reporting ≥4 insertive anal sex partners (P = .014). Overall, 39.0% (95% confidence interval (CI), 32.2%−46.1%) of men had at least 1 HPV type: 23.0% (95% CI, 17.4%−29.5%) had a vaccine-preventable type (6, 11, 16 or 18). Conclusions. Early and high per partner transmission of HPV occurred between men soon after their first sexual experiences. HPV vaccination needs to commence early for maximal prevention of HPV among MSM. Keywords. human papillomavirus; HPV; men who have sex with men; vaccination; sexually transmitted infections.
The human papillomavirus (HPV) is the most prevalent viral sexually transmitted infection (STI) worldwide and is the cause of genital warts and HPV-associated neoplasia [1]. Men who have sex with men (MSM) are a major risk group for STIs including HIV and they have a high prevalence of anogenital HPV infection and HPV-
Received 13 September 2013; accepted 2 October 2013; electronically published 21 November 2013. a Joint last authors. Correspondence: Associate Professor Marcus Y. Chen, 580 Swanston Street, Carlton, Victoria, Australia, 3055 ([email protected]). The Journal of Infectious Diseases 2014;209:642–51 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/infdis/jit626
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related lesions including anogenital warts, anal intraepithelial neoplasia, and anal cancer [2–4]. Data indicate that the incidence of anal cancer among MSM is high, with the highest rates among HIV-positive MSM [2, 5]. In a metaanalysis of published studies, overall, 63% of HIV-negative and 92% of HIV-positive MSM were infected with anal HPV. The overall prevalence of HPV 16, the HPV type most commonly associated with anal cancer, among HIV-negative and HIV-positive MSM was 12% and 35%, respectively [6]. The quadrivalent HPV vaccine is effective in preventing infection with HPV types 6, 11, 16, and 18; in preventing the development of genital warts in males [7]; and in protecting against anal intraepithelial neoplasia in MSM [8]. Mathematical modeling suggests that HPV vaccination of MSM is likely to be cost effective [9].
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School of Population and Global Health, University of Melbourne, Melbourne, Australia; 2Department of Obstetrics and Gynaecology, University of Melbourne; 3Department of Microbiology and Infectious Diseases, Royal Women’s Hospital, Melbourne, Australia; 4Murdoch Children’s Research Institute, Melbourne, Australia; 5Kirby Institute, University of New South Wales, Sydney, Melbourne, Australia; 6Centre for Women’s Health, Gender and Society, University of Melbourne, Melbourne, Australia; 7Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia; 8Central Clinical School, Monash University, Melbourne, Australia; and 9Australian Research Centre in Sex, Health and Society, La Trobe University, Melbourne, Australia
Studies have shown a high incidence of low- and high-risk genital HPV infection associated with new sexual partners among teenage females [10]. Such studies have underscored the need for HPV vaccination prior to the onset of sexual activity. No previous studies have been designed to examine factors associated with HPV infection among teenage MSM when initial infection with HPV would be expected to occur [11]. Such data would help to inform the development of policies that govern HPV vaccination of MSM. In this study, we sought to elucidate the determinants of initial anogenital HPV infection among teenage MSM and the proportion infected with HPV.
Men used a single-use paper emery board to gently exfoliate the epidermis over the entire penile shaft and glans penis and, if uncircumcised, the inner and outer aspects of the foreskin. Men then rolled a saline-moistened swab firmly over these areas. Swabs were placed in RNA (Ambion). A physician verified anal or penile warts. Blood for HPV serology was collected in 10-mL serum collection tubes (Greiner Bio One International AG) and centrifuged at 4800 × g for 10 minutes to separate cells from serum. Serum samples were aliquoted and stored at −80°C until testing. Laboratory Methods
METHODS Subjects and Recruitment
Specimen Collection
Specimens were obtained from men for HPV DNA testing in the following order: an oral rinse, an anal canal swab, a perianal swab, and a penile swab. The oral rinse and penile swab were self-collected by men after watching a video that demonstrated how to self-collect these specimens [12]. The study nurse collected the anal and perianal swabs using a technique that prevents cross-contamination of HPV DNA between the 2 sites. For the oral rinse men, rinsed and gargled 10 mL of saline for 20 seconds. The anal swab was obtained using a salinemoistened, flocked swab (Copan Flock Technologies) that was inserted 3 cm into the anal canal and rotated 6 times. The nurse then used a single-use paper emery board to gently exfoliate the epidermis of the perianal area within 5 cm of the anus. A saline-moistened swab was then rolled over the abraded area.
HPV Serology Serum samples were tested at PPD Vaccines and Biologics Lab. Antibodies against HPV types 6, 11, 16, and 18 were measured using a Luminex competitive immunoassay as previously described [16]. STI Testing Men were screened for pharyngeal and rectal Neisseria gonorrhoeae using modified Thayer-Martin media. First-void urine and a rectal swab were tested for Chlamydia trachomatis by strand HPV infection among teenage MSM
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To be eligible for the Human Papillomavirus in Young People Epidemiological Research (HYPER) Study, participants had to be males aged 16 to 20 years who self-identified as being samesex attracted. Men were not required to have engaged in sex with other males. Men were recruited between October 2010 and September 2012 via a number of avenues that focus on gay teenage males. These included community organizations that support gay teenagers with study promotion at social events such as dance parties; gay clubs at 6 Melbourne universities; gay community events including the Midsumma Festival; gay media including radio and magazine; the study Web site; and social networking Web sites including Facebook, Twitter, and Grindr. Recruitment also took place through 3 sexual health services in Melbourne. The study nurse assessed men at a baseline visit and then 3, 6, and 12 months later. On each occasion, specimens were obtained for HPV DNA testing, blood was obtained for HPV serology, and men completed a questionnaire regarding their sexual experiences. Men were also examined for the presence of anogenital warts. The results from the baseline visit are presented here. Men were offered vaccination with Gardasil (Merck, NJ) free of charge after completing the 12- month visit.
HPV DNA Detection and Genotyping Swab and oral rinse samples were tested at the regional HPV Labnet Reference Laboratory, Molecular Microbiology Department, Royal Women’s Hospital, Melbourne. Cellular material from oral rinses was pelleted by centrifugation at 5000 × g for 15 minutes and resuspended in 400 µL of phosphate buffered saline. Total DNA was extracted from 200 μL of each swab and oral rinse sample on 1 of 2 automated extraction platforms with equal performance and using magnetic bead capture of nucleic acids, either the VERSANT kPCR Molecular System SP (Siemens) or the MagNA Pure 96 using the MagNA Pure 96 DNA and Viral NA small volume kit (Roche Diagnostics GmbH). Extracted DNA was prescreened to assess its integrity by quantitative polymerase chain reaction (PCR) amplification of a 260 base-pair product of the human beta-globin gene [13]. Samples were subsequently amplified for the HPV L1 gene using consensus primers PGMY09–PGMY11[14], and amplicons were detected using PCR enzyme-linked immunosorbent assay (ELISA; Roche Diagnostics GmbH) as described previously [15]. Briefly, a generic probe for detection of the presence of any HPV sequences in the sample was employed using biotin-labeled probes able to detect all mucosal HPV types [13, 15]. Samples that were positive by ELISA were further genotyped by HPV linear array genotyping assay (Roche Molecular Systems), which involved PCR amplification of target DNA followed by nucleic acid hybridization and detection of 37 HPV genotypes (6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51–56, 58, 59, 61, 62, 64, 66–73, 81–84, 82v, and 89). DNA samples that were negative for both beta-globin and HPV were considered unassessable and excluded from the analysis.
Table 1. Demographic Characteristics and Sexual Behaviors Among Teenage Men Who Have Sex With Men
Table 1 continued. Participant Characteristic
Participant Characteristic
No./Median (IQR)
%
%
100 10
50.3 5.0
Age of sexual partners
Demographic
Mostly older partners Mostly younger partners
Age at recruitment (year) 16
No./Median (IQR)
6.5
22
11.0
18 19
37 62
18.5 31.0
20
66
33.0
Education level Less than final year of secondary school
Ever had vaginal sex Time since first vaginal sex (years)
34
17.5
No. of females with vaginal sex over lifetime
2 (1–4)
Final year of secondary school
137
70.6
23
11.9
Condom use always with all vaginal sex partners over lifetime
14
Tertiary or university qualification Route of recruitment Universities or gay community organizations Word of mouth
49
24.7
Sexual health clinics Circumcised Yes No
127
64.1
d
Partner’s penis in participant’s anus.
29
14.5
171
85.5 18.5
No. of cigarettes smoked per day Sex with males
5 (3–15)
No. of males kissed over lifetime
15 (7–29)
Ever had insertive oral sexa Time since first insertive oral sex (years)a
191 2.7 (1.4–4.0)
No. of males with insertive oral sex over lifetimea Ever had receptive oral sexb
9 (4–15) 195
Time since first receptive oral sex (years)b
2.6 (1.3–3.8)
No. of males with receptive oral sex over lifetimeb
8 (4–15) 173
95.5
97.5
86.5
1.8 (1.0–3.1) 4 (1–8)
Condom use always with all insertive anal sex partners over lifetimec Ever had receptive anal sexd
60
34.7
170
85.0
1.9 (0.8–3.0) 4 (2–8) 65
38.2
Insertive mainly
54
27.0
Receptive mainly Insertive and receptive
71 58
35.5 29.0
Never had any anal sex Unsure
15 2
7.5 1.0
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21.6 23.1
85
42.5
39 2.8 (1.6–3.9)
19.5
36.8
displacement assay (Becton Dickinson ProbeTec ET). In addition, men were screened for syphilis using enzyme immunoassay (EIA) and rapid plasma reagin and tested for HIV using EIA. The Alfred Hospital Research Ethics Committee ( project number 174/10) and the University of Melbourne Ethics Committee ( project ID 1034462) approved this study. Written informed consent was obtained from each participant. HYPER is registered on the Australia New Zealand Clinical Trials Registry (ACTRN12611000857909) and by the National Institutes of Health (NCT01422356). Participants gave informed consent for data sharing. Statistical Analyses
Time since first insertive anal sex (years)c No. of males with insertive anal sex over lifetimec
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Partner’s penis in participant’s mouth. Participant’s penis in partner’s anus.
81.5
•
43 46
Participant’s penis in partner’s mouth.
b c
37
644
a
11.1
163
Condom use always with all receptive anal sex partners over lifetimed Predominant role in anal sex
Ever had a female partner
22
No
Time since first receptive anal sex (years)d No. of males with receptive anal sex over lifetimed
Various ages Sex with females
Abbreviations: IQR, interquartile range.
Smoker Yes
Ever had insertive anal sexc
Mostly of a similar age
A sample size of 200 men was required to provide acceptable 95% confidence intervals (CIs) around the expected proportion of men with HPV. Proportions were used for categorical variables. Median and interquartile ranges were used for continuous variables. CIs for proportions were calculated using exact methods. Univariate and multivariate logistic regression models were used to calculate odds ratios to estimate the association between potential risk factors and HPV infection. The χ2 test with a P statistic was used to assess the significance of trends in HPV prevalence with number of lifetime sexual partners and with time since first sex. Concordance between HPV 6, 11, 16, and 18 DNA and antibody results were measured using kappa scores with 95% CIs. Statistical analyses were conducted using SPSS 19.0. RESULTS Participant Characteristics
Two hundred males aged 16 to 20 years were recruited into the study. The characteristics of men including circumcision status
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17
Table 2.
Human Papillomavirus DNA Detection and Seropositivity Among Teenage Men Who Have Sex With Men A. DNA Positivitya and Seropositivityb HPV DNA Positivity, n (%)c Anal N = 198
HPV Type d
Any type tested
High-risk typese Any high-risk types
Perianal N = 196
Penile N = 199
Any Site N = 200
Seropositivity N = 200c
n
%
n
%
n
%
n
%
n
%
61
30.8
60
30.6
19
9.5
78
39.0
...
...
21.7
47
24.0
15
7.5
62
31.0
...
...
10
5.1
9
4.6
3
1.5
13
6.5
7
3.5
HPV 18 HPV 26
4 0
2.0 0
3 0
1.5 0
2 0
1.0 0
6 0
3.0 0
6 ...
3.0 ...
HPV 31
0
0
0
0
0
0
0
0
...
...
HPV 33 HPV 35
0 1
0 0.5
0 1
0 0.5
0 1
0 0.5
0 2
0 1.0
... ...
... ...
HPV 39
2
1.0
2
1.0
1
0.5
4
2.0
...
...
HPV 45 HPV 51
7 7
3.5 3.5
7 11
3.6 5.6
2 2
1.0 1.0
9 12
4.5 6.0
... ...
... ...
HPV 52
0
0
0
0
0
0
0
0
...
...
HPV 53 HPV 56
7 1
3.5 0.5
6 1
3.1 0.5
1 0
0.5 0
9 1
4.5 0.5
... ...
... ...
HPV 58
1
0.5
2
1.0
0
0
2
1.0
...
...
HPV 59 HPV 66
8 8
4.0 4.0
8 8
4.0 4.0
2 6
1.0 3.0
10 14
5.0 7.0
... ...
... ...
HPV 67
3
1.5
4
2.0
1
0.5
6
3.0
...
...
HPV 68 HPV 69
2 1
1.0 0.5
0 1
0 0.5
0 0
0 0
2 1
1.0 0.5
... ...
... ...
HPV 70
1
0.5
1
0.5
0
0
1
0.5
...
...
HPV 73 HPV 82
3 3
1.5 1.5
4 7
2.0 3.6
2 1
1.0 0.5
7 7
3.5 3.5
... ...
... ...
Any low-risk type HPV 6
47 22
23.7 11.1
45 16
23.0 8.2
13 3
6.5 1.5
61 25
30.5 12.5
25
12.5
HPV 11
14
7.1
15
7.5
4
2.0
19
9.5
14
7.0
HPV 40 HPV 42
1 4
0.5 2.0
2 3
1.0 1.5
1 3
0.5 1.5
3 7
1.5 3.5
... ...
... ...
HPV 54
2
1.0
3
1.5
0
0
4
2.0
...
...
HPV 55 HPV 61
0 0
0 0
0 0
0 0
0 0
0 0
1 0
0.5 0
... ...
... ...
HPV 62
2
1.0
2
1.0
1
0.5
1
0.5
...
...
HPV 64 HPV 71
0 0
0 0
0 0
0 0
0 0
0 0
0 0
0 0
... ...
... ...
HPV 72
0
0
1
0.5
0
0
1
0.5
...
...
HPV 81 HPV 83
3 0
1.5 0
3 1
1.5 0.5
1 1
0.5 0.5
4 2
2.0 1.0
... ...
... ...
HPV 84
7
3.5
7
3.6
2
1.0
11
5.5
...
...
HPV 82v HPV 89
1 7
0.5 3.5
1 7
0.5 3.6
0 5
0 2.5
1 11
0.5 5.5
... ...
... ...
HPV 6/11/16/18 HPV 6/11
39 33
19.7 16.7
35 29
17.9 14.8
9 6
4.5 3.0
46 39
23.0 19.5
39 33
19.5 16.5
HPV 16/18
14
7.1
12
6.1
5
2.5
19
9.5
11
5.5
Low-risk typese
Vaccine-preventable typesf
HPV infection among teenage MSM
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HPV16
Table 2 continued. B. Detection of Multiple HPV Types HPV DNA Positivity, n (%) Anal N = 198 No. HPV Type Detected
n
Perianal N = 196 %
Any type Range
n
Penile N = 199 %
0–7
n
Any Site N = 200 %
0–6
n
0–5
Seropositivity N = 200 %
n
%
...
...
0–9
...
0
137
69.2
136
69.4
180
90.5
122
61.0
...
...
1 2
25 16
12.6 8.1
22 18
11.2 9.2
7 5
3.5 2.5
24 22
12.0 11.0
... ...
... ...
3
13
6.6
9
4.6
2
1.0
15
7.5
...
...
7
3.5
11
5.6
5
2.5
17
8.5
...
...
4+ Vaccine-preventable types
0–2
0–2
0–3
0–3
0–3
0 1
159 28
80.3 14.1
161 27
82.1 13.8
190 7
95.5 3.5
154 30
77.0 15.0
161 29
80.5 14.5
2 3
11 0
5.6 0
8 0
4.1 0
1 1
0.5 0.5
15 1
7.5 0.5
7 3
3.5 1.5
Abbreviations: HPV, human papillomavirus. a
HPV DNA includes swabs from the anus, perianal area, and penis and oral rinse. Four men tested positive for HPV DNA from the oral rinse: data not shown in table.
b
Seropositivity was determined for HPV types 6, 11, 16, and 18.
c
Eight samples for HPV DNA were excluded from the analysis due to insufficient sample.
d
Any of the 37 HPV types tested.
e
Classification based on Schiffman et al [1]. High risk types: HPV 16, 18, 26, 31, 33, 35, 39, 45, 51–53, 56, 58, 59, 66–70, 73, or 82. Low risk types: HPV 6, 11, 40, 42, 54, 55, 61, 62, 64, 71, 72, 81, 83, 84, 82v, or 89. f
Quadrivalent vaccine types refer to HPV types 6, 11, 16, and 18.
and lifetime sexual experience are shown in Table 1. The median age was 19 years. Most men had previously engaged in insertive (86.5%) and receptive anal sex (85.0%) with men; 19.5% reported past vaginal sex with women. Men reported a median duration of 1.9 years since first receptive anal sex with a man. Thirty-six percent of men were recruited from gay community sources, universities, or by word of mouth and 64% were recruited from sexual health clinics. Anal warts were present in 7.0% of men and penile warts were present in 1.0% of men. The proportion with pharyngeal gonorrhea, rectal gonorrhea, urethral chlamydia, rectal chlamydia, and early latent syphilis at baseline was 3.0%, 5.5%, 3.0%, 4.0%, and 1.0%, respectively. All men were HIV negative. HPV DNA Detection and Genotypes
One anal swab sample and 1 perianal sample that was unavailable as well as 3 perianal samples and 1 penile swab sample that were beta-globin negative were excluded from the analysis. The proportion of men with each of the 37 HPV types detected by PCR is shown in Table 2A by anatomical site. Overall, 39.0% (95% CI, 32.2%–46.1%) of men had at least 1 of the 37 HPV types detected at any of the anatomical sites tested, with 23.0% (95% CI, 17.4%–29.5%) having at least 1 of the quadrivalent 646
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vaccine-preventable types (HPV 6, 11, 16, and 18) present. The prevalence of HPV of any type was significantly higher in the anal canal (30.8%; 95% CI, 24.5%–37.7%) than the penis (9.5%; 95% CI, 5.8%–14.5%; P < .001) and oral rinse (2.0%; 95% CI, .6%–5.1%; P < .001). The proportion of men who had at least 1 of the quadrivalent vaccine–preventable HPV types was higher in the anal canal (19.7%; 95% CI, 14.4%–25.9%) than the penis (4.5%; 95% CI, 2.1%–8.4%; P < .001) and oral rinse (0.5%; 95% CI, 0%–2.8%; P < .001). There was high concordance between HPV types detected from the anal canal and perianal swabs (kappa = 0.80; 95% CI, .71–.89). At least 1 high-risk HPV type was found at any site in 31.0% (95% CI, 24.7%–38.0%) of men. Anal HPV type 16 DNA was found in 5.1% (95% CI, 2.4%–9.1%) of men. Multiple HPV DNA types were commonly found on the penis and in the anal canal. Infection with ≥2 HPV types was present in 11.0% of men (Table 2B). Anal HPV was absent in 27 of the 30 men who reported no prior receptive anal sex. HPV Seropositivity
The proportion of men who were seropositive for HPV types 6, 11, 16, and 18 was 12.5% (95% CI, 8.3%–17.9%), 7.0% (95% CI, 3.9%–11.5%), 3.5% (95% CI, 1.4%–7.1%), and 3.0% (95% CI,
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Range
Table 3.
Concordance Between Human PapillomavirusDNA and Serology Results
HPV DNA HPV 6 DNA
HPV 6 Antibody Detected Not detected
Detected
Not detected
14 11
11 164
Agreement Kappa, 95% CI 0.50 (.30, .70)
HPV 11 Antibody HPV 11 DNA
Detected
Not detected
Detected
7
12
Not detected
7
174
Detected
Detected 3
Not detected 10
Not detected
4
183
Detected
Detected 1
Not detected 5
Not detected
5
189
0.37 (.11, .64)
HPV 16 Antibody HPV 16 DNA
0.27 (−.10, .64)
HPV 18 Antibody 0.14 (−.38, .66)
Abbreviation: CI, confidence interval; HPV,human papillomavirus.
1.1%–6.4%), respectively. Five percent (95% CI, 2.4%–9.0%) were seropositive for 2 or more HPV types. Concordance between HPV DNA and antibody results ranged from low to moderate (kappa scores, 0.14–0.50) between the 4 HPV types (Table 3). Factors Associated With Anal and Penile HPV DNA Detection
The factors associated with detection of HPV DNA of any type in the anal canal and penis are shown in Table 4A and 4B, respectively. In the multivariate model, smoking (adjusted odds ratio [AOR] = 2.30; 95% CI, 1.04–5.28) and having 4 or more receptive anal sex partners in the prior 12 months (AOR = 3.74; 95% CI, 1.64–8.50) were significantly associated with anal HPV. A history of vaginal sex was significantly associated with detection of penile HPV DNA in the multivariate model (AOR = 4.50; 95% CI, 1.70–12.10). Nineteen (11.1%) of the 171 uncircumcised men but none of the 29 circumcised men had penile HPV detected (P = .059). Trends in the proportion of men with anal and penile HPV and numbers of lifetime anal/vaginal sex partners are shown in Figure 1A, C, E, and G. The proportion of men with anal HPV DNA of any type increased significantly from 10.0% in men who reported no prior receptive anal sex to 47.3% in men who reported 4 or more receptive anal sex partners (P < .001). Similarly, the proportion of men with anal HPV DNA of any type increased significantly, with increasing numbers of receptive anal sex partners with whom condoms were used inconsistently, with HPV among 52.0% among men who had 2 or more such partners (P = .002). The proportion of men with HPV type 16 DNA increased significantly from 0% in men who reported no prior receptive anal sex to 7.9% in men who reported
4 or more receptive anal sex partners (P = .044). Among the 30 men who had never had receptive anal sex, 70% reported being fingered anally and 83% reported receiving penile contact with their anus without penetration. The proportion of men with penile HPV DNA of any type increased significantly from 3.7% in men who reported no prior insertive anal sex to 14.8% in men who reported 4 or more insertive anal sex partners (P = .014). The proportion of men with penile HPV DNA of any type increased significantly from 6.2% in men who reported no prior vaginal sex to 57.1% in men who reported 4 or more vaginal sex partners (P < .001). Trends in the proportion of men with anal and penile HPV DNA and time since first anal or vaginal sex are shown in Figure 1B, D, F, and H. The proportion of men with anal HPV DNA of any type, anal HPV 16 DNA specifically, and penile HPV DNA of any type increased significantly with time since first anal sex with another man. The proportion of men with penile HPV DNA of any type increased significantly with time since first vaginal sex with a woman. When asked at the first study visit if they would be willing to disclose their sexuality to a doctor if the HPV vaccine was available free of charge, 85.5% indicated they would; 96.0% of men accepted HPV vaccination following completion of the study. Of the 173 men who had a doctor who provided care, 55.5% had already disclosed their sexuality for other reasons. DISCUSSION In this study, the proportion of men infected with HPV increased with each additional reported sex partner. These data HPV infection among teenage MSM
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HPV 18 DNA
Table 4. Men
Factors Associated With Anal and Penile Human Papillomavirus DNA Detection Among Teenage Men Who Have Sex With
Risk Factor
% (no. with HPV/no. men)
Crude OR (95% CI)
Adjusted OR (95% CI)
A. Anal HPV of Any Type Age difference with male sex partners Similar age
1
1
Mostly older
35.0 (35/100)
16.3 (7/43)
2.77 (1.12–6.87)
1.82 (.67–4.97)
Mostly younger Both older and younger
10.0 (1/10) 39.1 (18/46)
0.57 (.06–5.26) 3.31 (1.21–9.01)
0.90 (.09–8.71) 1.73 (.57–5.24)
Mainly insertive Mainly receptive
20.4 (11/54) 40.8 (29/71)
1 2.70 (1.20–6.09)
1 1.29 (.48–3.52)
Insertive and receptive
32.8 (19/58)
1.90 (.81–4.50)
1.32 (.49–3.55)
Role in anal sex with males
Current smoker No No. receptive anal sex partners in the past 12 moa ≤3 ≥4
27.0 (44/163)
1
1
45.9 (17/37)
2.30 (1.10–4.79)
2.30 (1.04–5.28)
19.6 (27/138)
1
1
54.8 (34/62)
5.00 (2.60–9.60)
3.74 (1.64–8.50)
Condom use in receptive anal sex during the past 12 moa No receptive anal sex in past 12 mo 10.0 (3/30) Inconsistent condom use Condom always B. Penile HPV of Any Type
1
1
38.8 (33/85)
5.7 (1.60–20.34)
1.35 (.23–7.77)
29.4 (25/85)
3.8 (1.04–13.50)
1.20 (.22–6.62)
6.7 (11/163) 21.6 (8/37)
1 3.81 (1.41–10.30)
1 2.72 (.94–7.87)
5.0 (6/121) 16.5 (13/79)
1 3.78 (1.37–10.40)
1 2.77 (.88–8.77)
Current smoker No Yes No. of insertive anal sex partners in the past 12 mob ≤2 ≥3
Condom use with insertive anal sex during the past 12 mob No insertive anal sex in past 12 mo Inconsistent condom use
3.7 (1/27) 10.5 (10/95)
1 3.06 (.37–25.03)
1 1.13 (.11–11.44)
Condom always
10.3 (8/78)
2.97 (.35–24.93)
1.42 (.15–13.50)
Ever had vaginal sex with a woman No Yes
6.2 (10/161) 23.1 (9/39)
1
1
4.50(1.70–12.10)
3.52 (1.26–9.82)
Abbreviations: CI, confidence interval; HPV, human papillomavirus; OR, odds ratio. a
Partner’s penis in participant’s anus.
b
Participant’s penis in partner’s anus.
suggest early and high per partner transmission of HPV among MSM soon after their first sexual experience. These data indicate that HPV vaccination needs to commence early for maximal prevention of HPV among MSM. While there have been previous studies of anal HPV among MSM, most of these cases have been in older men, most of whom have already had high numbers of sexual partners and who, in many cases, are HIV positive. These studies have shown that most adult MSM have anal HPV infection [6]. In contrast, data from this study suggest a greater prevalence of anal HPV among teenage MSM, from men with limited sexual 648
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experience to those who have accrued an increasing number of receptive anal sex partners. This applies to anal HPV 16 specifically, the HPV type most commonly found in anal cancers; HPV 16 increased in prevalence with increasing numbers of receptive anal sex partners. Approximately 10% of men who reported never receiving anal sex had anal HPV detected, possibly reflecting transmission via sexual behaviors other than receptive anal sex. Our study is unique in that it is one of the first to specifically focus on initial HPV infection among teenage MSM, with men recruited from a variety of sources. Data on HPV infection in
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Yes
teenage MSM are scarce. In a systematic review, there were only 6 studies that combined provided data on anal HPV for a total of 698 MSM aged ≤25 years, most of whom were aged >20 years. Previous studies have had potential biases, for example, sole recruitment from clinics including STD clinics; selection criteria that are potentially biased toward higher-risk or lower-
risk men; and studies where teenage MSM only comprised a small subset of men [11]. Most data are from a study that was designed to determine HPV vaccine efficacy among MSM rather than HPV prevalence. In that study, MSM were aged 17 to 27 years, with a median age of 22 years, and reported fewer than 5 lifetime sexual partners [17]. In another study, the HPV infection among teenage MSM
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Figure 1. Proportion of men with anal and penile human papillomavirus (HPV) and number of lifetime anal or vaginal sex partners or time since first anal or vaginal sex. Proportion of men with (A) anal HPV of any type and number of lifetime receptive anal sex partners; (B) anal HPV of any type and years since first receptive anal sex; (C) anal HPV type 16 and number of lifetime receptive anal sex partners; (D) anal HPV type 16 and years since first receptive anal sex; (E) penile HPV of any type and number of lifetime insertive anal sex partners; (F ) penile HPV of any type and years since first insertive anal sex; (G) proportion with penile HPV of any type and number of lifetime vaginal sex partners; and (H) proportion with penile HPV of any type and years since first vaginal sex.
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would be greater. Second, the data on HPV presented here are cross-sectional, with detection of HPV at 1 time point. Studies suggest that detection of HPV DNA at a single time point may represent contamination from very recent sexual contact as opposed to established HPV infection, which has generally been defined by the presence of the same HPV type at 2 separate time points [29]. In this study, the overall proportion of men with anal HPV was 3 times higher than for penile HPV. This may suggest that the anal mucosa is more susceptible to HPV infection than the keratinized, squamous epithelium of the penis or that the duration of anal HPV infection is longer, or it may reflect more receptive anal sex. Longitudinal studies have verified the persistence of HPV infection in the anus among MSM, particularly those who are HIV positive [30, 31]. In Australia, starting in 2013, free universal HPV vaccination was rolled out among males aged 12 to 13 years with a catch-up program in 2013 and 2014 for males aged 14 to 15 years. This will be part of an existing national school-based vaccination program that targets girls aged 12 to 13 years. Of interest will be the effect that male vaccination has on the prevalence of HPV-associated disease in males including MSM, though the benefits from cancer prevention may not be evident for years. The additional benefit to men and women that the 9-valent HPV vaccine, which also protects against HPV types 31, 33, 45, 52, and 58, warrants research. Notes Acknowledgments. We extend our thanks to the following organizations and individuals for their support: Minus18; Australian Life Styles Organisation (ALSO) Foundation; Youth Action Kommittee (YAK); the Action Centre; Family Planning Victoria; queer clubs at the University of Melbourne, Royal Melbourne Institute of Technology (RMIT), Monash University, Deakin University, Latrobe University, Victoria University; Joy FM; Melbourne Community Voice (MCV); Rainbow Network Victoria; Gay and Lesbian Health Victoria; Country Awareness Network (CAN) Resource Centre; Prahran Market Clinic; Tim Read; Lenka Vodstrcil; David Lee; Matiu Bush; Mark Chung; Helen Henzell; Helen Kent; Julie Silvers; Rabia Thomson; staff at the Melbourne Sexual Health Centre; Ed Yap; David Towl; Greg Adkins; Amanda Grattan and Merck Australia; TaNisha Evans; Sneha Kishnani; and Tania Tabone. Contributors. This study was conceived and designed by M. Y. C. and C. K. F. in consultation with the other authors. H. Z. designed the questionnaire and was responsible for data collection and analysis. S. N. T. and A. M. C. supervised HPV testing. All authors have contributed to interpretation of data and study findings. H. Z., C. K. F., and M. Y. C. drafted the manuscript with all authors critically reviewing the paper. Transparency declaration. The guarantor of this paper affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Data sharing statement. Participants gave informed consent for data sharing. Information in any publication arising from this study is provided in a way that participants cannot be identified. If chlamydia, gonorrhea, syphilis, or human immunodeficiency virus shows up on participants’ tests, infection would be reported to the Health Department as required by law, but without revealing participants’ identity.
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number of male receptive anal sex partners was also found to be significantly associated with anal infection, as in our study. However, the number of men in that study was much smaller than in our study and men were on average older and selected based on sexual behavior [18]. Among men in this study, the proportion with penile HPV also rose incrementally with increasing numbers of insertive anal sex partners but to an overall proportion that remained lower than for anal infection. Furthermore, among men who were also having sex with women, the prevalence of penile HPV rose with increasing number of vaginal sex partners. While there have been studies of early genital HPV acquisition in young females, which as in this study suggests a high rate of HPV transmission per partner [10], ours is the first study to examine early acquisition of penile HPV in any teenage male population. Although several studies have shown that male circumcision is protective against penile HPV infection, these are the first data to suggest there is also a protective effect of male circumcision against HPV among MSM, indicating that circumcision may be protective against the acquisition of penile HPV infection via insertive anal sex [19–21]. While receptive oral sex among men in this study was common, oral HPV was uncommon. The rapid rise in HPV prevalence seen in this population of young MSM underscores the need to vaccinate such men against HPV at the earliest possible time, ideally prior to the onset of sexual activity. The age of first anal sex among MSM in Australia has fallen over time. In one study, the median age of first anal sex among younger MSM was 18 [22], similar to age 17 years reported in this study. To date, while the number of countries with HPV vaccination programs targeting females increases, with evidence of falling HPV-related disease [23–26], no country, except for Australia, has implemented universal vaccination of schoolaged boys despite evidence for the potential additional benefit this might confer [27]. While universal vaccination of schoolaged boys would confer maximal prevention against HPV among MSM, in its absence, opportunistic vaccination of young MSM could still be beneficial. However, for targeted vaccination of MSM to achieve maximum HPV prevention, young MSM would need to be willing to disclose their sexuality in order to obtain the vaccine at a time when they are not already infected with HPV. The willingness to make such a disclosure may differ between different populations of MSM. In one study, MSM would only have disclosed their sexuality to obtain the HPV vaccine after a median of 15 male sex partners, a point at which many would already have been infected [28]. There are limitations to this study. First, the findings from this study may or may not extend to other populations of teenage MSM. A lower HPV prevalence would be expected among teenaged MSM who are less sexually experienced than those in this study. In such populations the potential benefit from opportunistic HPV vaccination targeting young MSM
References 1. Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer 2009; 4:8. 2. Chin-Hong PV, Vittinghoff E, Cranston RD, et al. Age-specific prevalence of anal human papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE study. J Infect Dis 2004; 190:2070–6. 3. Palefsky JM, Holly EA, Ralston ML, et al. Anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual and bisexual men: prevalence and risk factors. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17:320–6. 4. Palefsky JM, Holly EA, Ralston ML, Jay N. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis 1998; 177:361–7. 5. Grulich AE, Jin F, Conway EL, Stein AN, Hocking J. Cancers attributable to human papillomavirus infection. Sex Health 2010; 7: 244–52. 6. 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; 13:487–500. 7. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 2011; 364:401–11. 8. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 2011; 365:1576–85. 9. Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis. Lancet Infect Dis 2010; 10:845–52. 10. Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003; 157:218–26. 11. Zou H, Fairley C, Hocking J, Garland S, Grulich A, Chen M. The prevalence of anal human papillomavirus among young HIV negative men who have sex with men. BMC Infect Dis 2012; 12:341.
12. Read TR, Hocking JS, Vodstrcil LA, et al. Oral human papillomavirus in men having sex with men: risk-factors and sampling. PLoS One 2012; 7:e49324. 13. Resnick RM, Cornelissen MT, Wright DK, et al. Detection and typing of human papillomavirus in archival cervical cancer specimens by DNA amplification with consensus primers. J Natl Cancer Inst 1990; 82:1477–84. 14. Gravitt PE, Peyton CL, Alessi TQ, et al. Improved amplification of genital human papillomaviruses. J Clin Microbiol 2000; 38:357–61. 15. Layton-Henry J, Scurry J, Planner R, et al. Cervical adenoid basal carcinoma, five cases and literature review. Int J Gynecol Cancer 1996; 6:193–9. 16. Opalka D, Lachman CE, MacMullen SA, et al. Simultaneous quantitation of antibodies to neutralizing epitopes on virus-like particles for human papillomavirus types 6, 11, 16, and 18 by a multiplexed luminex assay. Clin Diagn Lab Immunol 2003; 10:108–15. 17. Goldstone S, Palefsky JM, Giuliano AR, et al. Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men. J Infect Dis 2011; 203:66–74. 18. Glick SN, Feng Q, Popov V, Koutsky LA, Golden MR. High rates of incident and prevalent anal human papillomavirus infection among young men who have sex with men. J Infect Dis 2014; 209: 369–76. 19. 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; 199:14–9. 20. Tobian AA, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009; 360:1298–309. 21. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002; 346:1105–12. 22. Lyons A, Pitts M, Grierson J, Smith A, McNally S, Couch M. Age at first anal sex and HIV/STI vulnerability among gay men in Australia. Sex Transm Infect 2012; 88:252–7. 23. Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet 2011; 377: 2085–92. 24. Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis 2011; 11:39–44. 25. Fairley CK, Hocking JS, Gurrin LC, Chen MY, Donovan B, Bradshaw CS. Rapid decline in presentations of genital warts after the implementation of a national quadrivalent human papillomavirus vaccination programme for young women. Sex Transm Infect 2009; 85:499–502. 26. Read TR, Hocking JS, Chen MY, Donovan B, Bradshaw CS, Fairley CK. The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination programme. Sex Transm Infect 2011; 87:544–7. 27. Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis 2007; 13:28–41. 28. Simatherai D, Bradshaw CS, Fairley CK, Bush M, Heley S, Chen MY. What men who have sex with men think about the human papillomavirus vaccine. Sex Transm Infect 2009; 85:148–9. 29. Widdice L, Ma Y, Jonte J, et al. Concordance and transmission of human papillomavirus within heterosexual couples observed over short intervals. J Infect Dis 2013; 207:1286–94. 30. Nyitray AG, Carvalho da Silva RJ, Baggio ML, et al. Age-specific prevalence of and risk factors for anal human papillomavirus (HPV) among men who have sex with women and men who have sex with men: the HPV in men (HIM) study. J Infect Dis 2011; 203:49–57. 31. de Pokomandy A, Rouleau D, Ghattas G, et al. Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study. J Infect Dis 2009; 199:965–73.
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Financial support. This work was supported, in part, by a research grant from the Investigator Initiated Studies Program of Merck Sharp Dohme (grant number 39379). This study was in part funded by an National Health and Medical Research Council (NHMRC) Program grant (568971). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp and Dohme or NHMRC. Potential conflicts of interest. This investigator-initiated study was funded by Merck. Merck had no input into the design, analysis, or reporting of the study. C. K. F. has received honoraria from CSL Biotherapies and Merck and research funding from CSL Biotherapies. C. K. F. owns shares in CSL Biotherapies, the manufacturer for Gardasil. J. S. H. has received an honorarium from CSL Biotherapies and is an investigator on an Australian Research Council–funded project (LP0883831) that includes CSL Biotherapies as a research partner. A. E. G. has received honoraria and untied research funding from CSL Biotherapies and has received honoraria from Merck. S. M. G. has received advisory board fees and grant support from CSL Biotherapies and GlaxoSmithKline and lecture fees from Merck, Glaxo Smith Kline (GSK), and Sanofi Pasteur; in addition, she has received funding through her institution to conduct HPV vaccine studies for Merck Sharp Dohme (MSD) and GlaxoSmithKline. S. M. G. is a member of the Merck Global Advisory Board as well as the Merck Scientific Advisory Committee for HPV. None of this relates to this specific work. M. Y. C. reported his institution received a grant from Merck Sharp Dohme that supported the conduct of the study. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
