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Original Studies

Risk Factors for Oral Human Papillomavirus Infection Among Young Men Who Have Sex With Men—2 Cities, United States, 2012–2014

Oliver, Sara E. MD, MSPH*; Gorbach, Pamina M. MHS, DrPH†; Gratzer, Beau MPP‡; Steinau, Martin PhD§; Collins, Tom BS; Parrish, Adam PhD; Kerndt, Peter R. MD, MPH§; Crosby, Richard A. PhD; Unger, Elizabeth R. PhD, MD∥; Markowitz, Lauri E. MD*; Meites, Elissa MD, MPH*

Author Information

From the *Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA,

†Fielding School of Public Health, University of California at Los Angeles, Los Angeles, CA,

‡Howard Brown Health, Chicago, IL,

§Division of Global HIV and TB, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA,

College of Public Health, University of Kentucky, Lexington, KY; and

∥Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA

Sources of funding: Centers for Disease Control and Prevention.

Conflicts of Interest: None declared.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Parts of these data were presented at the 2017 International Papillomavirus Conference in Cape Town, South Africa, on March 2, 2017 (Poster 432).

Acknowledgments: Cody Randel, Janell Moore, Steven Carrasco, Mark McGrath, Jim Braxton, Akbar Zaidi, Gitika Panicker, and staff at participating clinics.

Correspondence: Sara Oliver, MD, MSPH, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30329. E-mail: [email protected].

Received for publication January 31, 2018, and accepted March 28, 2018.

doi: 10.1097/OLQ.0000000000000845
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Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, with an estimated 14 million persons newly infected annually.1 Although most infections are asymptomatic and self-limited, persistent infections can lead to a variety of diseases, including genital warts and cancers. A causal link between oncogenic HPV types and cervical cancer has been established; knowledge is broadening to include associations between HPV and other anogenital cancers, as well as oropharyngeal cancers.2,3

Increases in HPV-associated oropharyngeal cancers have been observed over the last several decades, particularly in North America and Europe, with pronounced increases among males in developed countries.4,5 In the United States, the population-level incidence of HPV-positive oropharyngeal cancer increased by 225% from 1988 to 2004, from 0.8 per 100,000 to 2.6 per 100,000;6 among US males, oropharyngeal cancers accounted for 78% of HPV-associated cancers in 2009.7

Oral HPV infection has been associated with oropharyngeal cancer.8 Prevalence of oral HPV has been evaluated among various populations. A systematic review of 9 studies found a 7.5% oral HPV prevalence among cancer-free and human immunodeficiency virus (HIV)-negative individuals, with a 12-month cumulative incidence estimated at 4.8% (95% confidence interval [CI], 3.2–7.3%).9 In 2009 to 2010, an estimated 10.1% (95% CI, 8.3–12.3%) of US males aged 14 to 69 years had any of 37 types of HPV DNA detected in oral rinse specimens in a nationally representative study.10

Men who have sex with men (MSM) are at high risk for both HPV infections and HPV-associated diseases, with both a high incidence and prevalence of anal HPV infection and anal cancer rates among young MSM.11 Studies evaluating risk factors for oral HPV detection among MSM and the general male population identified associations with sexual behaviors, including oral sex frequency and lifetime number of sex partners and kissing partners.12–15 However, studies have been conflicting regarding the association between HPV infections and lifetime or recent sex partners among this population.

In the United States, 2 prophylactic HPV vaccines have been licensed for use among men.16 A quadrivalent HPV vaccine (4vHPV) (Gardasil, Merck and Co., Inc., Kenilworth, NJ) protecting against 4 HPV types (6, 11, 16, and 18) was used during 2006–2016. A 9-valent HPV vaccine (9vHPV) (Gardasil 9, Merck and Co., Inc.) protecting against 4vHPV types and an additional 5 oncogenic types (31, 33, 45, 52, and 58) has been used since 2015. In the United States, of 11,600 oropharyngeal cancers attributed to HPV annually, an estimated 9900 (85.3%) are due to types HPV 16 and 18, the oncogenic types included in the quadrivalent HPV vaccine, and an additional 900 (7.8%) to the additional 5 oncogenic HPV types prevented by the 9-valent HPV vaccine.17 Human papillomavirus vaccination is recommended for US boys and girls aged 11–12 years (or starting at age 9 years), and through age 26 years for gay, bisexual and other MSM; transgender women; and persons with certain immunocompromising conditions including HIV infection, who were not adequately vaccinated previously.16,18

The purpose of this analysis was to evaluate oral HPV prevalence and risk factors among a population of young gay, bisexual and other MSM aged 18 through 26 years, a population eligible for HPV vaccination in the United States.

MATERIALS AND METHODS

Study Design and Population

The cross-sectional Young Men's HPV (YMHPV) study enrolled gay, bisexual and other MSM, including transgender women, aged 18 through 26 years. Detailed study methods have been provided elsewhere.19–21 Briefly, enrollment was conducted at 3 community health clinics focused on providing sexual health services to lesbian, gay, bisexual, and transgender populations in 2 US cities (Chicago, IL, and Los Angeles, CA) from July 2012 to August 2014. The study protocol was reviewed and approved by institutional review boards at the participating institutions. Eligible participants were aged 18 through 26 years, assigned male sex at birth and either (a) identified as gay, homosexual, or bisexual, and/or (b) reported ever having oral or anal sex with a male partner. Participants who reported previous receipt of HPV vaccination were excluded from this analysis. Each consenting participant completed a 30-minute standardized computer-assisted interview; all participants included in this analysis completed the survey, but were not required to provide a response to all questions. The survey assessed demographic characteristics, sexual orientation, sexual behavior, and medical history (including self-reported HIV status and HPV vaccination history), as well as knowledge, attitudes and practices regarding HPV infection, associated diseases, and HPV vaccination. The survey assessed participants' perception of the severity of HPV-associated oropharyngeal cancer on a 5-level scale (not very serious, slightly serious, moderately serious, very serious, or extremely serious). The perceived efficacy of HPV vaccine in preventing oral and throat cancers was assessed on a 4-level scale (not at all effective, slightly effective, moderately effective, or extremely effective); responders could also answer they did not know or were not sure.

Laboratory Testing

Oral sampling and HPV testing were performed as previously described.22 Briefly, each participant provided a self-collected oral rinse specimen by swishing and gargling 10 mL of sterile saline for 30 seconds. Extracted DNA was tested by using the Research Use Only Linear Array HPV Genotyping Test (Roche Molecular Diagnostics, Indianapolis, IN) with supplementary HPV-52 quantitative polymerase chain reaction. This standardized commercial research assay uses L1 consensus polymerase chain reaction followed by type-specific hybridization for qualitative detection of 37 HPV types (6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 63, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, 89, or IS39) and β-globin (control for sample amplification). Specimens that tested negative for both HPV and β-globin were considered inadequate.

Data Analysis

This analysis was limited to vaccine-eligible participants, defined as those not reporting prior HPV vaccination, with survey information and adequate specimen results. Demographic and behavioral factors were analyzed for associations with detection of any of 37 HPV types (“any HPV”) and any of the 9 HPV types protected against by the 9-valent vaccine (“9vHPV types”) detected by Linear Array in the oral specimen.

We calculated descriptive statistics and assessed risk factors using chi-square tests, with a P value less than 0.05 considered significant. We also used log-binomial models to report prevalence ratios (PR) and 95% CIs. For variables with a P value less than 0.10 in bivariate analysis, we calculated adjusted prevalence ratios (aPR), adjusting for variables chosen a priori that could be associated with both sexual behavior and HPV prevalence. Separate models were built for each association. Each model was adjusted for age, race, smoking cigarettes, and self-reported HIV status, unless one of these was the variable tested; for example, the final model for self-reported HIV status was adjusted only for age, race, and smoking. Human immunodeficiency virus status was categorized as positive for participants who self-reported their most recent HIV test result as positive (n = 88) (“known HIV positive”), compared with all other participants, who reported their most recent HIV test result to be negative (n = 712), indeterminate (n = 11), unknown (n = 26), or did not answer (n = 85) (combined into “HIV negative or unknown”).

RESULTS

Overall, 1033 participants aged 18 through 26 years enrolled in the YMHPV study, completed the questionnaire, and provided specimens with adequate test results. Of those, 111 (10.7%) reported having previously received at least 1 dose of HPV vaccine and were excluded from this analysis; the remaining 922 were considered vaccine-eligible and included here. All participants were aged 18 through 26 years; mean participant age was 23 years, and median age was 24 years. Most participants identified as male gender (853, 92.5%) and as homosexual or gay (643, 69.7%). Mean number of lifetime sex partners of any gender was 37 (median, 15 sex partners; range, 0–2002, among 751 participants answering this question). There were 88 (9.5%) participants who self-reported their most recent HIV test result was positive.

In oral specimens from 922 vaccine-eligible participants, 87 (9.4%) had any HPV detected; 37 (4.0%) had at least 1 9vHPV type, 29 (3.1%) had at least 1 of the 7 oncogenic 9vHPV types and 11 (1.2%) had HPV type 16 detected. Detection of any oral HPV by demographic characteristics is presented in Table 1. Characteristics associated with detection of any oral HPV included reporting a positive HIV test result, as well as sexual behaviors including 18 years of age or younger at first sex, having more than 20 lifetime sex partners, more than 5 partners of any gender within the last 1 month, more than 5 male sex partners within the last 3 months, performing oral sex on more than 5 partners within last 3 months, and performing oral sex on a male partner more than 5 times within the last 3 months. Characteristics associated with detection of any oral 9vHPV types were assessed and were similar to associations for any oral HPV. Although there was an observed trend with increased detection of oral HPV as the time since performing oral sex decreased, overall time since performing oral sex on a male partner did not reach statistical significance.

T1
TABLE 1:
Oral HPV Detection, by Demographic, Behavioral and Sexual Characteristics of 922 Vaccine-Eligible Young MSM — Young Men’s HPV Study, 2012–2014

After adjusting for age, race, and smoking, HIV status remained a significant factor associated with the detection of any oral HPV (aPR, 1.99; 95% CI, 1.14–3.48) (Table 2). After adjusting for age, race, smoking, and self-reported HIV status, age at first sex (aPR, 2.44; 95% CI, 1.16–5.12), number of sex partners of any gender in the last 1 month (aPR, 1.93; 95% CI, 1.13–3.31), numbers of partners performing oral sex on within the last 3 months (aPR, 1.87; 95% CI, 1.12–3.13), times performed oral sex with a male partner in the last 3 months (aPR, 1.83; 95% CI, 1.09–3.07), number of male partners in the last 3 months (aPR, 1.76; 95% CI, 1.08–2.87) and number of lifetime partners (aPR, 1.61; 95% CI, 1.04–2.50) were all significantly associated with oral HPV among study participants overall.

T2
TABLE 2:
Unadjusted and aPRs for Detection of Any Oral HPV Among 922 Vaccine-Eligible Young MSM—Young Men's HPV Study, 2012–2014

Oral HPV prevalence was assessed by self-reported HIV status (Fig. 1). Prevalence of both any oral HPV and any 9vHPV type was significantly higher among participants who reported being HIV-positive versus among those with negative or unknown HIV status (any HPV, 19.3% vs 8.4%, P = 0.004; 9vHPV: 10.2% vs 3.4%, P = 0.004).

F1
Figure 1:
Prevalence of any oral HPV and 9vHPV types among vaccine-eligible young MSM, overall and by self-reported HIV status—YMHPV Study, 2012–2014.

Participants were asked about their perception and understanding regarding HPV-associated diseases and HPV vaccines. Only 454 (49.4%) of participants knew that HPV can cause oropharyngeal cancer. Although 798 (86.6%) of participants thought a diagnosis of oropharyngeal cancer would be very or extremely serious, only 132 (14.3%) believed HPV vaccine would be moderately or extremely effective at preventing oropharyngeal cancer.

DISCUSSION

This study assesses prevalence of any oral HPV and 9-valent vaccine-type oral HPV specifically among MSM within the recommended target age range for HPV vaccine, through age 26 years, who reported not being previously vaccinated. Oral HPV was detected in almost 10% of this large group of 922 young gay, bisexual and other MSM, including transgender women, and in nearly 20% of those who reported being HIV-positive. A high proportion of infections detected were 9vHPV types; thus, many potentially could be prevented by pre-exposure HPV vaccination. At least 1 9vHPV type was detected in 4.0% of unvaccinated participants and 10.2% of known HIV-positive participants. Sexual behaviors were significantly associated with oral HPV detection, including younger age at first sex, and more lifetime and recent sex partners, including oral sex partners. Concerningly, a majority of participants were unaware that HPV can cause oropharyngeal cancers, and few thought that HPV vaccination would effectively prevent oropharyngeal cancer.

Human papillomavirus prevalence, including oral HPV, is common among MSM; in previous analyses of data from the YMHPV study, anal HPV was detected in 661 (71.7%) participants, and 70 (7.6%) had both oral and anal HPV detected, yet type-specific concordance between anal and oral HPV infectious was infrequent.19,21 Our findings, an oral HPV prevalence of 9.4% among all participants and 19.3% among known HIV-positive participants, are somewhat higher than among men in general in this age group, yet lower than reported in some previous studies of older MSM. A meta-analysis estimated pooled prevalence of any oral HPV DNA was 17.1% (95% CI, 7.3–26.8) among HIV-negative MSM of all ages (6 studies, total N = 1329) and 28.9% (95% CI: 19.1–38.7) among HIV-positive MSM of all ages (11 studies, total N = 1886).23 Importantly, median ages of participants in these studies were all 30 years or older. Furthermore, several studies found older age to be a significant predictor of oral HPV infection among MSM.10,14,15,23 Thus, the lower HPV prevalence we observed may be attributable to the younger age group studied by limiting to MSM 18 through 26 years of age. Additionally, a unique feature of our study is that it assessed oral HPV prevalence among transgender women; prevalence was similar among men and transgender women in this analysis.

This study specifically included MSM aged 18 through 26 years because they fall within the age group in which catch-up HPV vaccination is recommended by the Advisory Committee on Immunization Practice (ACIP).16,18 Human papillomavirus vaccination coverage in this population remains low; in this study, only 10.7% of participants reported receiving any doses of HPV vaccine. This is a useful group in which to characterize HPV prevalence from multiple body sites, since this information could be used to assess vaccine effectiveness in this at-risk population in potential future post-licensure studies, especially as HPV vaccination coverage increases. Efficacy studies for the initial vaccine licensure evaluated cervical precancer lesions, genital warts, or persistent cervicovaginal infections in women.24,25 Additional studies then demonstrated efficacy for the prevention of external genital lesions in males and anal intraepithelial neoplasia among MSM.26,27 Information is emerging regarding efficacy of vaccination against oral HPV infection.28 However, lack of an identified precursor lesion for oropharyngeal cancer has prevented efficacy studies for this outcome to date. Data from this study may serve as a baseline for future monitoring of HPV vaccine impact on oral HPV prevalence in this population. As more boys and men receive HPV vaccination at the recommended age, oral HPV prevalence among vaccinated MSM can be compared with historical prevalence among unvaccinated MSM.

Our study included assessment of several other behavioral risk factors, including smoking cigarettes and smoking marijuana, yet only sexual behavior risk factors were found to be significantly associated with oral HPV prevalence. Other studies have found tobacco or marijuana use associated with oral HPV detection among both MSM and other men.10,12,15,29 However, as noted previously, these studies had broader age ranges, suggesting that sexual behavior could have more impact on oral HPV prevalence than other behaviors among this young population.

We also found that HIV was an important risk factor for oral HPV detection. This could be related to changes in immune function due to HIV infection, or sexual behaviors among this population. One study in the Netherlands found that several sexual behaviors were associated with oral HPV prevalence among HIV-negative MSM, but not among HIV-positive MSM.14 Studies of HIV-positive men found HIV infection limited clearance of genital HPV infection; among HIV-positive MSM, immune function might be more important risk factor than sexual behavior,30 or some men might change their sexual behaviors once they are aware of their HIV-status. Additional research is needed to evaluate the effects of both HIV infection and sexual behaviors on oral HPV prevalence.

Our findings are subject to several limitations. First, the study population was from a limited geographic area and might not be representative of all young MSM across the United States. Second, medical record reviews were not performed as a part of this study; HIV test results, HPV vaccination eligibility, and all behavioral information were based on self-report and could be subject to recall bias or social desirability bias. Third, this study assessed prevalence of oral HPV detection at 1 time point. The oral sample may not fully represent the HPV status of the oropharynx, and the cross-sectional nature of the study does not assess persistent infection or development of HPV-associated disease. Additionally, multiple sexual behaviors were assessed, but multiple comparisons were not accounted for in the bivariate analysis. Finally, many participants reported no female sex partners, and so were not asked about sexual behaviors with females.

Despite the available of safe and effective HPV vaccines, and national guidelines recommending vaccination for MSM and transgender women through age 26 years, young MSM remain an at-risk population for HPV infections and HPV-associated diseases that are potentially preventable with vaccination. Many oral HPV infections among MSM could be prevented by pre-exposure vaccination, potentially preventing oropharyngeal cancers in the future. In addition, our results suggest that education regarding HPV-associated oropharyngeal cancers and HPV vaccination could be useful among this at-risk population. Raising awareness of oropharyngeal cancers among MSM might help increase HPV vaccination uptake.

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