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Epidemiology and Social

Oral human papillomavirus infection in HIV-negative and HIV-infected MSM

Mooij, Sofie H.a,e; Boot, Hein J.b,†; Speksnijder, Arjen G.C.L.a; Stolte, Ineke G.a; Meijer, Chris J.L.M.c; Snijders, Peter J.F.c; Verhagen, Dominique W.M.d; King, Audrey J.b; de Vries, Henry J.C.a,b,f; Quint, Wim G.V.g; van der Sande, Marianne A.B.b,h; Schim van der Loeff, Maarten F.a,e

Author Information
doi: 10.1097/QAD.0b013e328362395c



Human papillomavirus (HPV) is the most common sexually transmitted viral infection. Oncogenic HPV types are related to several types of cancer of the anogenital tract and the head and neck region [1]. In particular, HPV type 16 has recently been recognized as a causative agent in oropharyngeal cancer and might play a role in some oral cancers as well [2–4]. Although HPV prevalence in head and neck tumors varies widely, it is relatively high in oropharyngeal squamous cell carcinomas (on average 36−41%) [4,5]. The incidence of HPV-related oropharyngeal cancer is rising, especially in men [6–11].

Certain sexual behaviors and HIV infection are potential risk factors for oral HPV infection and are associated with HPV-related head and neck cancer [12–20]. Data on the prevalence of oral HPV infection are scarce, especially for specific high-risk groups. A recent review found a 4.5% prevalence of oral HPV infection in healthy individuals [21]. In HIV-infected individuals, oral HPV infections are more common and more often involve an oncogenic (high-risk) HPV type [13,20,22]. Previous studies showed an oral HPV prevalence of up to 45% in HIV-infected men [22–24]. The extent to which their higher HPV prevalence reflects HIV-related immunosuppression or the shared transmission routes of HIV and HPV is unclear.

Increased knowledge about oral HPV infection, including the role of HIV infection, will help in planning and targeting prevention strategies for HPV-related head and neck cancer. HPV vaccination, for example, could be a powerful primary prevention tool for HPV-related head and neck cancer, although currently no evidence for the effectiveness of the vaccines against these cancers exists.

This study estimates the prevalence of oral HPV infection and aims to identify risk factors for prevalent oral HPV infection among HIV-negative and HIV-infected MSM, focusing on high-risk oral HPV infection.

Materials and methods

This analysis presents the first results of the HIV & HPV in MSM (H2M) Study, an ongoing cohort study of HIV and HPV in MSM that seeks to compare the prevalence, incidence, and clearance of anal, penile, and oral HPV infection in HIV-negative and HIV-infected MSM.

Study participants

From July 2010 through July 2011, HIV-negative and HIV-infected MSM were recruited at three sites in Amsterdam, the Netherlands: the well established Amsterdam Cohort Study (ACS) among MSM (Public Health Service of Amsterdam) [25], a sexually transmitted infection clinic (Public Health Service of Amsterdam) [26], and an outpatient infectious disease clinic (Jan van Goyen Medical Center). At the ACS, mainly HIV-negative participants were recruited, whereas HIV-infected participants were recruited at the clinics. Men were eligible for participation if at least 18 years of age and conversant in Dutch or English. The Medical Ethics Committee of the Academical Medical Center Amsterdam approved this study, and all participants provided written informed consent prior to participation.

Sample and data collection

Data pertaining to baseline H2M visits were included in this analysis. Participants were asked to rinse the oral cavity and gargle for a total of 30 s, using 10−15 ml Scope mouthwash (Procter & Gamble, Toronto, Ontario, Canada). Self-administered questionnaires were completed as to sociodemographic characteristics, general health-related issues (e.g. smoking habits and circumcision status), and details of sexual behavior (e.g. recent and lifetime oral and anal sexual behaviors). HIV-related data including CD4+ cell count, HIV viral load, and use of combination antiretroviral therapy (cART) were obtained from the national HIV patients’ database of the Dutch HIV Monitoring Foundation [27].

Human papillomavirus DNA detection and genotyping

After collection, the oral-rinse and gargle specimens were stored at 4°C. Within 10 days the specimens were centrifuged (10 min; 3000g) and the pellets were washed with 10 ml sterile normal phosphate saline buffer. After another centrifugation (10 min; 3000g), the pellets were resuspended in 1 ml normal phosphate saline buffer and stored at −20°C. DNA extraction was performed on 200 μl of the resuspended pellet, by using the MagNA Pure LC Total Nucleic Acid Isolation Kit (Roche, Mannheim, Germany). Broad-spectrum HPV DNA amplification was performed using the highly sensitive short PCR fragment (SPF)10-PCR-DNA Enzyme Immuno Assay (DEIA)/LiPA25 system (version 1) [28], which amplifies a 65 base-pair open reading frame of the L1 region of the HPV genome. The amplified biotinylated PCR products were tested for HPV DNA with a DEIA (HPV DEIA; Labo Biomedical Products, Rijswijk, the Netherlands), by use of hybridization with a cocktail of probes that recognizes at least 54 HPV genotypes. Optical densities were measured and compared with previously determined cutoff values obtained from internal control specimens, to be classified as negative, borderline, or positive for HPV DNA. Borderline samples were retested, with and without dilution, by DEIA. Positive samples were genotyped by a reverse-hybridization line probe assay (LiPA25) (HPV LiPA25; Labo Biomedical Products, Rijswijk, the Netherlands). LiPA25 allows simultaneous detection of 25 specific mucosal HPV genotypes: 6, 11, 16, 18, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68/73, 70, and 74. (Genotypes 68 and 73 are indistinguishable by methods used.) Positive hybridization was exposed as purple bands on a blot, which was independently interpreted by two readers. In case of discrepancies, a third reader was decisive.

The reproducibility of HPV DNA testing and genotyping was assessed by retesting 5% of all HPV-positive and HPV-negative DNA extracts in a different laboratory [Rijksinstituut voor Volksgezondheid en Milieu (RIVM)] using the same technique. The overall agreement was high, only 5% of results were discordant. Retesting yielded identical results in 96% of HPV-negative samples (23/24). All initial HPV-positive samples were also HPV-positive upon retesting (data not shown).

Not all PCR-DEIA-positive samples could be typed by the LiPA25. To evaluate whether no high-risk oral HPV infections would be missed with the laboratory methods used, these designated ‘untypable’ samples were subjected to SPF10 sequencing and/or the PM-PCR reverse hybridization assay method for detecting β-papillomavirus genotypes [29], or primer set II sequencing 104 bp [30]. These analyses of untypable samples were performed at DDL Diagnostic Laboratory (Rijswijk, the Netherlands).

Classification of human papillomavirus genotypes

Of the 25 types covered by LiPA25, we classified 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 as high-risk, or oncogenic, as defined by International Agency for Research on Cancer guidelines [2]. The remaining HPV types 6, 11, 34, 40, 42, 43, 44, 53, 54, 66, 68/73, 70, and 74 were classified as low-risk.

Samples found negative in PCR-DEIA were considered HPV-negative; samples positive in PCR-DEIA were considered HPV-positive. Samples that were positive by the LiPA25 for single or multiple HPV genotype(s) were considered positive for any of the 25 HPV typable genotypes. This group was designated ‘25-HPV’, and all these samples were further designated ‘low-risk only’ (if all HPV types were low-risk) or ‘high-risk’ (if at least one of their HPV types was high-risk). We also categorized samples based on the presence of two or more different HPV genotypes (‘multiple HPV infections’) and on the presence of at least one of HPV types 6, 11, 16, and/or 18 (‘HPV 6/11/16/18’), types covered by the quadrivalent HPV vaccine. Samples that were PCR-DEIA-positive and LiPA25-negative were classified ‘untypable’.

Statistical analyses

HIV-negative and HIV-infected participants were compared using rank-sum tests for not normally distributed continuous data, and χ2 tests for categorical data. The prevalence of high-risk HPV and other HPV infection categories, as well as of infections with individual HPV types, was estimated with 95% confidence intervals (CIs). In univariable logistic regression analyses, we calculated odds ratios (ORs) and 95% CI to estimate the associations between sociodemographic and behavioral factors and oral HPV infection. We considered high-risk oral HPV as primary outcome, and also evaluated 25-HPV.

We first made models using multivariable logistic regression analyses to assess the effect of HIV infection on oral HPV, adjusting for potential confounders. As previous studies observed different determinants for oral HPV infection among HIV-negative and HIV-infected participants [13,22], we performed all further analyses stratified by HIV status. Variables associated with oral HPV with a P-value < 0.05 in univariable logistic analysis were entered into a multivariable logistic regression model. Variables considered relevant based on the literature (age, smoking, lifetime number of male sex partners, number of recent oral sex partners, and recent oral–anal contact) were forced into each model. If two or more variables were highly correlated, only one was included, based on relevance and completeness of data.

Subsequently, variables were removed to yield a parsimonious model. If a variable had more than 40 missing values in overall models or more than 20 missing values in stratified models, the multivariable model included a category for missing values to limit loss of observations. P-values were two-sided and considered statistically significant at P < 0.05. All analyses were performed using Stata software package version 11.2 (Stata Intercooled, College Station, Texas, USA).


Participant characteristics

Of 794 participants recruited into the H2M study, 767 MSM had sufficient questionnaire data and sample results for this analysis. The 27 excluded MSM did not differ in age or HIV status from the included MSM (data not shown). Baseline characteristics of the 767 MSM are shown in Table 1, stratified by HIV status. At enrolment, 453 (59.1%) were HIV-negative and 314 (40.9%) were HIV-infected. The median age was lower in HIV-negative than in HIV-infected MSM (37.6 versus 45.6 years; P < 0.001). As compared to HIV-negative MSM, those with HIV infection were more likely to be born in countries outside the Netherlands; less likely to be highly educated; more likely to have smoked at least 15 pack years of tobacco [1 pack year is equal to smoking 20 cigarettes (1 pack) per day for 1 year], and to have recently used cannabis and poppers (alkyl nitrites). Risky sexual behaviors tended to be more common among HIV-infected MSM, and the median lifetime number of male sex partners was nearly three times higher. Most HIV-infected MSM were receiving cART (234/268; 87.3%) and had undetectable HIV viral load at enrolment (203/261; 77.8%), with high CD4+ cell counts (median 535 cells/μl).

Table 1-a:
Baseline characteristics of 767 MSM participating in the HIV & HPV in MSM Study, overall and stratified by HIV status (Amsterdam, 2010–2011)a.
Table 1-b:
Baseline characteristics of 767 MSM participating in the HIV & HPV in MSM Study, overall and stratified by HIV status (Amsterdam, 2010–2011)a.

Oral human papillomavirus prevalence

We analyzed the prevalence of oral HPV infection, stratified by HIV status (Table 2). The PCR-DEIA was positive in 303 (39.5%) samples, including 116 (15.1%) untypable by the LiPA25. The remaining 187 (24.4%) were positive for 25-HPV, with significantly higher prevalence in HIV-infected than HIV-negative MSM (38.5 versus 14.6%; P < 0.001). Overall, the prevalence of high-risk oral HPV infection was 15.4% (118/767) and significantly higher in HIV-infected than in HIV-negative MSM (24.8 versus 8.8%; P < 0.001). The same pattern was observed for low-risk HPV (22.0 versus 7.1%; P < 0.001), low-risk HPV only (13.7 versus 5.7%; P < 0.001), multiple HPV infections (15.0 versus 2.6%; P < 0.001), and HPV 6/11/16/18 (10.2 versus 3.5%; P < 0.001).

Table 2:
Number of baseline oral samples and percentage (95% confidence interval) that are PCR-DNA Enzyme Immuno Assay-positive; positive for 25-human papillomavirus; high-risk human papillomavirus; low-risk human papillomavirus; low-risk human papillomavirus only; multiple human papillomavirus infections; human papillomavirus type(s) 6, 11, 16, and/or 18; and untypable, overall, and stratified by HIV status (HIV & HPV in MSM Study, Amsterdam, 2010–2011).

Generally, type-specific HPV prevalence was higher in HIV-infected than HIV-negative MSM, except for HPV types 34 (low-risk) and 35 (high-risk) (Fig. 1). HPV type 16 was the most frequently detected high-risk type (26/767; 3.4%), with a prevalence of 2.0% in HIV-negative and 5.4% in HIV-infected MSM (P = 0.010). HPV type 66 was the most prevalent low-risk type (26/767; 3.4%).

Fig. 1:
Type-specific oral human papillomavirus (HPV) prevalence and 95% confidence intervals of HPV types in baseline oral samples from 767 MSM participating in the HIV & HPV in MSM (H2M) study, stratified by HIV status (Amsterdam 2010–2011): (a) high-risk types and (b) low-risk types.

Further analyses of untypable oral samples (115/116) revealed HPV genotypes in 85% of these samples (98/115), which mainly involved β-papillomavirus types and low-risk α-papillomavirus types not covered by the LiPA25, such as HPV types 13 and 32 (data not shown).

Association between HIV infection and oral human papillomavirus infection

HIV infection was associated with oral infection with high-risk HPV [adjusted odds ratio (aOR) 2.6; 95% CI = 1.6–4.1] after adjusting for age, smoking, and sexual behavior (Table 3). HIV infection was also significantly associated with 25-HPV (aOR = 2.8; 95% CI = 1.9–4.2) and multiple HPV infection (aOR = 5.1; 95% CI = 2.5–10.2), adjusting for the same variables (data not shown).

Table 3:
Multivariable model to asses the association between HIV status and high-risk oral human papillomavirus infection in 767 MSM, adjusting for age, smoking, and sexual behavior (HIV & HPV in MSM Study, Amsterdam 2010–2011)a.

Risk factors for high-risk oral human papillomavirus infection

In HIV-negative MSM, increased age, recent use of poppers, and factors related to sexual behavior (i.e., more lifetime male sex partners, anal intercourse in the last 6 months, recent anal sex partners, and oral-anal contact) were significantly associated with high-risk oral HPV infection in univariable analysis (Table 4). In multivariable analysis, increasing age was the only factor that remained significantly associated with high-risk oral HPV infection in HIV-negative MSM. Age showed a linear association, with the highest OR (aOR = 4.0, 95% CI = 1.2–13.3) for the age category of 45 years or older compared to the reference category aged 34 years or less.

Table 4:
Univariable and multivariable analyses of risk factors for high-risk oral human papillomavirus infection in HIV-negative MSM (n = 453) and HIV-infected MSM (n = 314) (HIV & HPV in MSM Study, Amsterdam 2010–2011)a.

In HIV-infected MSM, a higher amount of tobacco smoking pack years (OR = 2.8; 95% CI = 1.5–5.2 for ≥15 compared to < 15) and use of cannabis in the last 6 months (OR = 1.7; 95% CI = 1.0–2.9) were significantly associated with high-risk oral HPV infection in univariable analysis. Multivariable analysis showed no significant associations of the analyzed risk factors with high-risk oral HPV infection in HIV-infected MSM. In addition, further univariable and multivariable analyses revealed no significant association between nadir CD4+ cell count and oral high-risk HPV infection (data not shown).

Risk factors for oral 25-human papillomavirus infection

In HIV-negative MSM, older age, smoking, recent use of poppers, and factors related to sexual behavior were significantly associated with oral 25-HPV infection in univariable analysis (see Table S1, Supplemental Digital Content 1, which shows the analyses with outcome oral 25-HPV). In multivariable analysis, older age (aOR = 2.9; 95% CI = 1.1–7.4, for age ≥45 years compared to ≤34 years), tobacco smoking (aOR = 1.6; 95% CI = 0.8–3.0 for current smokers compared to never smokers), and recent use of poppers (aOR = 3.1; 95% CI = 1.5–6.1) were significantly associated with oral 25-HPV infection in HIV-negative MSM. In HIV-infected MSM, increased smoking pack years (OR = 1.9; 95% CI = 1.0–3.4 for ≥15 compared to <15) was significantly associated with oral 25-HPV infection in univariable analysis. Multivariable analysis showed no significant associations with oral 25-HPV infection in HIV-infected MSM.


This study revealed a high prevalence of oral HPV infection among MSM, including infection with oncogenic HPV types. HIV infection was strongly and independently associated with oral HPV infection. In addition, multiple HPV infections were more common among HIV-infected than HIV-negative MSM. The observed oral HPV prevalence was high compared to that found in other studies among HIV-negative men [14,21,31–33], HIV-infected men [24], and HIV-infected adults [13,34], but similar to prevalence found among HIV-positive and HIV-negative individuals in the United States [22]. Comparisons across studies, however, are hampered by differences in laboratory methods used, including the number and HPV types targeted, and our use of the highly sensitive SPF10-PCR method [28]. Consistent with the literature, HPV type 16 was the most frequently detected high-risk type [13,22,32]. HPV type 66 was also common in this study, like in some [32] but not in all studies [22,31].

It is not clear why HIV-infected individuals have generally higher oral HPV prevalence compared to HIV-negative individuals. Factors involved are probably a higher HPV exposure due to more sexual high-risk behavior (leading to increased HPV acquisition), an increased susceptibility for HPV infection in the oral cavity, and an increased HPV persistence due to immunosuppression (as a consequence of HIV infection). The higher oral HPV prevalence among HIV-infected compared to HIV-negative men is in line with findings regarding genital HPV infections in men [35]. In HIV-infected individuals, the level of immunosuppression (lower CD4+ cell count) or use of cART may affect oral HPV infection [13,22,36]. In contrast, we observed no association between oral HPV prevalence and CD4+ cell count or HIV viral load, which may be explained by the fact that most of our HIV-infected participants had high CD4+ cell counts (only 15% had CD4+ cell count ≤350 cells/μl) and undetectable HIV viral load. Further studies are needed to elucidate the role of HIV-related immunosuppression versus shared transmission routes of HIV and HPV, in the increased oral HPV prevalence in HIV-infected compared to HIV-negative individuals.

Smoking is associated with HPV infection through immunosuppressive changes in adaptive and innate immunity [37,38], and is also a well established risk factor for head and neck cancer [39]. However, we observed no independent effect of smoking on high-risk oral HPV infection. Up to date, the relative contributions of smoking and HIV-related immunosuppression in oral HPV infection and sequelae are unclear and hence need further investigation.

We found no independent significant association between oral sexual behaviors and oral HPV prevalence. Some studies identify oral sexual behaviors, including orogenital sex and open-mouthed kissing, as risk factors for oral HPV infection [13,14,22,40], but the literature is inconsistent [31]. That we did not identify such behaviors as independent determinants for oral HPV could reflect the lack of discriminative power for some variables: almost all participants had recently engaged in oral sex. It could reflect colinearity between behaviors, that is, men who engage in oral sex are likely also to practice other sexual behaviors. However, we did find a significant association between recent use of poppers and 25-HPV in HIV-negative MSM. We speculate that use of poppers can serve as a proxy for high-risk sexual behavior with high-risk partners.

Increasing age tended to be linearly associated with oral HPV prevalence. Also reported by others, this finding is hypothesized to be related to decreased oral HPV clearance or reexpression of latent oral HPV infection due to age-related changes in immunity [41,42]. In addition, it might reflect cumulative lifetime HPV exposure. A bimodal age pattern was observed in a large population-based study in the United States [32]. Interestingly, the association between age and oral HPV infection was more distinct in our HIV-negative than HIV-infected participants. This dissimilarity has been observed before [13] and might be due to age-related loss of immunity being masked by the much stronger effect of HIV-related immunosuppression.

Strengths of our study include its relatively large population, well documented through detailed questionnaires. Sampling by oral-rinse and gargle collected cells from the entire oral cavity and oropharynx, yielding more HPV DNA than use of oral swabs or brushes [13,43]. Roughly a third of PCR-DEIA-positive samples were untypable by the LiPA25, but this did not lead to an underestimation of high-risk and low-risk HPV types present in the LiPA25 test because further analysis found the vast majority to be positive for HPV types not covered by LiPA25. Moreover, it showed that the oral cavity contains a broad spectrum of nonmucosal HPV types, as described by Bottalico et al.[44]. HPV types 32 and 13, which are associated with a rare and benign condition called focal epithelial hyperplasia (Heck's disease), were relatively common in our population.

As for limitations, the participants were recruited at different study sites, but we tried to minimize bias by using the same sampling protocol and by adjusting for potential confounders. However, residual confounding cannot be ruled out. The detailed character of the questionnaires led to incomplete data for some variables, but we addressed that by including a category for missing values in multivariable analyses. Finally, it is not clear to what extent the detection of HPV DNA in the oral cavity indicates an established HPV infection or deposition from previous oral sex acts or nonsexual transmission/autoinoculation [45].

It is unknown but plausible that vaccination with the currently available HPV vaccines may prevent HPV-related head and neck cancer [41,46], given its pathogenetic similarities with cervical cancer. Hence the overall health benefit of the vaccines could be greater than assumed. Evaluation of the effectiveness of the vaccines is ongoing, but as there are no well defined precancerous states in head and neck cancer many years may be needed to establish epidemiological evidence for efficacy against these cancers. Vaccination against HPV could be as important for men as for women, particularly for HIV-infected men and others at increased risk for HPV-related head and neck cancer [16,47].

In conclusion, this study demonstrates a high HPV prevalence in the oral cavity of sexually active MSM, and particularly in HIV-infected MSM. HIV infection was strongly and independently associated with high-risk oral HPV infection. Further studies are needed to assess the factors affecting the natural history of oral HPV infection, including HIV, and the subsequent risk of developing HPV-related head and neck cancer.


The authors would like to thank Stichting HIV Monitoring (SHM), in particular Frank de Wolf and Colette Smit, for their contributions in data collection; the members of the H2M steering committee, and Roel Coutinho in particular, for their advice; the personnel of the ACS, MC Jan van Goyen, and the Amsterdam STI outpatient clinic for their contributions in implementation of the study and data collection; Wilma Vermeulen (Public Health Service Amsterdam) for HPV genotyping; Jan Sonsma (RIVM) for DNA isolation; Anna Giuliano for advice and support, and Lucy Phillips for editorial review. Above all, we gratefully acknowledge all study participants for their co-operation.

S.M. analyzed and interpreted the data, and wrote a draft manuscript. H.B. raised the idea of oral sampling and together with A.S., A.K., and W.Q. analyzed and interpreted laboratory results. I.S. was scientifically involved through supervision of the ACS; H.d.V. through the STI clinic and D.V. through MC Jan van Goyen. C.M. and P.S. provided substantial scientific advice. M.S.v.d.L. and M.v.d.S. designed and supervised the overall study, and contributed to data analyses and interpretation of the data. All authors contributed to conception and design of the study, and critical revision of the manuscript, and saw and approved the final version.

This study was funded through a grant from Aids Funds (grant number 2009029) and additional funding from the Public Health Service Amsterdam and RIVM.

Conflicts of interest

M.S.v.d.L. received funding for a substudy on HPV from Sanofi Pasteur MSD and participates in a Merck-funded investigator-initiated study on Gardasil. For the remaining authors there are no conflicts of interest.


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HIV; human papillomavirus; MSM; oral; prevalence; risk factors

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