Introduction
Human papillomavirus (HPV) is one of the most common sexually transmitted infections. The vast majority of HPV infections are transient and asymptomatic, but persistent infection with high-risk (oncogenic) HPV is associated with a variety of cancers in both women and men, including several types of anogenital cancer [1,2]. An estimated 80–90% of anal cancers and 40–50% of penile cancers are attributable to high-risk HPV, mainly HPV type 16 [1,3,4]. Although the annual incidence of anal and penile cancer in the general population is low [1,5], anal cancer incidence is substantially higher in MSM, and in particular in HIV-infected MSM [6–8]. Moreover, incidence of anal cancer appears to have been on the increase over the last decades [9,10].
Prevalence of anogenital HPV infection in men varies widely across different studies (between 1 and 84%) [11,12]. Prevalence of anal HPV infection in MSM is higher than in heterosexual men [13], with even higher estimates of up to 93% among HIV-infected MSM [12]. Risk factors for anogenital HPV infection are similar to those for other sexually transmitted infections [14], and also include factors related to the host's immunity, such as HIV infection and age. However, large studies assessing determinants for both anal and penile HPV infection in HIV-negative and HIV-infected men are scarce. Moreover, there is limited understanding regarding the interactions between HPV and HIV infection, and the roles of sexual behavior versus HIV-related immunosuppression in the increased HPV prevalence among HIV-infected MSM.
As MSM, and in particular HIV-infected MSM, are at increased risk for HPV-related cancer [7,15,16], more insight into HPV infections and potential risk factors among HIV-negative and HIV-infected MSM is warranted. This study aims to assess the effect of HIV infection on anal and penile high-risk HPV prevalence, and compares determinants for HPV infection between HIV-negative and HIV-infected MSM.
Materials and methods
Study participants
Between July 2010 and July 2011, HIV-negative and HIV-infected MSM were invited to participate in the H2M (HIV & HPV in MSM) study at three sites in Amsterdam, the Netherlands: the Amsterdam Cohort Study (ACS) among MSM (Public Health Service Amsterdam) [17], a sexually transmitted infections clinic (Public Health Service Amsterdam) [18], and an infectious disease outpatient clinic (Jan van Goyen Medical Center). HIV-negative participants were mainly recruited at the ACS, whereas HIV-infected participants were recruited at the two clinics. Men were eligible for participation if they were aged 18 years or older and conversant in Dutch or English. The Medical Ethics Committee of the Academic Medical Center (AMC) Amsterdam approved this study and all participants provided written informed consent prior to enrolment.
Data collection
At the enrolment visit, participants completed a self-administered questionnaire regarding socio-demographic characteristics, health-related issues, and lifetime and recent sexual behavior. Participants collected one anal and one penile self-swab of themselves [regular flocked swab with 1 ml Universal Transport Medium (UTM); Copan, Brescia, Italy]. For the anal swab, participants were instructed to insert the swab 3 cm into the anal canal and turn it around for 5–10 s. For the penile swab, participants were asked to rub the swab firmly over the skin of the penile shaft, including the foreskin, for 20 s (i.e., 5 s per side). HIV-related data were obtained from the Dutch HIV Monitoring Foundation's national HIV patients database [19].
Human papillomavirus DNA detection and genotyping
The anal and penile samples were stored at −20°C. DNA extraction was performed on 200 μl of each sample using the MagNA Pure LC Total Nucleic Acid Isolation Kit (Roche, Mannheim, Germany). Broad-spectrum HPV DNA amplification was performed using the highly sensitive SPF10-PCR DEIA/LiPA25 system (version 1) [20], 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 DNA enzyme immunoassay (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 cut-off 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 use of DEIA. Positive samples were genotyped by a reverse hybridization line probe assay (LiPA25, HPV LiPA25; Labo Biomedical Products). 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), in which HPV 68 and 73 cannot be discriminated by the methods used. Positive hybridization was exposed as purple bands on a blot, which were independently interpreted by two readers. In case of discrepancies, a third reader was decisive.
Quality control for detection and typing of the samples was performed by retesting 5% of all HPV-positive and HPV-negative DNA extracts in a different laboratory (RIVM) using the same technique. Results of the HPV-positive samples revealed 10.2% discordance (5/49). Retesting of HPV-negative samples yielded identical results in 96.7% of the samples (29/30; data not shown).
Classification of human papillomavirus genotypes
Samples positive for one or more HPV genotypes were considered positive for any HPV. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 were classified as high-risk (oncogenic) HPV genotypes, according to International Agency for Research on Cancer guidelines [2]. The other HPV genotypes covered by LiPA25 were classified as low-risk genotypes. Samples that were PCR-DEIA-positive and LiPA25-negative were classified ‘untypable’.
Statistical analyses
All statistical analyses were conducted separately but in the same way for the anal and penile site of infection. The main outcome of interest was high-risk HPV infection. Baseline characteristics of the study population, and anal and penile HPV type specific and composite HPV (e.g., high-risk HPV, low-risk HPV) prevalence estimates with 95% confidence interval (95% CI) were explored using descriptive statistics. We compared the distribution of the characteristics between HIV-negative and HIV-positive participants using the χ2 test for categorical data and the rank sum test for continuous data.
In univariable and multivariable logistic regression analyses, high-risk HPV types were analyzed in one model as described by Xue et al.[21]. We used generalized estimating equations (GEEs) in order to account for the analysis of multiple HPV infections within the same participant. An exchangeable correlation structure was assumed. Multivariable analyses were conducted to estimate the independent effect of HIV infection on anal/penile high-risk HPV infection. All variables that were associated with high-risk HPV (P value <0.1, Wald test) in univariable analyses were included, after which a backward selection procedure was performed; age group was forced into the model. Variables that did not change the association between HIV and HPV infection by more than 10% were removed one by one from the multivariable model. Records with missing data were excluded in univariable analyses, but if values were missing for more than 40 participants (around 5% of the study population), an extra category was generated so that these could still be included in multivariable analyses.
Next, we stratified analyses by HIV status to identify determinants for anal and penile high-risk HPV infections separately for the HIV-negative and the HIV-positive participants. Variables that were biologically plausible as well as known determinants from the literature were included a priori. If variables were highly correlated, the most relevant variable was included. Again, records with missing data were excluded in univariable analyses; extra categories for missing data were generated when values from more than 20 participants (around 5% of study participants per group) were missing, so that these records could still be included in multivariable analyses.
The variables age, smoking, poppers use, number of lifetime and recent (i.e. in the past 6 months) anal sex partners, receptive anal intercourse, and being fisted were included a priori in the multivariable model with the outcome anal high-risk HPV infection for the HIV-negative study population. The multivariable model for the HIV-positive study population additionally included nadir CD4+ count and HIV viral load.
The multivariable model with the outcome penile high-risk HPV infection for the HIV-negative study population a priori included the variables age, smoking, poppers use, circumcision status, number of lifetime and recent anal sex partners, and insertive anal intercourse. The variables nadir CD4+ count and HIV viral load were additionally added into the multivariable model for the HIV-positive study population.
P values were considered statistically significant at P <0.05. All analyses were performed using Stata (version 11.2; Stata Corp, College Station, Texas, USA).
Results
Characteristics of the study population
From 778 of the 795 MSM recruited for the H2M study, anal and penile samples and questionnaire data were available. The main baseline characteristics of the study population are summarized in Table 1. More than half of the study population was HIV-negative (N = 461; 59%) and 317 (41%) MSM were HIV-infected. The median age of HIV-negative and HIV-positive MSM was 38 [interquartile range (IQR) 33–42] and 46 (IQR 39–53), respectively (P <0.001). Circumcision status, and insertive and receptive anal intercourse in the last 6 months were similar between HIV-infected and HIV-negative MSM, whereas HIV-infected MSM showed higher numbers for other measures of sexual risk behavior. In HIV-infected MSM, most were receiving combination antiretroviral therapy (cART; N = 235; 87%), the median CD4+ cell count at enrolment was 530 cells/μl (IQR 410–700), the median CD4+ nadir cell count was 227 cells/μl (IQR 160–320), and 77% had an undetectable HIV viral load.
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Table 1: Baseline characteristics of the study population (N = 778), overall and stratified by HIV status (H2M study, Amsterdam 2010–2011).a
Anal and penile human papillomavirus prevalence
The PCR-DEIA was positive in 304 (66%) and 254 (80%) anal samples of HIV-negative and HIV-positive MSM, respectively, of which 27 (6%) and six (2%) were untypable by LiPA25 (Table 2). Any HPV (i.e., any of the 25 HPV types detectable by LiPA25) was present in 277 (60%) and 248 (78%) anal samples, respectively. Anal high-risk HPV was significantly higher in HIV-positive MSM (65%; 95% CI 59–70) compared with HIV-negative MSM (45%; 95% CI 41–50; P <0.001).
Table 2: Numbers and percentages of anal and penile composite human papillomavirus in HIV-negative (N = 461) and HIV-positive MSM (N = 317; H2M study, Amsterdam 2010–2011).
The PCR-DEIA was positive in 203 (44%) and 209 (66%) penile samples of HIV-negative and HIV-positive MSM, respectively, of which 67 (15%) and 52 (16%) were untypable by LiPA25. Any HPV was present in 136 (30%) and 157 (50%) penile samples, respectively. The prevalence of penile high-risk HPV was 16% (95% CI 13–20) and 32% (95% CI 27–38) for HIV-negative and HIV-positive MSM (P <0.001), respectively.
Figure 1a and 1b show the prevalence of anal and penile high-risk HPV types by HIV status. The prevalence pattern of high-risk HPV types in HIV-negative and HIV-infected MSM was similar for the anal and penile site of infection: HPV types 16, 18, 31, 51, and 52 were most frequently found, and HPV infections were about twice as common in HIV-infected compared with HIV-negative MSM. HPV-16 was the most frequently detected anal (17%) and penile (6%) high-risk HPV type. Prevalence of anal HPV-16 was 13% in HIV-negative and 22% in HIV-infected MSM (P = 0.001); prevalence of penile HPV-16 was 4% in HIV-negative and 8% in HIV-infected MSM (P = 0.026).
Fig. 1: Type-specific prevalence of human papillomavirus (HPV).(a) Type-specific prevalence (with 95% confidence interval, CI) of anal high-risk HPV in HIV-negative (N = 459) and HIV-infected (N = 317) MSM; H2M study, Amsterdam 2010–2011). (b) Type-specific prevalence (with 95% CI) of penile high-risk HPV in HIV-negative (N = 460) and HIV-infected (N = 317) MSM (H2M study, Amsterdam 2010–2011).
Concomitant infection
Among 775 participants with both anal and penile results, concomitant anal and penile high-risk HPV infection of the same HPV type was much more commonly observed than expected if these infections were independent [overall odds ratio (OR) 6.1; 95% CI 4.7–7.8]. This was also the case for individual HPV types (OR's varying between 2.3 and 15.9). Similar results were obtained in multivariable analysis adjusting for age, HIV status, and sexual behavior [overall adjusted odds ratio (aOR) 5.5; 95% CI 4.2–7.2].
Association between HIV infection and high-risk human papillomavirus
The OR for anal high-risk HPV infection was 2.5 (95% CI 2.1–3.1; P < 0.001) for HIV-infected MSM compared with HIV-negative MSM in univariable analysis. The variables tobacco smoking, poppers and cannabis use, age of first sexual anal intercourse, number of lifetime and recent anal sex partners, condom use, receptive anal intercourse, rimming, and fisting were associated (P < 0.1) with high-risk HPV in univariable analyses. In the final multivariable model adjusting for age and number of recent anal sex partners, the aOR of anal high-risk HPV was 2.2 (95% CI 1.8–2.7; P < 0.001) for HIV-infected MSM compared with HIV-negative MSM.
The OR for penile high-risk HPV infection was 2.5 (95% CI 1.8–3.4; P <0.001) for HIV-infected MSM compared with HIV-negative MSM in univariable analysis. Other variables that were associated with penile high-risk HPV (at P <0.1) were cannabis and poppers use, lifetime and recent number of anal sex partners, and having had insertive anal intercourse. The aOR for the association between HIV and penile high-risk HPV was 2.0 (95% CI 1.4–2.9; P < 0.001) in the final multivariable model adjusting for age and cannabis use.
Determinants of anal high-risk human papillomavirus infection
Multivariable analyses revealed that HIV-negative MSM with a higher number of recent anal sex partners (overall P = 0.012) and MSM with a higher number of lifetime male sex partners (overall P <0.001) were more likely to be infected with anal high-risk HPV (Table 3).
Table 3: Univariable and multivariable analyses of determinants of anal high-risk human papillomavirus infection in HIV-negative MSM (N = 459) and HIV-infected MSM (N = 317; H2M study, Amsterdam 2010–2011).a
In a multivariable model for HIV-infected MSM, anal high-risk HPV infection was less common among older men (overall P = 0.047). Having had receptive anal intercourse in the past 6 months (aOR 1.5; 95% CI 1.0–2.2; P = 0.035) and a higher nadir CD4+ cell count (overall P = 0.039) were significantly associated with anal high-risk HPV.
Determinants of penile high-risk human papillomavirus infection
In HIV-negative MSM, a higher number of lifetime male sex partners (overall P = 0.004) was significantly associated with penile high-risk HPV infection in multivariable analyses (Table 4). In HIV-infected MSM, no sexual behavior variable was associated with penile high-risk HPV infection. A detectable HIV viral load (aOR 2.6; 95% CI 1.4–4.8; P = 0.003) was significantly associated with penile high-risk HPV.
Table 4: Univariable and multivariable analyses of determinants of penile high-risk human papillomavirus infection in HIV-negative MSM (N = 460) and HIV-infected MSM (N = 317; H2M study, Amsterdam 2010–2011).a
Discussion
We found a high prevalence of anal and penile high-risk HPV infection in MSM, and particularly in HIV-infected MSM. HIV infection was a strong and independent risk factor of anal and penile high-risk HPV infection. HPV types 16 and 18, which are considered the causative agents of most anal cancers [22], were among the most common high-risk HPV types at both the anal and penile site of infection and in both HIV-negative and HIV-infected MSM.
The prevalence of anal HPV in the current study was similar to results of a recent meta-analysis, in which the pooled anal prevalence of high-risk HPV, HPV-16, and HPV-18 was much higher in HIV-infected MSM (respectively 74, 35, and 19%) than in HIV-negative MSM (respectively 37, 13, and 5%) [7]. Consistent with a study that examined the prevalence of anogenital HPV infection in HIV-negative MSM [23], our results showed lower penile than anal HPV prevalence rates. This indicates a different natural history of HPV infection at these two anatomical sites; the penile squamous epithelium may be less susceptible to HPV infection than the anal squamous or columnar epithelium and transformation zone [24]. In addition, differences between anal and penile sampling methods and DNA yield could play a role. The prevalence of penile shaft HPV infection is rarely reported separately for HIV-negative and HIV-infected MSM. A systematic review found a wide range of HPV prevalence of 6–52%, based on three studies that evaluated the prevalence of HPV infections of the penile shaft of HIV-negative (heterosexual) men [11]. However, comparisons across studies are hampered by differences in sampling and laboratory methods used, including the number of HPV types evaluated.
The finding that HIV is a strong risk factor for anal and penile high-risk HPV infection is consistent with existing literature [7,25]. The higher HPV prevalence in HIV-infected individuals might be due to a higher acquisition and persistence rate and reactivation of latent infection [26], which is probably caused by combined effects of impaired cellular immunity [27] and shared routes of transmission (i.e., sexual behavior).
Results from previous studies are inconsistent, but suggest that the risk of anal and penile HPV infection increases with a lower CD4+ cell count [28–30]. The growing risk of anal cancer among HIV-infected individuals since the introduction of cART might indicate that improved immune status in HIV-infected MSM is not sufficient to clear or suppress HPV infection, and that the longer life expectancy in HIV-infected individuals associated with cART might allow persistent HPV infections to develop into cancer [31–33]. Data on the association between nadir CD4+ cell count and anal HPV infection are scarce, but it is hypothesized that a history of low CD4+ cell count may permanently affect immunity [34]. Previous studies investigating the association between nadir CD4+ cell count and abnormal anal cytology [34,35] or anal cancer precursors [35,36] suggest that low nadir CD4+ cell count of less than 50 cells/μl increases risk of these HPV-related outcomes [34–36]. Surprisingly, we observed a positive association between higher nadir CD4+ cell count and anal high-risk HPV infection. Our findings could be influenced by the relatively high nadir CD4+ cell counts exhibited by our HIV-infected participants, as we had few MSM with a nadir CD4+ cell count less than 50 cells/μl. Also, unmeasured differences in characteristics of MSM with higher nadir CD4+ cell counts in terms of risk behavior might be responsible for this unexpected increased anal high-risk HPV prevalence with higher nadir CD4+ cell count. Finally, we cannot exclude the possibility that this observation was a chance finding.
Age showed no association with high-risk HPV in HIV-negative MSM, which was in line with flat age-specific prevalence curves estimated for genital HPV in men in general [12], and lack of association between age and anal HPV in HIV-negative MSM specifically [37]. The high anal HPV prevalence in MSM at all ages after adulthood may be explained by biological factors or sexual risk behavior during the life span of MSM [37]. In contrast, we observed a decreased risk for anal HPV infection in HIV-infected MSM above 35 years of age. Interestingly, Del Amo et al.[38] observed that prevalence of anal high-risk HPV in HIV-infected MSM was highest around the ages of 30–40 years. The reasons are unclear, but in our study it could be a chance finding due to having a relatively small number of HIV-infected participants below 35 years of age (N = 44).
As for sexual behavior, we found that a higher number of lifetime male sex partners was significantly associated with both anal and penile high-risk HPV infection in HIV-negative MSM. Moreover, a higher number of recent anal sex partners was associated with anal HPV infection in HIV-negative MSM only. We also found that receptive anal intercourse, which is an important mode of anal HPV acquisition [14,39], was associated with anal HPV infection in HIV-infected MSM, but not in HIV-negative MSM. Insertive anal intercourse was not independently associated with penile HPV infection, although the association was borderline significant in HIV-negative MSM. Thus, interestingly, we observed differences in determinants for HPV infection between HIV-negative and HIV-infected MSM, which may be related to immunological, biological, or behavioral factors.
The quadrivalent HPV vaccine, targeting HPV types 6, 11, 16, and 18, has been licensed for use in men, but is not routinely offered to boys in many countries. Our data confirm the high prevalence of HPV-16 infection in MSM, and especially HIV-infected MSM, making them an important target group for prevention of HPV-related cancer. Vaccinating boys at early age, as well as girls, could substantially further reduce the burden of HPV-related diseases.
Important strengths of this study include the relatively large study population consisting of both HIV-infected and HIV-negative MSM, and the evaluation of both anal and penile shaft high-risk HPV infections. The penile shaft is considered the most important anatomical site for assessing anogenital HPV infection in heterosexual men [40]. Here we show this is not the case for MSM, as the number of anal HPV infections far exceeds that of the penile infections. The detailed character of the questionnaires enabled us to explore a broad range of potential risk factors. As these are baseline data of a prospective cohort study, we hope to provide data on the natural history of HPV infection by location and its interaction with HIV infection in the near future.
As for limitations, estimating the effect of HIV-induced immunosuppression on HPV infection was challenging, because most participants had relatively high (nadir) CD4+ cell counts and undetectable HIV viral loads. Thus, the observed associations should be interpreted with caution. Also, our study population consisted of a relatively homogeneous group of MSM with a high level of (correlated) risk behavior, potentially diluting the effect of certain behaviors. For example, the lack of association between number of sex partners and HPV infection in HIV-infected MSM might be related to the high median number of sex partners in this group. Finally, study participants’ self-collected anal and penile swabs might be subject to interindividual variation. However, HPV type-specific concordance between self-collected and clinician-collected anorectal swabs has been shown to be very high [41].
In conclusion, our results confirm that the prevalence of anogenital high-risk HPV infection among MSM is high. HIV-infected MSM were at increased risk compared with HIV-negative MSM for both anal and penile HPV infection, after adjusting for potential confounders. Determinants for HPV infection differed per anatomical location and HIV status, highlighting the importance of understanding HPV in the context of different anatomical sites and coinfection with HIV. The high prevalence of HPV infection in MSM in combination with a rising anal cancer incidence calls for adequate prevention efforts.
Acknowledgements
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, in particular Roel Coutinho, for their advice and critically reading the article; the personnel of the ACS, MC Jan van Goyen, and the Amsterdam STI outpatient clinic for their contributions to the implementation of the study and data collection; Martijn van Rooijen for assisting in data management; Wilma Vermeulen (Public Health Service Amsterdam) for HPV genotyping; Jan Sonsma and Marina Burger (RIVM) for DNA isolation; Ronald Geskus for critically reading the article; and Claire Buswell for editorial review. Above all, they gratefully acknowledge all study participants for their co-operation.
This work was funded through a grant from Aids Fonds [grant number 2009029] and additional funding from the Public Health Service Amsterdam and RIVM.
F.v.A. analyzed the data and wrote a draft article. S.M. organized the study logistics, did the data management, contributed to the analysis, cowrote the draft article, and wrote the final version of the article. A.S. and A.K. analyzed and interpreted the 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. 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 article, and saw and approved the final version.
Conflicts of interest
M.S.v.d.L. received funding for a substudy on HPV from Sanofi Pasteur MSD and participated in a Merck-funded investigator-initiated study on Gardasil. For the remaining authors, no conflicts of interest were declared.
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