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Original Study

HIV is an Important Risk Factor for Human Papillomavirus Types 16 and 18 Seropositivity Among Sexually Active Men Who Have Sex With Men

Alberts, Catharina Johanna MSc*†; van Rooijen, Martijn S. MSc*; Prins, Maria PhD*†; Pawlita, Michael MD; Schim van der Loeff, Maarten F. MD, PhD*†; Waterboer, Tim PhD, MSc

Author Information
Sexually Transmitted Diseases: March 2015 - Volume 42 - Issue 3 - p 129-134
doi: 10.1097/OLQ.0000000000000244

Human papillomavirus (HPV) is a sexually transmittable infection (STI). Most individuals will get infected with HPV at some point in their life1; however, the majority will clear an HPV infection within 1 to 2 years.2–4 Not everyone with an HPV infection will develop type-specific antibodies (in women 40%–60%5–8; in men <36%9), and the factors that influence the development of these antibodies remain poorly understood.5,10

Several risk factors for HPV seropositivity have been identified. For instance, it has been established that (i) HPV seropositivity differs by sex and sexual orientation due to differences in site of exposure, as previous studies have demonstrated that cervical and anal sites of exposure are associated with a higher risk for seropositivity than penile exposure11–13; (ii) lifetime number of sexual partners is the strongest predictor for HPV antibody detection7,14–16; (iii) persistent rather than transient infections are significantly associated with seroconversion6,15,17; and (iv) women with a high HPV viral load have a significantly increased risk for detection of HPV antibodies compared with women with a low viral load.7,8,14 The association between HIV status and HPV seropositivity has been less clear; some studies report no association,18,19 whereas other studies show that HIV-positive individuals are more likely to be HPV seropositive.13,20–22 This growing body of literature, however, mainly concerns data on women, whereas data on men (specifically men who have sex with men [MSM]) are scarce.13,18,21

In this study, we aim to address this knowledge gap by investigating the association of HIV and HPV seropositivity in MSM. As it has been shown that the site of exposure is associated with HPV seropositivity,11–13 we restricted this analysis to MSM who reported having had receptive anal sex in the 6 months before the study. Our research questions are (i) whether HIV infection is a main risk factor for HPV-16 and HPV-18 seropositivity in this MSM population, and (ii) which other risk factors are associated with HPV-16 and HPV-18 seropositivity.

MATERIALS AND METHODS

At the STI clinic of the Public Health Service of Amsterdam, free and anonymous STI testing and treatment is offered. At this clinic, an anonymous survey was conducted biannually among visitors 16 years or older and fluent in Dutch or English. During each survey period, consecutive clinic visitors were invited to participate, until a total of approximately 1000 attendees per survey period were included in the study.12 The medical ethics committee of the Academic Medical Center (Amsterdam, the Netherlands) approved the study.

For a previous study comparing the HPV seroprevalence between different risk groups, participants from the survey period of 2008 and 2009 were selected and tested for HPV antibodies.12 A total of 6165 persons visited the STI clinic during the 4 survey periods in 2008 and 2009. Of these visitors, 4171 (68%) agreed to participate in the survey, of which 927 (22%) were MSM. For this study, MSM reporting no receptive anal sex in the preceding 6 months or with a missing serum sample were excluded, resulting in 620 MSM reporting receptive anal sex in the 6 months preceding the clinic visit. These MSM were categorized in 2 groups based on HIV status.

Study procedures have been described before.12 Briefly, after written informed consent was obtained, questions regarding demographic characteristics and sexual behavior (e.g., education, country of birth of client and parents, number of lifetime sexual partners, age of sexual debut, condom use, type of sex [i.e., oral, penile, vaginal, and anal], sexual behavior in the preceding 6 months [number of casual partners, unprotected anal fisting, condom use behavior during sex with an HIV-positive partner(s)], history of sex work, being client of a sex worker, and being transgender) were posed to the client by nurses and trained interviewers. At the same visit, blood samples were taken to be tested for HPV antibodies, as well as for syphilis and HIV antibodies, and both urogenital and anal swabs were taken to be tested for current infection with chlamydia or gonorrhea. Ethnicity was defined on the basis of maternal and paternal country of birth according to the definition used by Statistics Netherlands (Centraal Bureau voor de Statistiek). Educational level was divided into 2 categories: low educational level (up to intermediate vocational education) and high educational level (higher general secondary education and above). Age, age of sexual debut, lifetime number of sexual partners, and number of casual partners in the preceding 6 months were categorized into 4 categories based on quartiles.

Sera were centrifuged within 4 hours, stored at −20°C within 48 hours, and were analyzed for HPV antibodies to the major capsid protein L1 by Luminex-based multiplex serology assay.23 The specific reactivity of L1 antibodies (median fluorescence intensity [MFI]) for different HPV types (HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-45, HPV-52, and HPV-58) was calculated as the difference between the MFI of antigen-loaded beads and the background MFI of beads without antigen. Serology cutoffs were determined by calculating the mean reactivity plus 3 standard deviations of the sera of 125 virgins (a cohort of young Korean women who were HPV DNA negative and self-reported to never have had sex). This resulted in a cutoff of 400 MFI for HPV-16, HPV-18, HPV-33, HPV-45, HPV-52, and HPV-58 and a cutoff of 600 MFI for HPV-31 and HPV-35.12

The Kruskal-Wallis test and Pearson χ2 test were used to compare HPV antibody MFI and HPV seroprevalence between the HIV-negative and HIV-positive MSM for all HPV types tested. To assess the proportion of HPV-positive participants by antibody level, the cumulative distribution of MFI was plotted in which the strength of the antibody reactions (MFI) was plotted on the y-axis against the proportion of HPV seropositive individuals on the x-axis. The Pearson χ2 test was used to compare demographic and sexual behavior characteristics, and STIs diagnosed at visit between HIV-negative and HIV-positive MSM. Human papillomavirus seroprevalences were compared between HIV-negative and HIV-positive MSM using bivariable and multivariable logistic regression analysis for all HPV types tested. We constructed multivariable logistic regression models to study the association between HIV status and HPV seropositivity. These multivariable logistic regression models included the following a priori defined variables: (i) age in years (categorical), (ii) age of sexual debut (categorical), (iii) number of lifetime sexual partners (categorical), (iv) number of casual partners in the preceding 6 months (categorical), (v) condom use during receptive anal sex in the preceding 6 months, (vi) unprotected receptive anal fisting in the preceding 6 months, (vii) condom use behavior during sex with an HIV-positive partner(s) in the preceding 6 months, and (viii) STI diagnosed at visit (gonorrhea, chlamydia, or syphilis).

To assess the risk factors associated with HPV-16 seropositivity and HPV-18 seropositivity in HIV-positive MSM and HIV-negative MSM, odds ratios (OR,s) with 95% confidence intervals (CIs) were calculated using bivariable logistic regression analyses. Statistical tests were 2 sided and performed using Stata version 13 (Stata Intercooled, College Station, TX).

RESULTS

In total, 415 HIV-negative and 205 HIV-positive MSM reporting receptive anal sex during the preceding 6 months were included in this analysis. Demographic characteristics, reported sexual behavior, and STIs diagnosed at visit were compared between the HIV-negative and HIV-positive MSM (Table 1). HIV-positive MSM were older (P < 0.001); had an earlier age of sexual debut (P = 0.010); had more lifetime sexual partners (P < 0.001); reported more often to have sex with a casual partner (P < 0.001), to have unprotected receptive anal fisting (P < 0.001), to never or not always use a condom with an HIV positive partner (P < 0.001), and to not always use a condom during anal sex (P < 0.001); reported less often to be a client of a sex worker (P = 0.045); and were more often diagnosed with an STI (P = 0.017; Table 1).

TABLE 1
TABLE 1:
Demographic Characteristics, Reported Sexual Behavior, and Diagnosed STIs in MSM Reporting Receptive Anal Sex in the Preceding 6 Months Visiting the STI Clinic in Amsterdam, the Netherlands (Survey Period 2008–2009)

Table 2 shows the HPV antibody levels in MFI and the HPV seroprevalence for both HPV-16 and HPV-18. The median MFI for HPV-16 seropositive individuals was 173 (interquartile range [IQR], 76–525) for HIV-negative MSM and 753 (IQR, 264–1453) for HIV-positive MSM (P < 0.001). The median MFI for HPV-18 seropositive individuals was 141 (IQR, 61–453) for HIV-negative MSM and 409 (IQR, 180-945) for HIV-positive MSM (P < 0.001). Participants were considered positive for HPV-16 and HPV-18 if the measured antibody reactivity exceeded 400 MFI. Using this cutoff, we observed a seroprevalence for HPV-16 of 31% (130/415) in HIV-negative MSM and 65% (133/205) in HIV-positive MSM (P < 0.001), and a seroprevalence for HPV-18 of 28% (115/415) in HIV-negative MSM and 51% (104/205) in the HIV-positive MSM (P < 0.001). For all other HPV types tested, both HPV antibody level and HPV seroprevalence were significantly higher in HIV-positive MSM than those in HIV-negative MSM; only HPV-58 seroprelvance was not significantly higher (Supplementary Table 1, https://links.lww.com/OLQ/A99). The cumulative distributions of antibody levels are depicted in Supplementary Figure 1, https://links.lww.com/OLQ/A99 for HPV-16 and HPV-18 (data for other HPV types are not shown). For all HPV types, HIV-positive MSM had a higher antibody reactivity than HIV-negative MSM did. This observation was consistent over a large range of MFI values.

TABLE 2
TABLE 2:
HPV-16 and HPV-18 Antibody Level in MFI and HPV-16 and HPV-18 Seroprevalence Among 620 MSM Reporting Receptive Anal Sex in the Preceding 6 Months Visiting the STI Clinic in Amsterdam, the Netherlands (Survey Period 2008–2009)

The association between HIV status and both HPV-16 and HPV-18 seropositivity in MSM is shown in Table 3. In crude analysis, HIV-positive MSM had a 4.05 (95% CI, 2.84–5.77) higher odds to be HPV-16 seropositive than HIV-negative MSM, and this association remained significant after adjusting for important confounding factors (OR, 2.80; 95% CI, 1.75–4.49). Although the associations for HPV-18 were not as strong as for HPV-16, associations of similar significance were obtained in crude (OR, 2.69; 95% CI, 1.90–3.80) and multivariable (OR, 1.78; 95% CI, 1.11–2.85) analyses. Analyses were repeated for HPV-31, HPV-33, HPV-35, HPV-45, HPV-52, and HPV-58 (Supplementary Table 2, https://links.lww.com/OLQ/A99); the same positive association between HIV infection and HPV seropositivity for all 6 HPV types was observed and associations were significant, except for HPV-35 and HPV-58.

TABLE 3
TABLE 3:
Association Between HIV Status and HPV-16 and HPV-18 Seropositivity in MSM Reporting Receptive Anal Sex in the Preceding 6 Months Visiting the STI Clinic in Amsterdam, the Netherlands (Survey Period 2008–2009)

The crude associations of both HPV-16 and HPV-18 seropositivity with demographic characteristics, sexual behavior, and diagnosed STIs were assessed separately in HIV-negative and HIV-positive MSM (Supplementary Table 3, https://links.lww.com/OLQ/A99). In the HIV-negative MSM group, the association of age with HPV seropositivity was borderline significant for HPV-16 (P = 0.050) and significant for HPV-18 (P = 0.012). Furthermore, we found that the only other significantly associated risk factor with HPV-16 seropositivity was condom use during receptive anal sex in the preceding 6 months (P = 0.009); those never using a condom were significantly less likely to be HPV-16 seropositive. In addition to age, the only other significant risk factor for HPV-18 seropositivity was practicing unprotected receptive anal fisting in the preceding 6 months (P = 0.026; Supplementary Table 3.a, https://links.lww.com/OLQ/A99). In the HIV-positive MSM group, the risk factors significantly associated with HPV-16 seropositivity were condom use behavior during sex with an HIV positive partner(s) in the preceding 6 months (P = 0.038) and an STI diagnosed at visit (P = 0.023); no significant risk factors were associated with HPV-18 seropositivity (Supplementary Table 3.b, https://links.lww.com/OLQ/A99).

DISCUSSION

High-risk HPV types 16 and 18 are responsible for most cervical and anal cancers, and anogenital HPV infections and anal cancers are more common among HIV-positive individuals.24,25 In this study among MSM attending an STI clinic, we found that the HPV-16 and HPV-18 antibody levels (expressed in MFI) were substantially higher in HIV-positive than in HIV-negative MSM, and that HIV infection was a significant risk factor for HPV-16 and HPV-18 seropositivity, even after adjusting for important confounding factors. Similar trends were observed for 6 other high-risk HPV types. No other clear risk factors for HPV-16 and HPV-18 seropositivity were identified in this MSM population.

Whether or not an HPV infection leads to seroconversion depends on a multitude of factors.5–9 Recent studies have shown that HIV status is significantly associated with HPV seropositivity,20–22,26 although this association was not found in other studies.18,19 Data on the influence of HIV status on HPV seropositivity in an MSM population are scarce.18,21,26 In this study, that was restricted to MSM reporting recent receptive anal sex and therefore was not biased by site of exposure, we provided additional evidence that HIV is an important risk factor for HPV seropositivity. Furthermore, HIV-positive MSM are not only more often seropositive, they also have higher MFI-levels over the whole MFI range, when compared with HIV-negative MSM (Supplementary Figure 1, https://links.lww.com/OLQ/A99). This study adds to the small but growing body of literature that elucidates the factors influencing HPV seropositivity in MSM.

Although among women and heterosexual men lifetime number of sexual partners was previously found to be one of the strongest predictors for HPV seropositivity,7,14,16 lifetime number of sexual partners was not significantly associated with HPV seropositivity in this MSM population. We could not identify other clear risk factors with HPV-16 and HPV-18 seropositivity in HIV-negative or HIV-positive MSM. We hypothesize that we did not find any additional clear risk factors because we studied a very high-risk population (MSM visiting the STI clinic), of which nearly all reported very high numbers of lifetime sexual partners. In the HIV-negative MSM group, we found that individuals never using a condom in the preceding 6 months were significantly less likely to be HPV-16 seropositive. However, in this group, relatively many MSM reported to have had sex with only 1 partner during the past 6 months (data not shown), implying that the lack of condom use in these men is in fact an indication of lower sexual risk behavior. It should be noted that the HIV-positive MSM group was a relatively small group of 205 individuals, which limited the power to detect statistically significant associations.

Our results are robust to the cutoff value used. The cumulative MFI distributions of HPV-16 and HPV-18 in HIV-negative and HIV-positive MSM (depicted in Supplementary Figure 1, https://links.lww.com/OLQ/A99) are parallel to each other over a large range of MFI values. When a cutoff value lower or higher than 400 MFI would have been used, the apparent seroprevalence would have been different, but the ORs comparing the risk groups, however, would have remained qualitatively similar.

A limitation of this study is the inability to address temporality. It is unclear whether individuals who are HPV seropositive are more susceptible to become HIV positive, or whether HIV positive individuals are more susceptible to become HPV seropositive. However, we speculate that a higher HPV incidence and a lower clearance rate of HPV infection among HIV-infected individuals,27,28 leading to longer duration of infections, may be an explanation for higher HPV seroprevalence in HIV-positive MSM. A lower clearance rate of anogenital HPV infections in HIV-infected individuals may lead to a longer exposure of the HPV virus to the immune system, causing seroconversion to occur more often in this population. Cellular immunosuppression could also facilitate the occurrence of a complete life cycle of HPV, and because prolonged exposure to viral antigens is thought to be a major factor in the development of an antibody response, this may explain the higher seroprevalence of HPV in HIV-infected individuals. As pointed out above, a reverse scenario, in which men with prevalent HPV infections are more prone to become HIV infected, might also be the case.29,30

This study brings us one step closer to unraveling the factors influencing HPV seropositivity and implicates HIV status as one among several other factors that have been suggested in the recent literature. In conclusion, seroprevalence of HPV-16 and HPV-18 was high among MSM visiting an STI clinic, and HIV infection seems to be an important risk factor for being HPV seropositive. Groups who are at high risk for becoming both HIV and HPV seropositive, such as MSM visiting an STI clinic, may benefit from timely HPV vaccination because they are at higher risk for developing HPV-associated diseases.

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