The prevalence of oral HPV observed in this study is one of the highest ever reported in a non-cancer population. Specifically, this prevalence was higher than that reported in previous studies of HIV-positive (40% vs. 16–37%)(16
) and HIV-negative (25% vs. 4–18%)(15
) individuals. This may be explained at least in part by the older age and higher number of past and recent sexual partners of our population.(45
) The findings suggest that the higher oral HPV prevalence among HIV-positive individuals is not fully explained by differences in sexual behavior and cigarette smoking. Indeed, after controlling for cigarette smoking and sexual behavior, odds of oral HPV remained significantly elevated in HIV-positive compared to HIV-negative individuals, and were strongly associated with reduced current CD4. These findings are consistent with there being a strong independent association of HIV-related immunosuppression with the burden of oral HPV infection.
Risk factors for prevalent oral HPV infection differed among HIV-positive and HIV-negative individuals in this study. While odds of oral HPV infection were associated with recent
number of oral sex partners in HIV-negative individuals, they were associated with lifetime
number of oral sex partners and current CD4 in HIV-positive individuals. These differences are consistent with the hypothesis that prevalent oral HPV infections may represent primarily recently acquired infection among HIV-negative adults but in HIV-positive adults may be more likely to represent persistent, or previously acquired re-activated oral HPV infections. The strong association between current CD4 and oral HPV prevalence in this study is consistent with previous research demonstrating an association between immunosuppression and increased risk of cervical
HPV persistence (27
) and progression to cervical cancer (26
). In longitudinal follow-up of this study population we will explore whether HIV-related immunosuppression may have a similar effect on oral HPV natural history.
Our findings suggest that reduced current CD4 may have a stronger effect on oral HPV16 prevalence than other HPV types. This is in contrast to a previous study on cervical
HPV in the WIHS which reported a weaker effect of reduced current CD4 on cervical HPV16 infection than on other cervical HPV types.(39
) It is unclear whether there may be immunologic differences between the cervix and the oral cavity which might affect the relationship between CD4 and HPV type-specific clearance. Considering the relatively higher prevalence of oral HPV16 in this population (5.7%) and that HPV16 constitutes a larger percentage of HPV-positive oropharyngeal cancers than cervical cancers(1
) further exploration is warranted.
The significant association of recent oral sexual behavior with increased odds of oral HPV among HIV-negative participants in this study is consistent with several previous studies,(19
) although no association with oral sex was reported in one other recent study.(53
) To our knowledge, this is the first study to identify rimming (oral-anal contact) as a potential transmitter of oral HPV. As anal HPV prevalence is high among MSM,(54
) it is conceivable that rimming could lead to oral HPV exposure. However, while 32% of MACS participants reported rimming in the past six months, the behavior was highly correlated with oral sex behavior. Thus, it is difficult to determine whether there is an independent role for rimming in the transmission of oral HPV infection.
This study included participants from two high-risk cohorts, the MACS and the WIHS, with distinct study populations. While the findings were similar in the two cohorts, the associations between prevalent oral HPV with cigarette smoking and recent and lifetime sexual behavior differed between WIHS and MACS participants. Reasons for these differences are unclear and may be explained by the small sample sizes in stratified analyses. Alternatively, the effects of cigarette smoking on oral HPV persistence, if any, may be small in comparison to the risk of new acquisition with sexual risk taking and might therefore be harder to observe in a population such as the MACS with high median number of sexual partners (and thus heavier HPV exposure) than in the WIHS. In addition, the impact of age and tobacco-related immunosuppression may be expected to be less apparent among HIV-positive individuals, which might explain the lack of association among HIV-positive MACS participants, who were older and had lower nadir CD4 than WIHS participants. The higher number of lifetime sexual partners in the MACS may have led to saturation of risk that could explain why this association was significant in the WIHS, but not the MACS. The higher level of sexual risk taking in the MACS likely also explains why recent sexual behavior was more notable in the MACS than the WIHS.
There are several limitations to this study. The HIV-positive and HIV-negative populations studied were selected because of their high risk and may not be representative of others in the general population. Second, while we report heterogeneity in some risk factors by HIV-status and gender, some of these stratified analyses were underpowered. In addition, as oral HPV infection was only measured at one time point, we cannot differentiate between transient newly acquired infection and persistent or re-activated latent infections. Third, while oral HPV infections detected with the oral rinse have been strongly associated with odds of oropharyngeal cancer (3
) and shown to have a higher DNA yield and quality than other oral sampling techniques such as focal brush sampling(56
), oral rinse sampling cannot differentiate the site of infection, i.e. oral cavity or oropharynx. Lastly, while a strength of MACS and WIHS data is their extensive characterization of sexual risk behavior over time, each study relies upon self-reported data and missing values were imputed for lifetime number of oral sex partners which could lead to misclassification. Strengths of this study include the detailed biological and behavioral data collected, the optimized oral rinse processing and HPV testing technique,(35
) and the inclusion of both HIV-positive and risk-matched HIV-negative individuals of both genders.
This study suggests that oral HPV infection is common in HIV-positive and at risk HIV-negative women and MSM. HIV-positive individuals had a higher prevalence of oral HPV infection and different risk factors associated with infection than HIV-negative individuals. Whether HIV-related immunosuppression has an effect on oral HPV natural history, similar to that known for cervical HPV, will need to be explored longitudinally.