One Step Closer in Understanding the Natural History of Anal Infection With High-Risk Human Papillomavirus

(See the Major Article by Twisk et al, on pages 1018–26.) Over 120 different human papillomavirus (HPV) types have been identified, of which >40 infect the epithelial lining of the anogenital tract and other mucosa [1]. Twelve HPV types are classified as class 1 human carcinogens by the International Agency for Research on Cancer and are referred to as high-risk oncogenic HPV types [2]. It is widely accepted that high-risk HPV infection is a necessary (although insufficient) cause of virtually all cases of cervical cancer worldwide, a likely cause of 88% of anal cancers, and a likely cause of substantial proportions of other genital neoplasms and oral squamous cell carcinomas [3]. Our understanding of the natural history of anal HPV infection among males is far less well characterized than for cervical infection among women, but it is considered analogous. Steps along the pathway from infection to anal cancer are thought to include incident HPV infection (which may be followed by persistent infection), development of low-grade followed by high-grade anal intraepithelial neoplasia (which may regress), and eventual progression to anal cancer over a period of many years. A key question in the early stages of this pathway is whether detection of anal HPV infection among individuals who previously tested negative for HPV represents recent acquisition or reactivation of a previously acquired but dormant infection. Most initial HPV infections of the anogenital tract, believed to be acquired via sexual contact shortly after sexual debut, will become undetectable by current assays within months and are often described as having “cleared” [4, 5]. There are 3 possible scenarios following such clearance [4]. First, the infection cleared and the person is immune to reinfection. Among males, this first scenario is unlikely, given low seroconversion rates following natural infection, compared with females, and little influence of seropositivity on subsequent incident detection of anal or genital HPV infection [6, 7]. Second, the infection cleared and the person is susceptible to reinfection upon reexposure. Third, the infection entered a dormant state (known as viral latency) and has the potential to reactivate at some future time, such as when the person is immunocompromised because of human immunodeficiency virus (HIV) infection [1]. Establishing to what extent the detection of a new infection among sexually experienced men who have sex with men (MSM) can be attributed to these 3 scenarios has relevance beyond scientific curiosity. This knowledge would greatly influence the potential impact of the 2 major HPV prevention tools in our toolbox: primary prevention, using HPV vaccination, and secondary prevention, using cancer screening. If the second scenario is common and a considerable proportion of new detections represent novel acquisition, then there may be benefit in vaccinating older, sexually experienced MSM. The international randomized controlled trials of the quadrivalent vaccine indicated high efficacy against anal intraepithelial neoplasia among boys and men aged 16–26 years [8], evidence that has informed the indication for vaccination among males to age 26 years. Although immune response to vaccination generally declines with age, evidence of sexual reacquisition suggests the potential for benefit well beyond one’s twenties. Conversely, if the third scenario is common and detection of most new anal HPV infections represents reactivation of previously latent infections, then screening for precancerous lesions may be a more appropriate endeavor to prevent cancer. This would then further motivate accumulation of evidence to inform optimal anal cancer screening approaches among high-risk populations such as MSM. The magnitude of new HPV detections attributable to either scenario is what is important to guide prevention efforts. To determine this magnitude, an important first step is to establish whether an association exists between newly detected HPV DNA in the anal canal and recent sexual exposure. The absence of association, if unbiased, favors the viral latency and reactivation hypothesis. Enter new findings from the H2M-study, a 24-month longitudinal cohort of MSM in Amsterdam, reported by Twisk et al [9] in this issue of The Journal of Infectious Diseases. Their aim was to assess whether sexual exposure may explain all incident anal high-risk HPV detections among MSM. In addition to enrolling an impressive sample size of 714 men, the authors were meticulous regarding measurement of exposure and outcome. They defined the outcome as new detection of high-risk oncogenic strains of HPV 16, 18, 31, 33, 45, 52, or 58 preceded by at least 2 consecutive semiannual visits during which HPV test results were negative, which mitigates the potential of misclassifying intermittent infection as incident. In defining sexual exposure, Twisk et al [9] were cautious and inclusive of multiple forms of sexual activity. Correct classification of sexual exposure is greatly challenged by the myriad ways that HPV can transmit from person to person. It is well accepted that HPV transmits efficiently via anal and vaginal intercourse, but other means of transmission considered plausible are oral sex and rimming, deep kissing, and mutual masturbation, including fisting. Past studies of sexual exposures and anal HPV infection have generally focused on anal intercourse exposures. Twisk et al [9] took a novel approach by classifying recent sexual anal exposure into 3 categories—nonexposed, low exposure, and high exposure—taking into account not only the number of partners and receptive and insertive anal sex, but also whether men reported having been rimmed and/or fisted. For most HPV types, the highest incidence rate of newly detected anal infection was among men in high-exposure group, and the lowest was among nonexposed men; these differences were statistically significant only for HPV-45, however. Upon adjustment for markers of past sexual exposure (ie, HPV seropositivity status at baseline and lifetime number of male partners), potential for autoinoculation (ie, penile HPV infection), and immune function (ie, HIV status), the risk for incident high risk HPV detection for men with high exposure was nearly 2 times that for nonexposed men (adjusted hazard ratio, 1.90; 95% confidence interval [CI], 1.19 – 3.02). Nevertheless, differences in detection rates were not substantially different according to sexual exposure, despite many sensitivity analyses to test assumptions. Together, their findings suggest that, although some incident detections among MSM represent reinfection, the detections are also consistent with the hypothesis that a substantial proportion are, indeed, reactivation. Twisk et al [9] were conservative in their definition of sexual nonexposure, and it is within this category that incident detection of HPV is most likely to represent reactivation, rather than unmeasured sexual exposure. (Readers should note that the latter cannot be completely ruled out, given potential recall errors or sexual exposure via other means, such as the sharing of sex toys.) Incidence rates varied among nonexposed men according to HPV type. For all HPV types, detection rates were nonzero and ranged from a low of 2.0 detections/100 person-years (95% CI, .5–8.0) for HPV-45 to a high of 6.6 detections/100 person-years (95% CI, 3.0–14.8) for HPV-52. When the time frame for classification of nonexposure was extended from the past 6–12 months, results were generally similar. Regrettably, rate calculations among nonexposed MSM were imprecise, given the small number of person-years of observation in this group. Longer-term follow-up of men who remain sexually inactive for extended periods would allow for better estimation of incident detection rates and, thus, would clarify the reactivation question further. An important cofactor in the development of anal cancer among MSM is coinfection with HIV, given the effects of HIV on immune suppression [1]. Thirty-nine percent of men followed in the H2M-study were HIV positive, and it is within this subset that incident anal HPV detections would be more likely to represent reactivation events. Findings from Twisk et al [9] were suggestive of reactivation, but there was inadequate precision to be conclusive. As shown in Supplementary Table 2 of their article, the magnitude of the association between HIV status and CD4+ T-cell counts with incident HPV detection was greatest among nonexposed men. Nevertheless, HIV infection was associated with incident HPV detection even among highly-exposed men. Future research should investigate these hypotheses further in HIV-positive versus HIV-negative men, with larger sample sizes and longer-term follow-up, possibly through data sharing via cohort collaborations. It is particularly important to investigate this issue among HIV-positive MSM, as their risk for anal cancer is 100 times that in the general population, according to international cohorts, at 131 events/100000 person-years [10]. Although the authors’ observed association between recent sexual exposure and detection of a new anal HPV infection is consistent with the hypothesis that a portion of new detections were recently acquired, there is an alternative explanation. Some new detections among the sexually exposed men may have been reactivations stimulated by sexual activity itself, because latent infection of stem cells in the basal cell layer can be reactivated with microtrauma that could occur during anal intercourse [4]. This hypothesis would be testable with longitudinal follow-up of HPV-seropositive men and detailed measurement of their sexual exposure. Ultimately, the way forward will likely require both primary and secondary prevention. Many MSM continue sexual activity and acquire new partners well into late adulthood, with ongoing potential for reexposure. Studies such as that by Twisk et al [9] bring us one step closer to understanding the potential impact of anal cancer prevention strategies in this high-risk population across the life-span. Acknowledgment. I thank Dr Claire Kendall for comments on an earlier draft of this editorial. Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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