Prevention of Human Papillomavirus-Related Anal Cancer in Women Living With Human Immunodeficiency Virus Free

(See the Major Article by Liu et al on pages 932–8.)

People living with human immunodeficiency virus (PLH), most notably men who have sex with men (MSM), but also women, suffer from a disproportionally high burden of human papillomavirus (HPV)-related anal cancer [1]. In recognition of this burden, and supported by recent evidence from the ANCHOR study that treatment of histological anal high-grade squamous intraepithelial lesions (aHSIL) can prevent anal cancer [2], anal cancer screening in PLH is evolving from local initiatives towards nationally endorsed evidence-based clinical guidelines. Such programs are somewhat analogous to cervical cancer screening, based around high-resolution anoscopy (HRA), the equivalent of cervical colposcopy, to detect and treat histological aHSIL. However, limited capacity/expertise in HRA (a technique with a long learning curve that, to be viable on a large scale, should be reserved only for those at highest cancer risk), as well as concerns for over-treatment of histological aHSIL (of which only a fraction are destined for cancer), highlight the need to prioritize PLH at highest anal cancer risk for HRA referral and histological aHSIL treatment.

It is therefore highly relevant and timely for Liu et al, in this issue of The Journal of Infectious Diseases [3], to report on risk factors for anal HPV infection and aHSIL in their institutional experience of offering anal cancer screening to women living with HIV (WLH). It is the largest such report of WLH to date, and is particularly pertinent given that much of the existing relevant evidence in PLH comes from MSM [4], for whom the dynamics of genital/anal HPV transmission, and potential markers of risk stratification, differs considerably from that of women.

Liu et al focus their current report on WLH for whom anal cancer screening was performed concomitantly with cervical screening, thus allowing them to address the important female-specific question about how HPV and/or cytology results from cervical cancer screening might help to stratify WLH at highest aHSIL risk [3]. To this end, however, it is notable that the majority of histological aHSIL were diagnosed among WLH who were HPV negative and/or cytologically normal at the cervix, suggesting that routine cervical screening results do not offer clinical utility for stratification of WLH for aHSIL risk.

This result appears to be somewhat inconsistent with another important finding of Liu et al [3] (and of previous analyses [5]), namely that cervical HPV infection is a strong predictor of anal HPV infection and aHSIL. Indeed, multiple lines of evidence suggest that anal HPV exposure in women occurs principally from the cervix/external genital region via auto- or partner-assisted inoculation. These include associations between anal sexual intercourse and anal HPV incidence that are much less important than number of sexual partners per se [6], and that a majority of women with anal cancer report no history of anal sexual intercourse [7].

The answer to this apparent contradiction may lie in temporal/age-specific shifts in the relative prevalence of HPV infection in the cervix and anus. A recent meta-analysis of paired cervical and anal samples showed a predominance of cervical HPV in WLH aged 15–24 years, shifting to a predominance of anal HPV by age 35 years [8]. Liu et al, who screened WLH of median age 49 years, not only confirmed that HPV infection predominated in the anus over those in the cervix in this older age group, but also reported that HPV-related cytological abnormalities did too, including a prevalence of cytological aHSIL that was more than double that of cytological cervical HSIL [3]. This supports a hypothesis that, in WLH at least, HPV infections and their accompanying abnormalities tend to persist in the anus even after they have been cleared in the cervix.

So, if not cervical screening results, then could perhaps routinely available HIV-related immune suppression be used to triage WLH (as well as other PLH) for anal cancer screening? Unfortunately, however, Liu et al were not able to identify CD4 cell counts and HIV load measures as independent predictors of histological aHSIL (at least not after adjustment for anal HPV) [3]. In a similar, albeit slightly smaller, study of WLH, Stier et al reported a crude odds ratio (ie, unadjusted for anal HPV) of a 7-fold increase in histological aHSIL risk in WLH with CD4 < 200 compared to a CD4 > 350 cells/µL [9]. Nevertheless, in their WLH population, that was under long-term HIV control (as indeed was that of Liu et al [3]), 70% of all histological aHSIL were diagnosed in WLH with CD4 > 350 cells/µL, highlighting the gap between an epidemiological association and having practical clinical utility for risk stratification. Furthermore, HIV-related immunosuppression is a complicated historical exposure that is not easily captured by any single dichotomous measure. Thus, following the important experience of Liu et al [3], there still appears to be no clear approach for aHSIL risk stratification in WLH from routinely available variables, rather only markers that need to be obtained directly from anal swabs.

In this respect, anal HPV16 infection was by far the strongest predictor of histological aHSIL, of which approximately one-third were diagnosed among WLH with HPV16-positive anal swabs in the report by Liu et al [3]. At first glance, this would appear to be of unacceptable clinical sensitivity. However, there is increasing evidence (which does not exist for cervical cancer screening results or HIV-related immunodeficiency markers) to infer that a large majority of future anal cancers in this population would arise from the 13% of Liu et al's WLH population that tested HPV16 positive. Indeed, not all aHSIL is destined to progress to anal cancer, and prospective findings of untreated aHSIL in HIV-positive MSM have shown that aHSIL infected with non-HPV16 high-risk types are significantly more likely to regress than those infected with HPV16 [10]. In addition, a meta-analysis summarizing cross-sectional genotyping studies showed that the prevalence of anal HPV16 increases greatly between aHSIL and anal cancer (including in WLH), whereas non-HPV16 high-risk types accounted for high proportions of aHSIL but their prevalence (particularly as single infection in the absence of HPV16 coinfection) decreased in anal cancer [5]. Taken together, these data strongly suggest that HPV16-positive aHSIL are more likely to evolve to anal cancer than aHSIL positive for non-HPV16 high-risk types.

At a global level, the vast majority of WLH (and indeed other PLH) do not currently undergo any anal cancer screening. If the offer of screening to this high-risk group is to expand, focusing on those who test HPV16 positive on anal swabs, or even those have persistent anal HPV16 only, may be relevant for referral for preciously limited slots for high-quality HRA. Indeed, incorporating information on expected anal cancer risk, rather than focusing solely on maximizing aHSIL sensitivity, may be a more impactful approach to anal cancer prevention at a population level if it allows the offer to a wider baseline population from whom those at highest risk can be identified and appropriately monitored. This would result in more efficient allocation of scarce HRA resources, which is particularly relevant if anal cancer secondary prevention is to be expanded beyond the limited number of pioneering expert clinics such as that led by Liu and colleagues.

While we continue to search for better molecular markers to stratify anal cancer risk from anal swabs (for which methylation markers currently hold most promise [11]), Liu et al rightly advocate that anal HPV genotyping should play a more pivotal role in anal cancer screening, particularly for WLH. Indeed, moving to anal HPV(16) genotyping as a primary test may have additional programmatic benefits beyond its powerful risk stratification. The possibility for application of HPV DNA testing to self-collected anal swabs (in a fashion analogous to the shift in cervical screening towards self-sampling) also has the potential to improve acceptability and participation, avoiding the unnecessary burden of anal swab-taking on health systems. This approach needs validation and should be the focus of future research, first among highest-risk PLH. But if well validated, this approach could also open the application of anal cancer prevention concepts to other, lower-risk groups, who are not under as close medical surveillance as PLH. It has recently been estimated that only approximately 3% of female anal cancers globally (predominantly in sub-Saharan Africa), and only approximately 1% in the United States, are diagnosed in WLH [12]. So it would be great if experiences and concepts learned from screening high-risk WLH could also one day be applied to women uninfected with HIV, on whom two-thirds of the global anal cancer burden falls [12].

Notes

Disclaimer. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization.

References

Author notes