In this large multicohort study, we confirmed that HIV-infected MSM experienced the greatest risk for anal cancer with incidence rates >80 times as high as HIV-uninfected individuals. Incidence rates differed widely across the 13 individual cohorts, with a large amount (31%) of the variation accounted for by the cohort-specific prevalence of MSM. We also found that both HIV-infected other men and women had substantially higher rates than HIV-uninfected men and women, and that HIV-infected other men and women had similar rates. Finally, we observed that rates of anal cancer for HIV-infected individuals increased after the early ART era and then plateaued in more recent years.
The substantially higher incidence rate of anal cancer among HIV-infected MSM was observed initially in the pre-ART era [18
] and since has been confirmed by some studies [12
] but not others [4
]. The French Hospital Database study indicated that HIV-infected MSM had an 8 times as high incidence rate of anal cancer compared with HIV-infected women [12
], which is comparable to our finding of a 4 times as high rate comparing these same groups. Chaturvedi et al [19
] reported that MSM had an SIR of 52, the highest of all risk groups examined. Finally, Dal Maso et al [4
] reported that among Italians with AIDS, those with a history of IDU had the highest SIR (SIR, 85), followed by MSM (SIR, 47) and heterosexuals (SIR, 10).
We also observed that HIV-infected other men and women had similar anal cancer incidence, although both had elevated incidence rates compared with HIV-uninfected individuals. Piketty et al [12
] reported a higher incidence of anal cancer for both HIV-infected MSM and other men compared with HIV-infected women. Chaturvedi et al [19
], on the other hand, reported similar SIRs for heterosexual men (SIR, 14) and women (SIR, 15). Others have compared incidence rates by sex (ie, grouping MSM and other men together), with some indicating a higher incidence for anal cancer among men [13
], and others no difference by sex [2
]. However, sex differences in the incidence rate of anal cancer are difficult to interpret without also knowing the sexual orientation among men.
Discrepant results for sex and MSM status across studies may reflect variation in sexual risk behaviors among populations, thus contributing to differences in the prevalence of anal human papillomavirus (HPV). Prior studies have indicated very high anal HPV prevalence, particularly for HIV-infected MSM (prevalence ranging from 85% to 95%) [20
] but also for HIV-infected women (prevalence ranging from 76% to 90%) [23
], heterosexual men (prevalence of 60%) [20
], and injection drug users (prevalence of 46%) [22
]. D’Souza et al [11
] reported that among MSM, a higher cumulative number of reported unprotected anal receptive partners at study baseline was associated with a higher incidence rate of anal cancer.
We also found that among HIV-infected persons, anal cancer incidence rates increased between 1996–1999 and 2000–2003, followed by stable rates. This pattern was similar for MSM, other men, and women and was independent of other factors, including age, race/ethnicity, and baseline CD4. Many studies, but not all [2
], have reported increases in anal cancer incidence rates over time in HIV-infected persons [5
]; however, these studies compared rates between the pre-ART and ART eras. Among previous studies that evaluated trends over time during the ART era, some indicated continued increasing rates [8
], whereas others found no increases during more recent years [10
]. However, of the 3 studies showing continued increases, 2 had a small sample size and few events in the most recent era [25
], and the third evaluated trends only through 2003 [8
]. Similar to our results, the large French Hospital Database study observed an increase in anal cancer incidence rates for HIV-infected MSM, other men, and women through 1998, but no significant change in rates after 1999 [12
Our finding of stabilizing rates in the ART era may mask opposing pressures on anal cancer risk. On one hand, the improved survival for HIV-infected individuals in the ART era results in longer exposure to HPV infection, which may result in increased risk of HPV-associated cancers [8
]. Crum-Cianflone et al [26
], for example, observed that anal cancer was most common among HIV-infected patients with known duration of HIV infection of ≥15 years. On the other hand, anal cancer in HIV-infected patients may be related to immunosuppression [1
], which was supported here by the observed association of baseline CD4 and anal cancer incidence rates. If true, then improvements in immune function over time with the use of ART may result in decreased anal cancer risk.
Our study had limitations. First, we lacked data on several factors, including HPV infection, sexual behavior, smoking, and anal cancer screening, which would help further elucidate differences between groups. Regarding anal cancer screening, there might have been more vigilance for anal cancer among HIV-infected MSM than among HIV-infected other men and HIV-infected women, and among HIV-infected persons than among HIV-uninfected persons. Such differences in screening could have biased results in either direction, as screening could result in diagnosis of both anal cancers and of precancerous lesions. Treatment of the latter could result in decreased anal cancer incidence, which might explain the observed plateau in anal cancer rates. To the extent that screening practices differ from cohorts included here from the United States and Canada, results may have limited generalizability to other populations.
An additional limitation was the lack of information on sexual orientation for HIV-uninfected individuals. Because MSM, whether or not they are HIV-infected, may be at increased risk for anal cancer [31
], it is possible that confounding by MSM status contributed to the increased anal cancer risk we observed among HIV-infected MSM; however, few others have compared risk directly between HIV-infected and HIV-uninfected MSM to avoid this potential confounding [9
]. Also, among HIV-infected individuals, there may have been misclassification of sexual orientation, resulting in some MSM classified as other men. A further limitation was that anal cancer was rare in the HIV-uninfected population, limiting our statistical power and requiring us to use a single HIV-uninfected comparison group (not stratified by calendar era). Furthermore, there were no cases among women in the HIV-uninfected comparison group, precluding a direct comparison of anal cancer incidence rates by HIV status among women. Finally, neither the internal comparison group nor the external SEER rates included Canadians, even though our analysis included 3 HIV-infected Canadian cohorts.
Study strengths were evaluation of anal cancer rates for several well-defined groups of HIV-infected individuals (ie, MSM, other men, and women) and inclusion of an HIV-uninfected comparison group. The similarity of our results using this comparison group and the SEER rates as the comparison demonstrates the robustness of our findings. An additional strength was the very large sample size and the geographic and demographic diversity represented by the contributing cohorts.
Our finding of high anal cancer incidence rates in HIV-infected MSM, other men, and women suggests the need for enhanced primary and secondary prevention efforts among all HIV-infected persons, as opposed to a targeted approach. The HPV vaccine has been shown to be highly effective for prevention of anal cancer precursor lesions in women [32
] and was recently approved for prevention of anal cancer [33
]. Furthermore, vaccination of boys [34
] or high-risk groups, such as MSM [35
], can be highly cost effective. However, it remains to be seen how efficacious the vaccine will be for HIV-infected patients [36
]. Anal dysplasia screening may also prove to be a cost-effective approach to preventing cancer in HIV-infected individuals [37
]. The New York State AIDS Institute guidelines for anal cancer screening of HIV-infected patients recommend annual digital rectal examinations for all patients, and targeted anal cytology for MSM, for individuals with a history of anogenital warts, and for women with a history of abnormal cervical or vulvar histology [39
]. However, further research is needed to determine if such an approach will ultimately result in a decreased burden of anal cancer [40