Using population-based HIV and cancer registry data from 17 US areas, we estimated that 28% of males with anal cancer during 2001–2005 were HIV-infected, and that the temporal increase in male anal cancer rates during 1980–2005 was strongly influenced by the contribution of HIV-infected cancer cases. Furthermore, the vast majority of these HIV-infected males were MSM. In contrast, HIV had little impact on trends among US females, and the rates increased consistently over time in females, even in the absence of HIV-infected cancer cases.
Anal cancer is rare in the US general population but the fourth most common cancer in HIV-infected people, following non-Hodgkin lymphoma, Kaposi sarcoma, and lung cancer (9
). In the United States, the number of anal cancers occurring in HIV-infected individuals has increased over time because of the growth and aging of the HIV-infected population (9
). The elevated risk of anal cancer in HIV-infected individuals is partly because of the high prevalence of anal HPV infection (20
). HIV and HPV have a shared mode of transmission through sexual intercourse. MSM represent the largest HIV risk group in the United States, comprising more than half of all people living with HIV infection in 2008 (22
). Furthermore, among HIV-infected individuals, low CD4 cell counts are associated with increased risk of anal cancer (13
). Thus, HIV-associated immunosuppression may contribute directly to development of anal cancer by impairing cell-mediated immune control of HPV (24
). Though HAART partially restores immune function, HIV therapy does not lead to the regression of anal cancer precursor lesions (25
), and anal cancer incidence has increased in the HAART era (10
In this context, we note that not all anal cancers in HIV-infected people would be directly attributable to HIV infection. For example, as MSM are at increased risk of anal cancer, and most HIV-infected anal cancer cases occurred among MSM, we cannot say that HIV-infected anal cancer cases would not have occurred in the absence of HIV infection. However, HIV-infected MSM have a higher prevalence of abnormal anal cytology, and a 10-fold increased risk of anal squamous cell carcinoma, compared with HIV-uninfected MSM (26–28
). Thus, it is likely that a fraction of anal cancers in HIV-infected MSM (and HIV-infected people overall) are caused by coinfection with HIV and HPV.
Notably, the contribution of HIV-infected anal cancer cases to general population estimates of anal cancer was essentially limited to males, and in the absence of HIV-infected cases, anal cancer incidence was uniformly higher across age groups among females than males. The small proportion of HIV-infected anal cancer cases among females partly results from lower HIV prevalence among US women compared with men (0.2% vs 0.5%) (22
). The sex differences in incidence rates may be explained by differences in exposure to anal HPV infection. In 2009, 35% of US women aged 50–59 years, but only 10% of men, reported ever engaging in receptive anal sex (29
). Further, anal HPV prevalence appears to be higher in women, approaching the prevalence observed in MSM (30
). The cause of the increasing anal cancer incidence among women over time is unclear but may be due to an increase in the number of sexual partners or in the practice of receptive anal intercourse (4
). Further, this increase is consistent with rising trends in other HPV-related cancers, including oropharyngeal cancer, vulvar cancer, and cervical adenocarcinoma, perhaps reflecting an increasing prevalence of infection with oncogenic HPV types (32–34
Among males, blacks with anal cancer had more than double the prevalence of HIV infection compared with whites, likely reflecting the higher prevalence of HIV infection in black men compared with white men in the United States (1.7% vs 0.3%) (22
). The proportion of anal cancer cases in HIV-infected males was far greater for squamous cell carcinomas than for adenocarcinomas (31.3% vs 2.7%), which may be because of the difference in HPV prevalence reported in anal squamous cell carcinomas (78%) and adenocarcinomas (43%) (35
Two cancer prevention strategies have been suggested for reducing the burden of anal cancer: HPV vaccination and anal Papanicolaou (Pap) testing. Widespread vaccination against HPV 16 and -18 will reduce the burden of HPV-associated cancers, including anal cancer. The available bivalent and quadrivalent HPV vaccines are highly efficacious in preventing anal HPV infection and anal cancer precursor lesions due to HPV 16 and -18 (36
). The US Advisory Committee on Immunization Practices has recommended HPV vaccination for adolescent and young women since 2007 (38
) and recently endorsed vaccination of boys aged 11–12 years (39
). However, vaccine uptake remains low, and because most anal cancers in the general population occur among those aged 60 years or older, any benefits of HPV vaccination on anal cancer rates will not be observed for decades (40
). Among HIV-infected individuals, who develop anal cancer at a younger age (41
), the HPV vaccine is safe and highly immunogenic, but efficacy studies are still needed (42
Based on the success of the Pap test for cervical cancer screening, use of a similar Pap test for detection of anal cancer precursors could potentially reduce anal cancer incidence. Anal cancer screening may be cost-effective in HIV-infected and HIV-uninfected MSM (43
), and New York State guidelines recommend anal Pap testing for certain HIV-infected individuals (45
). However, anal Pap testing has not been shown to reduce anal cancer incidence or mortality (46
), and a recent study concluded that more information is needed about the natural history of anal cancer and the progression rates of high-grade anal intraepithelial lesions before anal cancer screening in high-risk groups should be implemented (28
The main strength of our study was the availability of population-based data on anal cancer and AIDS diagnoses from 17 regions of the United States over the entire course of the HIV epidemic. The size of our study allowed us to assess incidence trends despite the rarity of anal cancer.
This study had a few limitations. The main weakness of our study was the lack of complete data on anal cancer cases with HIV-only. However, we addressed this issue by upweighting prevalent anal cancers in people with AIDS to represent cancers in people with HIV-only. These upweighted results were quite similar to results based on more limited prospective data following HIV diagnosis. We also note that the HACM Study includes US areas with higher-than-average HIV prevalence; so the proportion of anal cancer cases with HIV infection may be higher that of the entire country. Finally, 21% of HIV-infected people in the United States are undiagnosed and are not captured in HIV/AIDS registries, which would lead to an underestimate of the proportion of HIV-infected anal cancer cases (47
In conclusion, a large proportion of US males with anal cancer in recent years, particularly younger and black males, were HIV-infected. Measures that would effectively prevent anal cancer in HIV-infected males could markedly reduce anal cancer rates at the population level. In contrast, very few females with anal cancer were HIV-infected, and more research is needed to understand causes of rising anal cancer incidence in females.