When we did not account for the underlying population age structures, we found that many cancers occurred at much younger ages in people with AIDS than in the general population, as suggested in previous studies (15
). However, these differences were almost completely driven by differences in the underlying age structures of the populations at risk of cancer. The prior studies that have reported on younger ages at cancer diagnosis in persons with HIV/AIDS have not taken into account that very few HIV-infected people who are at risk of cancer had attained older age, when most cancers develop. For example, in the present study only 1.5% of person-time among people with AIDS was contributed by those aged 65+ years. This underlying age difference creates a bias when the ages of the cancer cases arising in these populations are compared.
Cancer has recently been considered as a component of a potential syndrome of premature aging caused by HIV infection, motivated by clinical observations that the average age of onset of age-related cancers is younger in HIV-infected individuals than in the general population (15
). However, as shown here, these dramatic age differences were influenced by age differences in the populations at risk. Although we are not aware of previous mention of this type of confounding in the literature on HIV/AIDS and cancer, a similar mechanism has been discussed in studies of inherited diseases, such as Crohn disease. Studies of parent-child pairs with Crohn disease have observed that children are younger than their parents when diagnosed (29
). However, these generational age differences arose because children were younger than their parents when assessed for disease status, and were thus not followed across the same age range as their parents (31
). After properly accounting for differences in the periods at risk for Crohn disease, these age differences were eliminated (32
). This analysis highlights that statistical adjustment for differences in time at risk is essential when comparing ages at diagnosis (32
). In our study, indirect standardization allowed a comparison of the ages at cancer diagnosis in the AIDS and general populations after controlling for differences in the distributions of age and other demographics.
Small, but statistically significant, differences in the ages at diagnosis for anal cancer, lung cancer, and Hodgkin lymphoma were observed after adjusting for differences in population structure. These malignancies are among the select group where cancer risk is elevated among HIV-infected people (2
). We propose two potential explanations for the earlier age at diagnosis among people with AIDS for anal and lung cancers. First, the earlier age at diagnosis may represent an effect of HIV on the development of these cancers. For example, HIV increases risk for cancer by inducing loss of immune control of oncogenic infections (e.g., human papillomavirus [HPV] for anal cancer) (7
). By increasing the transition rate through intermediate stages of infection on the pathway to cancer, this biological mechanism dramatically increases the number of people with cancer, and may also lead to slightly earlier ages at cancer diagnosis. Second, an early onset of cancer in people with AIDS could reflect differences in the timing or intensity of exposure to other key risk factors for these cancers, e.g., earlier age at initiation of tobacco smoking or sexual debut (leading to HPV infection) or a greater number of cigarettes smoked per day. These explanations are not mutually exclusive, and both could explain the younger age at diagnosis for cancers known to be linked to HIV infection. Nonetheless, if AIDS directly accelerates anal and lung cancer development, one would likely observe more rapidly growing, distant stage cancers. However, we did not observe higher SIRs for distant stage anal and lung cancers, compared to local and regional stage cancers.
One additional explanation for these age differences is increased medical surveillance of persons with AIDS, resulting in lead time bias. This explanation is partly supported by our data for anal cancer. The SIR for anal cancer was highest for local stage disease, which would be compatible with a stage shift due to screening with anal Pap tests (targeted toward HIV-infected men who have sex with men). However, because many HIV-infected people do not receive regular medical care or cancer screening (33
), the overall magnitude and direction of this effect on age at cancer diagnosis are uncertain.
Among persons with AIDS, Hodgkin lymphoma was diagnosed at an older age than in the general population, but interpretation of this observation is hindered by the complexities of Hodgkin lymphoma epidemiology. In the general population, Hodgkin lymphoma exhibits a bimodal pattern in its age at onset. Nodular sclerosis often affects teenagers and young adults and is less strongly associated with Epstein Barr virus (EBV) than other subtypes, while mixed cellularity (often EBV positive) is the most common subtype among older adults (35
). Among persons with HIV, Hodgkin lymphomas mainly resemble this second peak, i.e., the mixed cellularity subtype predominates (36
), and EBV is detectable in 80–100% of cases (38
). Of note, the age distribution of Hodgkin lymphoma cases in people with AIDS did not show the bimodal pattern seen in the general population (), reflecting the relative lack of young and old people with AIDS (). Thus, the single peak in people with AIDS actually represents a mixture of both EBV-negative and EBV-positive Hodgkin lymphomas. We speculate that the apparent shift to older ages in the observed cases among people with AIDS represents a strong increase in the risk of the EBV-positive cases that occur at older ages, rather than a shift of EBV-negative cases to older ages. Indeed, HIV may accelerate the development of the EBV-positive Hodgkin lymphomas that occur at older ages, e.g., by leading to loss of immune control of EBV infection.
Our study has several strengths. Most importantly, our comparisons of age at cancer diagnosis were corrected for bias due to the differing underlying age structures of the AIDS and general populations. Additionally, the HIV/AIDS Cancer Match Study includes data on a large and representative sample of persons with AIDS in the U.S. (e.g., these analyses included approximately 20% of the 1.05 million cumulative AIDS cases in the U.S.). The main limitation of our study was the lack of risk factor information, including information on cigarette smoking, which prohibited us from directly assessing how exposure to known cancer risk factors influenced the age at cancer diagnosis. Additionally, our study was restricted to non-Hispanic whites and non-Hispanic blacks with AIDS, perhaps limiting the generalizability of our findings. However, any biologic effect of HIV in accelerating the development of cancer should be similar across racial and ethnic groups, and the lack of acceleration in cancer development among people with AIDS, who are most immune compromised, argues against an important effect in people with earlier HIV disease. Finally, we assumed that cancer rates were known without error, because the cancer registries included in our study cover a very large population with over 875 million person-years of follow-up. If this assumption is incorrect, then the variance of our estimates would be underestimated, increasing the probability of observing a statistically significant age difference when one does not exist. However, as we observed no age differences for most cancers, we do not believe that making this assumption biased our results.
To conclude, our results do not support inclusion of cancer as part of a general syndrome of premature aging in HIV-infected people. Apparent earlier ages at cancer diagnosis arise largely because there have been very few people with AIDS followed during older age when most cancers arise. As the AIDS population continues to age, we would expect more non-AIDS-defining cancers to occur at older ages, attenuating or eliminating the apparent age differences at cancer diagnosis. Our results do not support an accelerated screening schedule in HIV-infected individuals for most cancers (e.g., prostate, colon and breast cancers). However, HIV-infected individuals should still receive regular cancer screening based on recommendations made for the general population and established guidelines made specifically for HIV-infected people for those cancers where risk is particularly high (e.g. for cervical and anal cancers) (39