We determined that infection-related cancers (ADC and infection-related NADC combined) comprised almost 70% of all cancers in HIV-infected persons enrolled in an integrated healthcare system in California compared to only 12% in HIV-uninfected persons of similar age and sex. HIV-infected persons had a more than nine-fold increased risk of infection-related NADC compared to HIV-uninfected persons, which was largely influenced by differences in risk for anal squamous cell cancer and Hodgkin’s lymphoma. HIV-infected persons also had a 30% increased risk of infection-unrelated NADC compared to HIV-uninfected persons, including a higher risk of other anal, skin, other head and neck, and lung cancers, but lower risk of prostate cancer. Infection-related NADC risk declined over time for HIV-infected persons and increased for HIV-uninfected persons. In contrast, the overall infection-unrelated NADC risk did not change over time for HIV-infected or HIV-uninfected persons.
The substantially greater risk for cancers with a known infectious cause in HIV-infected persons compared with HIV-uninfected persons may be explained by higher virus co-infection rates, as demonstrated by others for human herpesvirus-8, HPV and hepatitis B and C [10
]. However, general population prevalence for certain viruses, such as Epstein-Barr Virus [21
], are very high and cannot account entirely for the large difference observed here for Hodgkin’s lymphoma. Alternatively, the greater risk for infection-related cancers observed in HIV-infected persons, could be further explained by the fact that the suppressed immune system in HIV-infected persons may reduce the ability to control infections and therefore suppress the oncogenic viral process. This mechanism is supported by a large meta-analysis by Grulich et al. [17
] who compared cancers elevated in persons with HIV infection and organ transplant recipients. These two very different populations have few shared risk factors for cancer except both populations have suppressed immune systems [17
]. Most of the cancers seen with higher frequency in both populations compared to general population rates had a known infectious cause including ADC, as well as the same infection-related NADC we report here. Others have demonstrated a higher risk of Hodgkin’s lymphoma [2
], oral cavity/pharynx [2
], anal [26
], liver [22
] and penis [23
] cancers with advanced immunosuppression measured mainly by closer proximity to an AIDS diagnosis [2
] or low CD4+ T-cell counts [4
]. One study, however, indicated a non-linear association of Hodgkin’s lymphoma risk and CD4+ T-cell counts [28
Further evidence of a strong link between immune function and infection-related cancer risk is provided by our observation that the increased risk of both ADC and infection-related NADC in HIV-infected persons compared to HIV-uninfected persons has narrowed in recent years. This observation is consistent with improvements during the ART era in immune function possibly leading to better control of co-infections [12
]. In fact, a recent study demonstrated that prolonged ART use predicts Hepatitis B virus clearance [29
], although studies of the effect of ART on other viruses were inconclusive, including Hepatitis C [30
], anal HPV [31
], cervical HPV [32
] and Epstein-Barr Virus [33
]. Others have actually demonstrated increases in the incidence of Hodgkin’s lymphoma [2
], anal cancer [4
], and liver [2
] cancer during the ART era, suggesting that these cancers may not be strongly associated with immune reconstitution resulting from ART use. It is not clear why trends are somewhat different in our study, since we observed no changes over time in HIV-infected persons for any cancer in adjusted models, with the exception of declines in anal squamous cell cancer. One possible explanation is that many prior studies compared rates between the pre-ART and ART eras, while ours focused only
in the ART era. Piketty et al. [27
], for example, in the largest study focusing on anal cancer, found an increasing trend for years 1992–2004, but no change for years 1999–2004. It is also possible that trends may be different for certain subgroups. Our cohort of predominantly HIV-infected White MSM, had very high anal squamous cell cancer rates early in the ART era. Therefore, it is possible that improvements in immune function may have a bigger impact in our population. Nevertheless, our findings need replication in other settings.
We also report here our finding that the risk of infection-unrelated cancers is only marginally increased in HIV-infected persons compared with HIV-uninfected persons. The meta-analysis by Grulich et al. [17
] demonstrated that other cancers not known to be associated with an infection were also elevated in both immunosuppressed populations, that is HIV-infected persons and transplant recipients, including lung and kidney cancers, multiple myeloma, and leukemia. Others have linked infection-unrelated cancers and immunosuppression [2
], most commonly for lung cancer [2
]. However, because the reported increased risk for infection-unrelated cancers is not large, results are more likely to be attributed to unmeasured confounding. Unfortunately, few cohorts have the necessary data for complete adjusted analyses. A recent study of skin cancer suggested that the higher risk of melanoma for HIV-infected persons was more likely due to confounding by sun exposure or perhaps increased medical surveillance than due to immunosuppression [37
]. However, there is some indication that the excess risk of lung cancer in HIV-infected persons remains even after accounting for cigarette use [35
]. Thus, a general effect of immune function on some infection-unrelated cancers is possible, but further research is warranted.
This study had certain limitations. First, we did not account for cancer risk factors such as smoking or alcohol use. However, it is not likely that confounding by these and other factors entirely explained the observed results for cancers with a known infectious cause, given the large effect sizes. Infection-unrelated NADC, on the other hand, had much smaller effect sizes and may in fact be explained by confounding factors. A related limitation was the ecologic evaluation of changes in cancer risk over time. Although we did adjust for differences in age and sex over time, it is possible that changes in cancer risk factors confounded our results. However, if this were the case, one would expect broader changes in cancer risk, rather than declines only among infection-related cancers. Furthermore, there is no data to suggest that HIV-infected persons have shown dramatic improvements in the prevalence of risk factors, such as smoking, alcohol use or viral coinfection. Therefore, we believe results are more likely attributable to improvements over time in immune function. Nevertheless, studies incorporating individual-level data are needed to address these questions. Finally, we had limited generalizability to women, the uninsured, and certain racial/ethnic minorities.
The major strength of our study is the selection and follow-up of large, well-characterized populations of HIV-infected persons and matched HIV-uninfected persons from the same health care system. Study results are likely to be highly generalizable to those with access to healthcare since KP provides care to approximately 30% of all insured Californians in its most populated areas, and data indicate members are very similar to the local surrounding and statewide population with respect to age, sex and race/ethnicity, with only slight underrepresentation of those in lower and higher income and education categories [16
]. Furthermore, demographics of HIV-infected KP members are very similar to reported AIDS cases in California [40
]. Another strength is the high quality case ascertainment of HIV infection status and cancer diagnoses. Finally, this analysis is unique in that we evaluated differences in the epidemiology of cancers with and without a currently known infectious cause.
In summary, we found that almost 70% of cancers in HIV-infected persons have a currently known infectious cause compared to only 12% in HIV-uninfected persons. These results have implications for prevention of cancers in HIV-infected persons. First, we found little evidence for the need for a different screening approach compared to general guidelines for breast, prostate or colorectal cancer among HIV-infected persons. However, the higher risk of lung cancer should be evaluated further including the possible association of this cancer with immune function, and the need for greater smoking risk reduction. Prevention efforts in HIV-infected persons, however, should continue to focus on infection-related cancers, including the evaluation of more routine vaccinations for infections such as hepatitis B, and possibly the extension of the recently approved HPV vaccine to adolescent boys. However, the HPV vaccine has not been evaluated in HIV-infected persons, nor has it been evaluated for the prevention of HPV-associated cancers other than cervical cancer. For anal squamous cell cancer, universal screening guidelines for the detection of early lesions may also greatly benefit this population. Finally, our study supports the concept of earlier initiation of ART [41
], since the burden of infection-related cancers may be reduced further with improved immune function.