In a large cohort of HIV-infected and demographically-similar HIV-uninfected individuals receiving care from the same healthcare system, we found that HIV-infected individuals had a higher risk for six of the ten cancer types examined (KS, NHL, HL, melanoma, anal cancer, and liver cancer), independent of several cancer risk factors. Except for melanoma, these cancer types have known viral etiologies. The risk for lung and oral cavity/pharynx cancers in HIV-infected individuals was elevated in demographic-adjusted analyses, but not after adjustment for the cancer risk factors smoking, alcohol/drug abuse and overweight/obesity. Further analysis suggested that immunodeficiency as measured by recent CD4 count was positively associated with the risk of all cancer types except prostate cancer, for which there was a suggestion of a negative association. Finally, there was little evidence for an association between recent HIV RNA levels and cancer risk, except for a positive association for KS and NHL.
The higher risk of cancer in HIV-infected individuals compared with the general population is well established, with substantially higher risk for cancers with known viral etiologies, such as anal cancer, HL, or AIDS-defining cancers (ADCs) (5
). However, other cancer types, including lung, liver, and oral cavity/pharynx cancers, have much smaller elevated risks among HIV-infected individuals, which are more likely explained by the higher prevalence among HIV-infected individuals of traditional cancer risk factors, such as smoking (6
), alcohol use (7
), and oncogenic virus coinfection (10
). Here, we did in fact find that there was no overall increased risk of lung and oral cavity/pharynx cancers comparing HIV-infected and HIV-uninfected subjects after adjustment for smoking, alcohol/drug abuse and overweight/obesity. When each of these risk factors was considered alone, adjustment for smoking attenuated the rate ratio for HIV status slightly more than did adjustment for each of the other two potential confounders, although only adjustment for all three risk factors simultaneously resulted in a non-significant p-value for HIV infection status. These results suggest that the observed higher risk of these cancers in HIV-infected patients may be a result of several confounding factors. Alternatively, since these variables are related, adjusting for all three confounders may reduce residual confounding that resulted from imperfect measurement. For example, those with an alcohol/drug abuse diagnosis were much more likely to be smokers (61%) compared with those without an alcohol/drug abuse diagnosis (26%).
For liver cancer, adjustment for smoking, alcohol (a known liver cancer risk factor)/drug abuse and overweight/obesity attenuated but did not eliminate the association. HBV and HCV infection status, which are established risk factors for liver cancer, were not included in adjusted models since HBV/HCV testing has become more routine for HIV-infected individuals, but is likely driven by clinical suspicion for HIV-uninfected individuals; thus adjusted estimates would likely be biased. Thus, because we did not adjust, it is possible that the observed elevated risk for liver cancer may be explained all or in part by the higher prevalence of HBV and HCV infection in HIV-infected individuals.
Finally, we also observed a decreased risk of prostate cancer with adjustment for demographics and other factors, consistent with prior studies (3
). The reason for the decreased prostate cancer risk is unknown, although some have attributed this observation to less screening in HIV patients (22
Others have adjusted for cancer risk factors in comparisons of cancer risk in HIV-infected versus uninfected individuals. Several studies (23
), for example, have indicated that the higher risk of lung cancer may be independent of smoking. Interestingly, our analysis did find a higher risk of lung cancer in the subgroup of HIV-infected individuals with low CD4 counts, independent of smoking and other risk factors. Thus, it is possible that the overall immune status of a cohort determines whether or not an overall elevated risk of lung cancer is found after adjustment for other risk factors.
Studies among U.S. Veterans have also been informative given the availability of an internal HIV-uninfected comparison group (17
). One study indicated that adjustment for HCV infection and alcohol abuse/dependence explained all of the increased risk of liver cancer for HIV-infected individuals (18
). Bedimo et al. (17
) reported higher risks among HIV-infected U.S. Veterans for ADCs, HL, melanoma, and anal, lung and liver cancers compared with HIV-uninfected Veterans after adjustment for age, race and sex.
The strong, direct relationship between lower CD4 count and increased risk for KS and NHL among HIV-infected individuals is well-established (27
). Similar observations for NADC and immunodeficiency are inconsistent likely due to the small numbers of cancer events, requiring analysis of grouped cancer types only (30
), or often insensitive, static measures of CD4 count, such as CD4 count at AIDS diagnosis or at enrollment (1
). Several recent studies have evaluated time-dependent measures of CD4 count for specific cancers (14
). In the multinational EuroSIDA cohort (14
), lower recent CD4 count was independently associated with increased incidence of anal cancer, HL, and lung cancer. In the ATHENA cohort (15
), longer exposure to CD4<200 cells/µL was associated with a higher risk of anal cancer, while lung and liver cancer were not related to immunodeficiency. Finally, in the French Hospital Database cohort (16
), the largest study to date, recent low CD4 count was the best predictor of KS, NHL, HL, lung, liver, and cervical cancer incidence, whereas longer exposure to CD4 count <200 cells/µL predicted anal cancer risk.
With adjustment for several cancer risk factors, and inclusion of an HIV-uninfected comparison group, our study extends the findings of others regarding the association of immunodeficiency to a broad range of cancers. For ADC, even among HIV-infected individuals with CD4≥500 cells/µL, there remained a 60-fold higher risk for KS, but only a 4-fold higher risk for NHL compared with HIV-uninfected individuals. We also found here that two NADCs with known viral etiology, anal cancer and HL, had significant trends of increasing risk (compared with HIV-uninfected individuals) with decreasing recent CD4 count, as did colorectal cancer, which is not known to be virus-related. Although trends were not significant, results also suggested an association between immunodeficiency and melanoma, as well as lung, liver and oral cavity/pharynx cancers. Analyses restricted to HIV-infected individuals supported these findings; all infection-related cancers were related to low CD4 count, while there was a suggestion of an association of low CD4 count with colorectal cancer, lung cancer, and melanoma. However, these observations require confirmation in other settings, particularly for colorectal cancer, which has not previously been linked to immunodeficiency.
The fact that most cancers associated with immunodeficiency have a known infectious cause suggests a mechanism in which an impaired immune system cannot adequately suppress human papillomavirus (HPV) (12
), HCV (38
), or other oncogenic virus infections, resulting in a higher risk of related cancers. Another possibility is that the impaired immune system may result in reduced immune surveillance for malignant cells (39
), possibly explaining the associations observed for lung cancer, colorectal cancer, and melanoma. It is also conceivable that these cancer types have an as yet unidentified infectious cause. One study, for example, indicated that recurrent pneumonia was a risk factor for lung cancer in AIDS cases, suggesting a role of chronic infection (40
HIV infection prior to ART is characterized by a chronically activated but impaired immune system (41
), which could conceivably contribute to the elevated risk of certain cancers. Higher HIV RNA levels has been used as a proxy for immune activation (44
), and has been linked to higher risk for ADCs, but not NADCs (16
). The French Hospital Database cohort (16
), however, did note a higher risk of anal cancer with longer duration of HIV RNA>100,000 copies/mL. Here, we observed that higher recent HIV RNA levels were associated with KS and NHL incidence, and suggestively, with lung cancer and melanoma, but not with any other cancer type. In models among HIV-infected individuals, only KS and NHL remained associated with higher HIV RNA levels with adjustment for recent CD4 count and other potential risk factors.
Our study had several limitations. First, the risk factors considered were obtained from routine clinical practice, and not in a standardized fashion. Smoking, for example, was captured during outpatient visit encounters, and only routinely in more recent years. The level of detail recorded for risk factors only allowed for broad categorizations (e.g., ever or never smoked). Alcohol/drug abuse diagnoses did not capture actual alcohol or drug use among health plan members. Those without documentation of these risk factors in their medical record were considered unexposed. Although each of these exposure measurement issues may have resulted in residual confounding, as discussed, adjustment for the potential confounders together may have overcome some of the residual confounding. Finally, we were unable to adjust for other known cancer risk factors for which sufficient data were not available, such as diet, sun exposure, and infection by HPV, HBV, and HCV.
Regarding race/ethnicity, 94% of HIV-infected health plan members, but only 57% of HIV-uninfected members, had recorded race/ethnicity. However, since HIV-uninfected subjects were matched to HIV-infected subjects by medical center, differences in race/ethnicity between groups were likely mitigated. In fact, our prior work in the same study population (5
) indicated that multiple imputation for missing race/ethnicity did not affect inferences for effect of HIV infection status on cancer risk. Despite the large sample size, another limitation was the inability to study less common cancers, or evaluate more refined CD4 count or HIV RNA categories.
The major strength of our study was the inclusion of large, well-characterized populations of HIV-infected individuals and matched, demographically-similar HIV-uninfected individuals from the same health care system. Another key strength was the high quality ascertainment of HIV infection status and cancer diagnoses from long-standing registries. In addition, information about several key risk factors was obtained from the KP electronic medical record. Finally, the 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 (19
). However, study results may have limited generalizability to women, or to those without access to healthcare.
In summary, this was one of the few studies to directly compare the risk of cancer in HIV-infected individuals with a demographically-similar, HIV-uninfected, internal comparison group, adjusting for several major cancer risk factors. The higher risk of infection-related cancers was confirmed, especially with more advanced immunodeficiency. The higher risk for certain NADCs, including lung, oral cavity/pharynx and liver cancers was explained in large part by traditional risk factors, but risk remained elevated for individuals with more advanced HIV/AIDS. We also revealed a possible increased risk for colorectal cancer for HIV-infected individuals with more advanced HIV/AIDS. Our observations that most cancers were either no longer elevated in HIV-infected individuals at CD4≥500 cells/µL compared with HIV-uninfected individuals, or had greatly attenuated risks supports the concept of earlier initiation of ART to maintain high CD4 levels. Such a strategy would not only reduce the risk of AIDS or death (46
), but may also reduce the burden of a wide range of cancer types. However, our observation that much of the increased risk for lung, oral cavity/pharynx, and liver cancer was attributed to traditional cancer risk factors implies that traditional risk factor reduction approaches, including smoking cessation and alcohol moderation, remain the most important strategies for reducing the burden of these cancers.