In our cART-era cohort of more than 110,000 Veterans, we found that HIV infected Veterans had a significantly higher incidence of lung cancer than uninfected Veterans, and that HIV infection was an independent risk factor for lung cancer after controlling for potential confounders including smoking. This is the largest cohort study with both HIV infected and uninfected subjects and individual-level smoking data to evaluate lung cancer incidence. Our analysis includes 457 cases of incident lung cancer among HIV-infected patients, more than eight times that of any previous analysis with individual-level smoking data.
Risk of lung cancer among HIV infected individuals has been more pronounced in most previous studies, with IRRs ranging from 2.2 to 4.7 when comparing HIV infected with uninfected persons[4
]. However, a recent study that compared HIV-infected and uninfected individuals enrolled in Kaiser Permanente observed a demographically-adjusted IRR of 1.8 and an IRR of 1.2 in an adjusted analysis including smoking[26
]. Our findings are similar to those from the ALIVE cohort, a single site cohort of injection drug users with HIV infected and uninfected subjects. The most recent analysis from this cohort found a hazard ratio of 2.3 for the incidence of lung cancer in HIV infected compared with uninfected subjects after adjustment for smoking[10
]. This study was limited by the characteristics of the underlying cohort; the patients in the analysis were from both the pre-cART era and the current era, were almost exclusively African-Americans from a single site, and reported a very high baseline prevalence of smoking (94%). Our findings confirm the independent association between HIV infection and lung cancer incidence found in the ALIVE study, and similarly, we find that smoking conveys a much greater magnitude of risk for lung cancer than HIV infection.
We adjusted for confounding by smoking using a categorical assessment of smoking prevalence but did not have data to adjust for smoking intensity and duration. However, we note that in a smaller cohort of HIV infected and uninfected Veterans in which we collected self-reported smoking histories, uninfected current and former smokers had significantly greater pack-year exposure than HIV infected current and former smokers[13
]. Also, the ALIVE cohort reported no difference in smoking intensity between their HIV infected and uninfected participants[9
]. In our stratified analysis, we noted a consistent magnitude of association of HIV infection with lung cancer risk across smoking strata, supporting an independent association. Additionally, in a sensitivity analysis where we assumed all HIV infected former and never smokers were current smokers, HIV infection persisted as a significant risk factor for lung cancer. Nevertheless, we cannot completely rule out the presence of residual confounding by smoking.
Although certain previous studies have suggested that HIV infected patients with lung cancer are more likely to present with advanced stage disease[4
], the largest cART-era series with morphology and stage data found similar distributions of morphologic type and stage at presentation in 75 HIV infected lung cancer patients compared to historical controls[27
]. Our study confirmed similar morphologic type and stage distributions between HIV infected and uninfected patients, with the added strength of an internal comparison group. The stage distribution observed in our cohort was similar to that reported from population-based SEER data[28
], with most cancers presenting at late stage. Thus, despite a greater frequency of healthcare encounters in the HIV infected patients compared with the HIV uninfected patients in our cohort[16
], the increased incidence of lung cancer among the HIV infected patients does not appear to be explained by more vigilant surveillance.
Other factors included in our adjusted analysis demonstrated an independent association with lung cancer risk, including age, COPD, and bacterial pneumonia. The association of age and lung cancer risk is well recognized; age did not modify the relationship between HIV infection and lung cancer risk, indicating that the association between HIV infection and lung cancer risk did not vary by age. COPD has been linked previously to an increased risk of lung cancer, independent of smoking[21
]. Although baseline COPD was a risk factor for lung cancer in our analysis, we found no evidence that the association between HIV infection and lung cancer risk differed according to baseline COPD status. A recently published study from the AIDS-Cancer Match, a registry linkage study, demonstrated an increased risk of lung cancer in AIDS patients with prior recurrent episodes of bacterial pneumonia[23
]. We found that HIV infected patients who develop lung cancer were more likely to have a baseline bacterial pneumonia diagnosis but that this relationship did not explain the excess risk of lung cancer noted in HIV infected patients in our adjusted model.
Although our primary study goal was to compare lung cancer incidence in HIV infected and uninfected patents, in univariate analyses we also compared HIV infected patients who developed incident lung cancer to HIV infected patients who did not develop lung cancer with respect to baseline CD4 cell count, nadir CD4 count, and baseline cART exposure, noting no differences. This was consistent with other cohort studies in HIV infected patients[5
]. However, a meta-analysis comparing cancer incidence in studies of HIV/AIDS patients and organ transplant recipients found similar risk increases for lung cancer in both groups, suggesting a causal role for immunosuppression[30
]. Furthermore, in other cohorts, recent (as opposed to baseline or nadir) CD4 count has been found to be inversely related to lung cancer incidence[26
] Thus, for the purpose of understanding the relationship between immunodeficiency and lung cancer risk among HIV infected patients, we plan to conduct additional more sophisticated analyses with time-updated modeling of CD4 cell count.
Our descriptive univariate analysis also revealed a lower median baseline HIV RNA level in HIV infected patients who developed lung cancer compared with those who did not. We speculate that a lower HIV RNA level at baseline may be a marker for greater likelihood of survival in our cohort and therefore represent greater time to develop lung cancer; however, it may also represent a spurious finding that requires further evaluation in multivariate models. Previous studies have consistently reported no association[6
] or a positive association[26
] between HIV RNA levels and lung cancer risk.
The strengths of this study include its large, multi-center design and national range. Importantly, the lung cancer cases were pathologically confirmed, and our HIV infected and uninfected subjects were demographically similar and drawn from the same national sample. In addition, although predominantly male, our cohort was racially and ethnically diverse.
Our study had several limitations. Incident lung cancer cases were identified using a VA-based cancer registry, and therefore cases diagnosed and treated outside of the VA system may not have been captured. However, previous data have suggested low rates of utilization of non-VA healthcare, among both HIV infected and uninfected Veterans[33
]. Another limitation, addressed by our multiple imputation analysis, was that smoking prevalence was unknown for 20% of HIV-infected Veterans and 15% of HIV-uninfected Veterans.
As HIV infected patients are aging on effective cART, lung cancer may become an increasingly common and often fatal diagnosis. The significantly higher overall mortality rate among HIV infected patients compared to uninfected patients in our cohort denotes a large competing risk for mortality among HIV infected patients[34
]. This suggests that as AIDS-related mortality decreases with improved treatment, an even greater incidence rate of lung cancer may be noted, and our study may under-represent both the incidence and enhanced risk of lung cancer. Additional investigations are required to understand the mechanisms by which HIV infection may increase the risk for lung cancer.