In our cohort of HIV-infected individuals in clinical care in the US, we found that mortality risk was three-fold higher among HIV-infected individuals compared to controls of a similar age during an approximate 5-year period beginning from 2000 to 2002. As expected, HIV-infected participants with advanced immunosuppression at the baseline exam (CD4 <200) had a 6-fold risk of death compared to controls. Nonetheless, HIV-infected participants with less advanced immunosuppression (CD4 >350) also appeared to have a higher risk of death than controls. Among HIV-infected participants, in addition to a low baseline CD4 count, current smoking and older age were strong independent predictors of mortality.
The findings of our study are important for several reasons. First, we observed a higher mortality risk in a representative US population of HIV-infected persons compared to controls of similar age in the recent HAART era. Our findings are consistent with European studies [7
] that have examined age-specific mortality risk in HIV-infected persons compared to controls in the recent HAART era. The excess risk in these studies appeared somewhat higher than our study, likely because they did not control for CVD risk factors such as smoking.
Second, we were able to estimate mortality risk stratified by the baseline CD4 count relative to controls. We found a higher risk of death in HIV-infected participants compared to controls in each CD4 stratum studied (CD4 <200, 200 to 350, >350); as expected, those in the lowest CD4 strata had the highest risk of death. The findings of a 2-fold risk of death in those with a CD4 >350 are notable as our HIV-infected participants were relatively young, were receiving clinical care and most were receiving antiretroviral therapy. When we further stratified to a CD4 >500, a 2-fold higher risk of death remained. In contrast, another study found that among HIV-infected patients with a CD4 >500, the mortality rate after 6 years of follow-up was similar to that of the general population [16
]. We followed patients for 5 years, so may not have observed this trend. Some have proposed that inflammatory changes related to HIV infection may contribute to a premature increase in non-AIDS related deaths irrespective of CD4 count [17
]. HIV infection may also be associated with specific behaviors that lead to an increased risk of death, although we were able to control for smoking, which is a major such behavior.
Among the factors associated with death in HIV-infected participants in our study, we found an independent association with cigarette smoking, older age and lower CD4 count. Smoking is highly prevalent in HIV-infected individuals and is a known risk factor for CVD and pulmonary diseases. A recent study found that cigarette smoking (current or past) (as well as older age and lower CD4 count) were associated with an increased risk of death from non-AIDS defining malignancy [18
] ; lung cancer being the most common fatal non-AIDS defining malignancy. While smoking could also indicate a less healthy lifestyle in general, the findings of our study and others suggest that smoking cessation may be an important target for intervention in individuals with HIV infection. Estimates from our multivariable model suggest that those who quit smoking may see a lowered risk of death equivalent to a 2.7-fold increase in CD4 count. Although the risk of death was 2-fold higher in those with HIV/HCV coinfection compared to those with HIV monoinfection in unadjusted analysis, HCV infection did not appear to be a strong independent risk factor for death, after controlling for HIV-related, demographic and traditional CVD risk factors.
Our study has limitations. A large percentage of participants could not be contacted (23% of HIV-infected and 5% of controls), which may have led to an underestimation in the mortality rate; those not contacted, especially the HIV-infected, may have died during the five-year follow-up period. We therefore performed sensitivity analyses to address missing death status in those not contacted; all sensitivity analyses produced results that were similar to our primary observed case approach. Cause of death was also unknown for our HIV-infected participants and the sample size was relatively small with few deaths in controls.
In summary, mortality risk remains 3 times as high among HIV-infected persons in the recent HAART era compared to controls of similar age. Cigarette smoking, older age and lower CD4 count were independent predictors of mortality in those with HIV infection. Furthermore, our observation that HIV-infected patients were at greater risk of death compared to controls even at higher CD4 levels could suggest a possible role of chronic inflammatory changes (from HIV infection) leading to increased mortality risk, an association that needs further investigation.