The introduction of highly active antiretroviral therapy (HAART) has led to marked reduction in HIV-related mortality.1 The decrease in HIV-related mortality, however, has been accompanied by increases in non-HIV-related mortality including cardiovascular, hepatic and pulmonary diseases, and non-AIDS malignancies.2-5 Furthermore, studies in the HAART era show that mortality in HIV-infected persons remains higher than in the general population.6-8 We evaluated the association of HIV infection with mortality risk relative to controls of similar age over a 5-year follow-up period in the recent HAART era. We studied a geographically and ethnically diverse US cohort of HIV-infected individuals in clinical care and controls with detailed information on demographic and cardiovascular disease (CVD) risk factors, allowing us to adjust for these factors. We also identified the HIV-related factors associated with mortality.
From June 2000 to September 2002, 1183 HIV-infected and 297 control participants were enrolled into the study of Fat Redistribution and Metabolic Change in HIV infection (FRAM). HIV infected were recruited from 16 HIV or infectious disease clinics or cohorts throughout the US. Control participants were recruited from 2 centers of the Coronary Artery Risk Development in Young Adults study,9,10 a population-based cohort that recruited a sample of healthy 18- to 30-year-old white and African American men and women from 4 US cities in 1985-1986 for a longitudinal study of cardiovascular risk factors. The FRAM study design, recruitment, and data collection procedures have been described elsewhere.11 A follow-up examination (FRAM2) was conducted from 2004 to 2007. The institutional review boards at all sites approved the protocols. Figure 1 shows FRAM2 retention outcomes. Available for analysis were 922 HIV-infected and 280 control participants known to be alive or dead.
After exclusion of HIV-infected participants with opportunistic infections or malignancies (OI/OM) in the same or previous calendar month as the baseline examination, and with an age outside of the 33- to 45-year age range of the controls, a total of 469 HIV-infected participants were included in multivariable exponential regression analysis comparing HIV infected with controls. Among the 469, there were a total of 54 deaths. Follow-up time was defined as elapsed time from baseline to follow-up examination or last contact. For deceased subjects, the left-censoring time was defined using the median follow-up time for HIV-infected or control participants, because death could have occurred at any time during this interval. Similar analyses were conducted categorizing HIV-infected participants by their CD4 count (>350, 200 to ≤350, and <200) compared with controls. Subsequent analyses of all 922 HIV-infected participants determined the demographic, CVD, and HIV-related factors independently predictive of mortality. We conducted sensitivity analyses using multiple imputation12 to estimate mortality status for participants with unknown vital status. In addition, sensitivity analysis using an inverse probability of censoring weight approach was performed to adjust estimates.13,14 All analyses were conducted using the SAS system, version 9.1 (SAS Institute Inc, Cary, NC).
Table 1 shows the baseline characteristics of the 469 HIV infected and 280 control participants of similar age (and the 922 HIV infected) with known vital status. Current smoking and diabetes were more common in HIV infected than in controls; total and high density lipoprotein (HDL) cholesterol was lower. Average elapsed time between examinations was shorter in HIV infected than in control participants; elapsed time ranged from 2.5 to 6.9 years. Among the 922 HIV infected, 76% were on HAART, 12% were HAART naive, and 13% received HAART in the past.
Over the 5-year period, the mortality rate was higher in HIV-infected than in control participants (12% vs. 2%, P < 0.0001). In multivariable analysis, controlling for demographic and traditional CVD risk factors, HIV infection remained associated with a higher risk of death (HR = 3.4, 95% CI: 1.35, 8.5, P = 0.0094). Compared with controls, mortality risk was highest for HIV infected with CD4 < 200 (HR = 6.3, 95% CI: 2.2, 18.2, P = 0.0007), followed by CD4 200-350 (HR = 4.3, 95% CI: 1.14, 16.0, P = 0.031) and CD4 > 350 (HR = 2.3, 95% CI: 0.78, 6.9, P = 0.13; Fig. 2). Mortality risk among HIV-infected participants with CD4 > 500 remained higher than controls, although the association did not reach statistical significance (HR: 2.1; 95% CI: 0.60, 7.6, P = 0.24). In sensitivity analyses to evaluate the potential effect of those with unknown vital status, HIV infection remained associated with higher risk of death (multiple imputation: HR = 4.2, 95% CI: 1.57, 11.0, P = 0.0046; inverse probability of censoring weight: HR = 3.6, 95% CI: 1.50, 8.5, P = 0.0040).
In multivariable analysis of HIV-infected participants alone (Table 2), higher baseline CD4 count was strongly associated with lower risk of death. Factors associated with higher risk of death included current smoking and older age. Mortality was highest among those with both low CD4 counts and current smoking status (40%) compared with the lowest risk group of high CD4 count nonsmokers (5.3%). Higher non-HDL cholesterol was associated with lower risk of death. There was little association between HAART use (ie, current use, total duration of use, and duration categorized by number of years used) and mortality risk (data not shown). Sensitivity analyses showed similar results (data not shown).
In our cohort of HIV-infected individuals in clinical care in the United States, we found that mortality risk was 3-fold higher among HIV-infected individuals compared with 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 examination (CD4 < 200) had a 6-fold risk of death compared with controls. Nonetheless, HIV-infected participants with less advanced immunosuppression (CD4 > 350) also seemed 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 with controls of similar age in the recent HAART era. Our findings are consistent with European studies7,8,15,16 that have examined age-specific mortality risk in HIV-infected persons compared with controls in the recent HAART era. The excess risk in these studies seemed 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 with 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 up 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, and older age and lower CD4 count) was associated with an increased risk of death from non-AIDS-defining malignancy18; lung cancer being the most common fatal non-AIDS-defining malignancy. Although 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 with those with HIV monoinfection in unadjusted analysis, HCV infection did not seem 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 5-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 with 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 with 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.
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