Abstract and Introduction
Abstract
Background: Studies considering the risk of atherosclerotic disease (AtD) associated with the use of HAART have reported inconsistent results.
Methods: Data on antiretroviral therapy (ART) use, risk factors for cardiovascular disease (CVD), AtD and death from other causes in 18 603 HIV-infected patients from two established cohorts were evaluated. The relative hazards of AtD and death from other causes were calculated using a proportional hazards competing risks framework. The impact of protease inhibitor (PI)-containing, non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing or PI + NNRTI-containing regimens on these outcomes were compared to nucleoside reverse transcriptase inhibitor (NRTI)-only regimens or stopping therapy, adjusting for known CVD risk factors.
Results: In 77 480 person-years of follow-up (median duration 3.49 years) there were 318 AtD events including 92 myocardial infarctions and 2044 deaths. Older age, hypertension, diabetes mellitus, having smoked and HIV disease stage were significantly associated with increased risk of AtD. PI- and NNRTI-containing regimens significantly reduced the joint risk of either AtD or death from other causes compared to NRTI-only or stopping therapy [hazard ratio (HR) for PI-containing ART, 0.76, 95% confidence interval (CI), 0.73-0.78, P< 0.001; NNRTI-containing ART, 0.69, 95% CI, 0.65-0.74; P< 0.001). PI-containing ART was associated with a borderline significant increased risk of myocardial infarction (cause-specific HR for PI-containing ART 1.19, 95% CI, 1.01-1.40, P = 0.04) but not with increased risk of AtD compared to NRTI-only regimens or stopping therapy (cause-specific HR for PI-containing ART, 1.03, 95% CI, 0.95-1.13, P = 0.44).
Conclusions: Overall benefits of PI- and NNRTI-based ART in reducing mortality significantly outweigh any risks of AtD in the 'short-term' follow-up of this study. Traditional cardiac risk factors play an important role in determining AtD risk status.
Introduction
The benefits of HAART for HIV infection have been demonstrated by the long-term improvement in clinical markers of disease progression and the associated reduction in HIV-associated morbidity and mortality. However, concern has been raised over the longer-term impact of toxic side effects, in particular metabolic abnormalities such as hyperlipidaemia, which have been associated with antiretroviral agents, and, concomitantly, their potential to induce cardiovascular disease (CVD). Several studies have investigated a possible association between HAART and CVD in HIV-infected patients using various statistical methodologies. Two of the most influential reported inconsistent results. The first, a retrospective study of 36 766 HIV-infected patients followed for up to 8.5 years in the Veterans Affairs Medical System, showed no significant association between the use of any class of antiretroviral therapy (ART), alone or in combination, and the hazard of cardiovascular or cerebrovascular events. The second, a prospective study of 23 468 HIV-infected patients enrolled from 11 established observational cohorts, reported a 26% relative increase in the rate of myocardial infarction (MI) per year of exposure to combination ART during the first 4-6 years of use. All studies noted that these risks are outweighed by the benefits of HAART, but none have formally calculated this by using competing risk methodologies. The use of such methods is necessary to study the survival of patients who are at risk from more than one event. The increase in survival associated with ART use makes observation of other serious conditions, such as CVD, more likely. Analyses that do not take this into account could falsely indicate an increased risk associated with ART use. Our aim was to compare the competing risks of atherosclerotic disease (AtD) events versus death from other causes in an established cohort of HIV-infected individuals. In addition, we consider whether differences in analysis methodologies used in previous studies explain the conflicting results.