Incremental new data from the landmark DAD (Data collection on Adverse 

event of anti-HIV Drugs) trial, which last year reported a 26% 

increased risk in the frequency of heart attacks (myocardial infarctions, or 

MI) per year of antiretroviral drug exposure, has found that HAART also 

increases the risk of stroke and other cardiovascular or cerebrovascular 

events (CCVEs) by the same amount. The results appear in the September 

3rd issue of the journal AIDS. 

DAD is an observational study established to track long-term 

antiretroviral safety involving over 23,000 HIV-positive people in eleven cohorts 

in three continents. Their first findings, published in 2003, was that 

during over 36,165 person-years of follow-up, 126 people suffered a 

heart attack, or myocardial infarction (MI), 36 of which were fatal. The 

incidence of MI increased with additional years on combination 

antiretroviral therapy, resulting in a 26% increased risk of MI per year of drug 

exposure. However, overall, the frequency of reported MI remained low 

at 3.5 cases per 1,000 person-years of follow-up. 

In this analysis, an additional 81 patients experienced at least once 

CCVE other than an MI. 

The other CCVEs included in this analysis were: 

- Invasive cardiovascular procedure: a procedure in which the interior 

of the body is "invaded" either by catheters placed in large blood 

vessels, or by surgical or related procedures, for example coronary artery 

angioplasty (blockage removal) or bypass surgery. This was the first 

CCVE in 39 patients, and no-one died.

- Stroke (a sudden disruption of the blood flow to the brain). This was 

the first CCVE in 38 patients, and nine were fatal.

- Deaths from other CCVEs. Four patients died from a CCVE, having never 

previously experienced another cardio- or cerebrovascular event.

The incidence of first CCVE was 5.7 cases per 1,000 person-years of 

follow-up (95% confidence interval [CI] 5.0 - 6.5), and increased with 

longer exposure to antiretroviral therapy (p < 0.001). Given the range of 

events reported, this is still a relatively low frequency, and is not 

enough for the investigators to pin the blame on a particular class of 

antiretroviral. 

To put this into perspective with the other, classic risk factors for 

CCVE, the authors examined the relative risk (RR) through multivariate 

analysis. 

They were, in order of risk: 

- Previous history of CCVE (RR, 7.12; 95% CI 4.91 - 10.3; p < 0.001).

- Male gender (RR, 1.82; 95% CI 1.10 - 3.00; p = 0.02).

- Smoking (RR, 1.66; 95% CI 1.14 - 2.42; p = 0.008).

- Family history of CCVE (RR, 1.62; 95% CI 1.05 - 2.50; p = 0.03).

- Older age (RR per five years older, 1.42; 95% CI 1.32-1.52; p < 

0.001).

- Antiretroviral therapy (RR per year of exposure, 1.26; 95% CI 

1.14-1.38; p < 0.001).

Additional analyses tested the association between CCVE and a number of 

metabolic and physiological causes. 

Factors independently associated with the risk of CCVE, were, in order 

of relative risk: 

- Diabetes (RR, 2.22; 95% CI 1.46 - 3.37; p < 0.001).

- High blood pressure (RR, 1.79; 95% CI 1.25 - 2.56; p = 0.001).

- High triglycerides (RR, 1.30; 95% CI 1.12 - 1.51 per log2 higher; p = 

0.006).

- High cholesterol (RR, 1.11; 95% CI 1.03 - 1.19 per mM higher; p = 

0.008).

The authors conclude that "the results of this study further support 

the hypothesis that [antiretroviral therapy] is associated with increased 

risk of atherosclerosis." However, more follow-up of this cohort is 

necessary to determine whether the risk will continue to increase with the 

length of antiretroviral therapy. So far, their analysis shows that the 

risk increases each year during four years of follow-up, with a 

doubling of risk after four years of antiretroviral treatment compared to 

someone who has not taken antiretrovirals. 

Importantly, the DAD study does not differentiate between different 

classes of antiretrovirals and their relative risk, since there have not 

been enough clinical endpoints for the investigators to be absoutely 

certain of the significance of their interpretations. These analyses are 

planned for the future. 

Reference:  The DAD Writing Committee. Cardio- and cerebrovascular 

events in HIV-infected persons. AIDS 18: 1811-1817, 2004. 

SOURCE:  aidsmap.com