Absolute risk is modest, but cumulative cardiovascular risk of HAART over five years is similar to ‘ever smoked’: new data on gender and age

18 April 2005. Related: Conference reports, Side effects, CROI 12 (Retrovirus) 2005.

Simon Collins, HIV i-Base

The D:A:D study is the largest and longest running prospective cohort study assessing the relationship between HAART and cardiovascular disease. This is a multinational study including over 23,000 patients enrolled in national cohorts from Europe, Australia and the US.

Data presented in an oral presentation from the latest analysis of this important dataset, which now includes over 76,000 patient years with median exposure to HAART of 4.5 years, continued to show that NNRTI- or PI-including combination therapy is an independent risk factor for cardiovascular disease.

By 2004, 277 patients experienced a first myocardial infarction (MI). The incidence of MI/1000 patient years increased from 1.39 in treatment naïve patient, to 2.53 in those exposed for < 1 year, to 6.07 in those exposed for ≥ 6 years (RR compared to no exposure:  4.38 [95% CI 2.39 to 8.04], p = 0.0001). After adjustment for other potential risk factors, there was a 1.17-fold [95%CI, 1.11 to 1.24] increased risk of MI per additional year of combined ART exposure.

After six years there are now sufficient events in the database to look at role of age and gender. Although the rate of myocardial infarction was higher in men than women (2.04 [1.30 to 3.21]), the RR associated with HAART was similar in men (1.14 [1.06 to 1.24]) and women (1.38 [1.07 to 1.76], p value for interaction 0.51). The relationship was similar in younger and older patients (men > 45 and women > 55 years; p value for interaction 0.41).

Including time-updated levels of serum total cholesterol in the same model, reduced the association of additional year of combined ART with myocardial infarction to 1.10 [1.01 to 1.19]. Adjustment for lipid-lowering medication did not further affect the association between HAART exposure and MI. Lipodystrophy was not associated with the risk of MI (RR 0.99 [0.75 to 1.30]).

The presentation concluded that while the overall absolute risk of myocardial infarction remains modest, the risk continues to increase with longer exposure to HAART and that these relative increases in risk appears similar in men and women, and in older and younger subjects.

Comment

The conclusion from this study is right to stress that the absolute risk for cardiovascular disease in many patients is low. Although accounting for lipid abnormalities explains much of the risk it does not explain it all. Also, if choice of HAART contributes to elevated lipids then the rationale for adjusting this out of the calculation may not help when considering implications for patients for whom HAART raises their lipids.

In an excellent symposium on CVD that included reference to D:A:D and other studies the cumulative risk was also pointed out to have a similar impact as ‘ever-smoked’ and that the management of individual patients should include evaluation for CVD risk prior to starting or changing HAART, and probably annually thereafter. [2, 3] On-line risk calculators provide a free and instant tool for assessing this with a patient, although a previous D:A:D analysis indicates that Framingham-based risk equations slightly underestimate risk for an HIV-positive population.

Best advice to patients remains lifestyle changes that significantly reduce risk, such as smoking cessation. However the same symposium included a long presentation and discussion on the target lipid concentrations. Recent studies in the general population have shown that reducing cholesterol levels provide a continuous range of benefit that is not just related to highest baseline levels. On a population basis, this has resulted in US guidelines reducing the target goals further and linking different goals to different individual 10-year risks.

Non-HDL NCEP targets in the US (possibly a more appropriate measure for HIV-positive patients who often have elevated triglyercides) for patients with >20% 10-year risk, <20% 10-year risk or 1-2 risk factors are now <3.36, <4.14 and <4.91 mmol/l respectively. LDL targets for the same risk groups are <2.59, <3.36 and <4.14 mmol/l respectively.

References:

1. El-Sadr W, Reiss P, De Wit S et al on behalf of the D:A:D Study Group. Relationship between prolonged exposure to combination ART and myocardial infarction: effect of sex, age, and lipid changes. 12th CROI, Boston, 2005.
   Oral Abstract 42.
2. Lundgren JD – Cardiovascular outcomes in HIV infection. Symposium: Heart and HAART. 12th CROI, Boston, 2005.
3. Martinez E – Managing cardiovascular risk and lipid disorders. Symposium: Heart and HAART. 12th CROI, Boston, 2005.