SMART Researchers Publish Findings Showing Abacavir (Ziagen) Is Associated with Elevated Risk of Cardiovascular Disease

By Liz Highleyman

The association between specific nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and cardiovascular disease risk was an issue of great interest at the XVII International AIDS Conference last month in Mexico City.

As previously reported, researchers with the large SMART treatment interruption study found that use of abacavir (Ziagen; also a component of the Epzicom and Trizivir fixed-dose combination pills) was associated with a significantly increased risk of myocardial infarction (MI; heart attack) and other cardiovascular events. The investigators subsequently published their findings as a "fast track" article in the September 12, 2008 issue of AIDS.

After researchers studying the large D:A:D cohort reported at the Conference on Retroviruses and Opportunistic Infections in February 2008 that patients who took abacavir or didanosine (ddI; Videx) within the past 6 months had a significantly higher MI rate than those taking other NRTIs, the SMART investigators conducted an analysis to see if they could find a similar association.

SMART included more than 5000 HIV patients randomly assigned to either stay on continuous antiretroviral therapy or interrupt treatment when their CD4 count was above 350 cells/mm3, resuming when it fell below 250 cells/mm3. As previously reported, participants who interrupted therapy not only had a higher risk of directly AIDS-related opportunistic illnesses and death, but also a higher rate of serious cardiovascular, liver, and kidney disease.

The present analysis included the 2752 participants in the continuous therapy arm. The researchers assessed electrocardiograms (ECGs) indicating ischemic changes (evidence of inadequate blood flow due to artery blockage) and rates of various predefined types of cardiovascular disease. In addition, biochemical markers were measured for patients in both the continuous therapy and treatment interruption arms.

Results

• Current use of abacavir was associated with an excess risk of cardiovascular disease compared with other NRTIs.

• Adjusted hazard ratios (AHR) were as follows:

• Clinical myocardial infarction (n = 19): AHR 4.3;

• Major cardiovascular disease, defined as MI, stroke, surgery for coronary artery disease, and death due to cardiovascular causes (n = 70): AHR 1.8;

• Expanded definition cardiovascular disease, defined as major cardiovascular disease (as above), plus congestive heart failure, peripheral vascular disease, coronary artery disease requiring drug treatment, and unwitnessed death (n = 112): AHR 1.9.

• In the subset of patients with available biomarker data, baseline high sensitivity C-reactive protein levels were 27% higher for those receiving abacavir compared with other NRTIs (P = 0.02), and interleukin-6 (IL-6) levels were 16% higher (P = 0.02).

• There were no significant differences in levels of D-dimer -- which was associated with an increased risk of death in an earlier SMART analysis -- or of amyloid A, amyloid P, or prothrobmin fragment 1+2 (F1.2).

• The excess cardiovascular risk associated with current use of abacavir tended to be higher in patients with 5 or more traditional cardiovascular risk factors.

• Excess cardiovascular risk was also observed when abacavir was compared with tenofovir (Viread, also in the combination pills Truvada and Atripla), which was not included in the earlier D:A:D analysis.

• Didanosine was associated with neither elevated risk of cardiovascular disease nor altered biomarker levels.

Based on these findings, the SMART study authors concluded, "Abacavir was associated with an increased risk of cardiovascular disease."

"In SMART, abacavir was used more often without an NNRTI or protease inhibitor than in D:A:D. Also, the reference group of patients on NRTIs other than abacavir and didanosine includes relatively more patients on tenofovir than were included in D:A:D," they wrote in their discussion. "Nevertheless, our findings concerning abacavir use were remarkably similar to those reported from D:A:D. This independent confirmation of the findings from D:A:D, derived from a population with a somewhat different pattern of use of the drug, strengthens the evidence that the association may be causal."

While these 2 large studies observed an increased risk of cardiovascular disease associated with abacavir, a retrospective analysis of more than 50 prior clinical trials by the drug's manufacturer, GlaxoSmithKline (GSK), found no such association. Results from the GSK analysis were also presented at the Mexico City AIDS conference.

The mechanism by which abacavir might predispose patients to heart disease -- if, in fact, it does so, which remains subject to debate -- has yet to be elucidated. Unlike the protease inhibitor class, abacavir is not known to adversely affect blood lipid levels or glucose metabolism, factors typically considered to promote atherosclerosis.

"The identification of a biological mechanism that may explain the increased risk of CVD in those receiving abacavir is important for two reasons," the SMART authors wrote. "First, such a mechanism would provide biological plausibility for associations that are derived from observational data. Second, understanding of any biological mechanism may permit the identification of patients who may be at particularly high or low risk of this event, thus allowing the drug to be used in a more targeted way."

"The biomarker findings suggest that abacavir may have proinflammatory properties. Abacavir causes hypersensitivity reactions in patients with HLA B*5701 and, as such, has already been demonstrated to have proinflammatory properties in genetically predisposed persons," they noted. "However, as the abacavir-associated hypersensitivity reaction is observed within the first 6-8 weeks after the drug is started, and most patients in SMART had been on the drug for considerably longer periods at entry in the trial, it is unlikely that a hypersensitivity reaction, per se, can explain our findings. Consistent with this, the D:A:D study found a continuously elevated risk of MI associated with abacavir irrespective of duration of exposure. However, approximately one third of patients with HLA B*5701 do not develop a hypersensitivity reaction after starting abacavir, and it is possible that ongoing subclinical inflammatory reactions in these patients may contribute to our findings, or that abacavir may stimulate inflammation by other mechanisms."

In summary, they continued, "on the basis of the data from D:A:D and the data presented here, the underlying mechanism by which abacavir may increase the risk of CVD appears to be through an increased propensity for subclinical atherosclerosis to manifest itself clinically as a consequence of the proinflammatory potential of the drug."

The authors also discussed the possibility that the excess risk of cardiovascular disease associated with abacavir could be due to a "channeling effect," in which patients with pre-existing cardiovascular risk may have been preferentially prescribed abacavir. "Only randomized controlled trials can effectively eliminate this possibility," they wrote.

Importantly, the overall rate of MI and other serious cardiovascular events was low in both the D:A:D and SMART cohorts, and in SMART, it was highest for patients with traditional risk factors. Thus, it is important to take cardiovascular risk into account when making decisions about which drugs to use. For all people with HIV, it is prudent to reduce cardiovascular risk as much as possible by managing controllable factors, for example through better diet, exercise, and smoking cessation.

9/09/08

Reference
SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 22(14): F17-F24. September 12, 2008.