By Liz Highleyman

Ziagen Tablet

When deciding what regimen to use for first-line antiretroviral therapy, safety is and avoidance of serious drug-related toxicities is as important as efficacy. Cardiovascular disease (CVD), in particular, is a concern as people with HIV live longer thanks to effective treatment.

As previously reported, researchers at the 2008 Conference on Retroviruses and Opportunistic Infections in February presented data from the large D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) cohort showing that patients who took abacavir (Ziagen, also in the Epzicom and Trizivir combination pills) and didanosine (ddI; Videx) within the past 6 months had a significantly higher rate of myocardial infarction (MI; heart attack) than those taking other nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

These results were unexpected, and the biological mechanism underlying this phenomenon is unknown. The findings therefore led other researchers to re-analyze their data to look for a similar link. Two such analyses were presented at the XVII International AIDS Conference last week in Mexico City.

SMART Study

Jens Lundgren and an international team of investigators analyzed cardiovascular outcomes in the SMART treatment interruption trial. As previously reported, SMART included 5,472 participants who were randomly assigned either to stay on continuous antiretroviral therapy, or to interrupt treatment when their CD4 count was remained 350 cells/mm3 and to resume when it fell below 250 cells/mm3. Patients 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.

In the present analysis, the researchers looked at data on cardiovascular events, including heart attacks and strokes, and at 6 biomarkers associated with inflammation, blood vessel damage, and coagulation (clotting), including high sensitivity C reactive protein (hsCRP) and interleukin-6 (IL-6). Only the 2752 participants in the continuous therapy arm were included in the cardiovascular events analysis, though interrupters were also included in the biomarker analysis.

Numbers were compared among patients in 3 groups, classified according to NRTI use:

• Abacavir but not didanosine (n = 1019);

• Didanosine, with or without abacavir (n = 643);

• NRTIs other than abacavir or didanosine (n = 2882; 7% had used abacavir in the past).

Overall, the SMART participants were at moderate risk for cardiovascular disease. About three-quarters were men, the average age was 44 years, about 40% were smokers, about 20% were on blood pressure or lipid-lowering medications, and 7% had diabetes; 15% had 5 or more cardiovascular risk factors. About 40% of abacavir users were on triple-NRTI-only regimens (typically the Trizivir pill).

Results

• Current use of abacavir was associated with an increased risk of cardiovascular events:

• MI: adjusted hazard ratio (AHR) = 4.3, or about a 4-fold risk;

• Major CVD, including MI, stroke, surgery for coronary artery disease (CAD), and cardiovascular-related death: AHR = 1.8, or nearly a 2-fold risk;

• Expanded definition of major CVD, which added congestive heart failure (CHF), peripheral vascular disease, treatment for CAD, and unwitnessed death: AHR = 1.9, again, a 2-fold risk;

• Minor CVD, including CHF and use of medications for CAD: AHR = 2.7, or nearly 3 times the risk.

• Among participants with available biomarker data, hsCRP levels were 27% higher and IL-6 levels were 16% higher in the abacavir recipients (both p = 0.02).

• These associations remained when comparing abacavir recipients to those taking tenofovir (Viread), which was not included in the D:A:D MI analysis.

• In contrast with D:A:D, didanosine was not associated with an elevated risk of CVD or biomarker alterations.

Based on these findings, the investigators concluded, "Consistent with the D:A:D study, in SMART, abacavir was associated with an increased risk of cardiovascular disease."

However, they added that "This adverse effect appears to be only clinically relevant to consider among patients with elevated underlying cardiovascular risk."

It remains unknown how abacavir might cause cardiovascular problems, but the researchers suggested its might be due to drug-induced inflammation. During discussion of the presentation, audience members wondered whether subclinical abacavir hypersensitivity reactions, which might be too subtle to prompt drug discontinuation, might play a role.

Rigshospitalet & University of Copenhagen, Copenhagen, Denmark; University of Minnesota, MN; MRC, London, UK; University of New South Wales, Sydney, Australia; Colombia University, New York, NY; Veterans Affairs Medical Center and George Washington University, Washington DC; Royal Free and University College London, London, UK; Wake Forest University School of Medicine, Winston-Salem, NC; Academic Medical Center, Amsterdam, Netherlands; University of Vermont, Burlington, VT; University of Zürich, Zürich, Switzerland.

54-study Analysis

After the D:A:D results were revealed earlier this year, researchers with abacavir manufacturer GlaxoSmithKline (GSK) performed a pooled analysis of the company's past clinical studies to look for a similar association between the drug and CVD.

The GSK HIV Data Repository includes 54 company-sponsored Phase II-IV clinical trials in which participants took abacavir for 24-96 weeks as part of a combination HAART regimen:

• 13 randomized clinical trials (12 adult, 1 pediatric) in which participants were randomly assigned to receive abacavir or a comparator drug;

• 33 trials in which all participants received abacavir as part of a background regimen;

• 8 trials in which participants did not receive abacavir.

The pooled analysis included data from 14,683 HIV positive study participants (14,174 adults, 509 children). A total of 9639 people took abacavir (representing 7845 person-years), while 5044 took regimens without abacavir (representing 4653 person-years).

Most participants (about 80%) were men, the median age was about 38 years, the median CD4 count was about 300 cells/mm3, and about two-thirds were treatment-naive at study entry. CVD risk factors such as lipid and glucose levels were comparable in the abacavir and non-abacavir groups. However, because these studies were not designed to look at cardiovascular outcomes, they did not systematically collect data on risk factors such as smoking, nor did they analyze inflammatory biomarkers.

Results

• Overall, rates of cardiovascular events in these studies were lower than those seen in SMART, were similar in the abacavir and non-abacavir groups, and were comparable to those of the general population.

• In the abacavir group, the MI rate was 0.114% (2.04 per 1000 person-years) vs 0.139% (2.36 per 1000 person-years) in the non-abacavir group.

• Looking at an expanded definition of CVD that included conditions related to ischemic coronary artery disorders (e.g., CAD, atherosclerosis, angina pectoris), the rates were 0.249% (3.45 per person-year) and 0.416% (5.82 per 1000 person-years), respectively (p = 0.055).

• Patterns were similar when looking only at randomized clinical trials.

Although the studies in this analysis did not measure relevant biomarkers, presenter John Pottage from GSK showed data indicating that hsCRP and IL-6 levels did not increase after starting therapy in the HEAT study, and did not differ significantly in the abacavir/lamivudine (Epzicom) and tenofovir/emtricitabine (Truvada) arms.

These findings led the investigators to conclude that there was "no difference in incidence of ischemic coronary artery events or myocardial infarction" in individuals who received abacavir-containing vs non-abacavir-containing antiretroviral regimens.

As with all medications, they added, "physicians and patients must weigh the risks of HIV disease against the risks and benefits of the antiretroviral agents available."

Pottage recommended that all future trials of antiretroviral therapy should include comprehensive data on cardiovascular risk factors as well as relevant biomarker assessment, in an effort to resolve the conflicting findings to date.

GlaxoSmithKline Research & Development, Research Triangle Park, NC and Greenford, UK.

8/12/08

References

J Lundgren, J Neuhaus, A Babiker, and others. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the SMART study. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract THAB0305. (Abstract)

A Cutrell, J Hernandez, J Yeo, and others. Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical trials. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract THAB0305. (Abstract)