Antiretroviral Abacavir Linked With Cardiovascular Events in REPRIEVE Trial

People with HIV who took the antiretroviral drug abacavir (Ziagen) had an increased risk of major adverse cardiovascular events (MACE), according to an exploratory analysis of the REPRIEVE trial.

Past use of abacavir increased the risk of MACE by 50% (risk-adjusted HR 1.50, 95% CI 1.04-2.15) and current use increased MACE risk by 42% (risk-adjusted HR 1.42, 95% CI 1.00-2.00), reported Carl Fichtenbaum, MD, of the University of Cincinnati, at the International AIDS Conference in Munich.

MACE incidence increased in a linear fashion over time. At 96 months of follow-up, cumulative incidence of MACE among former abacavir users was 9.74% and 7.63% in current users. In participants who had never used abacavir, the cumulative MACE incidence was 3.74%.

Of note, the REPRIEVE trial population was a “low-to-moderate risk group” for cardiovascular (CV) disease, Fichtenbaum said. The median age of the cohort was 50. Participants had a median LDL of 106 mg/dL and the median 10-year atherosclerotic CV disease (ASCVD) risk score was 4.5%.

Current or past use of other antiretroviral therapy (ART), including protease inhibitors, thymidine analogs, or tenofovir disoproxil fumarate (TDF) was not associated with increased risk of MACE.

In a Q&A session, Agnes Moses, MD, of Partners in Hope in Lilongwe, Malawi, commented, “I’m actually deflated to hear that it confers the cardiovascular risk, because usually [abacavir] is our go-to medicine for people with toxicity from TDF.”

“However, I’m more interested to find out the mechanisms or pathogenic pathways through which abacavir confers this risk,” she added. Moses was not associated with the study.

“We’re very interested in trying to find out those mechanisms, as well,” Fichtenbaum replied. “There may be some endothelial dysfunction. I think it would be very interesting to look at some of our genomics and proteomics to see whether or not there are any epigenetic changes that have occurred that are long-lasting.”

“Hopefully, with newer antiretrovirals and longer-acting therapy, perhaps this will become less and less of a problem as we’re able to shift away and use other things to control HIV replication,” he said.

Abacavir use showed similar trends for hard MACE events, defined as CV death, myocardial infarction, and stroke, but was not statistically significant, Fichtenbaum reported.

Fichtenbaum indicated that ART guidelines should revisit the positioning of abacavir where it is recommended as a first-line agent. “Since there are many other options available — certainly in high-income countries — I think we have to consider the fact that the most important thing is controlling HIV replication, but that where we can, it may be helpful to avoid the use of abacavir,” he stated.

In response to a question from the audience whether there is a CV benefit to discontinuing abacavir among patients already on the drug, Fichtenbaum responded that “the preponderance of evidence suggests that stopping it is still a good idea,” while also paying attention to modifiable CV risk factors.

It has been known for some time that people with HIV are at higher risk for MACE than people without HIV, even when traditional CV risk factors, such as hypertension, cholesterol, and smoking status, are accounted for.

To investigate a potential intervention for this increased risk, the pivotal REPRIEVE trial looked at the efficacy of the cholesterol-lowering agent pitavastatin (Livalo) in people with HIV in lowering MACE and found that pitavastatin safely reduced incidence of any MACE by 35%.

Among the 7,769 participants enrolled in REPRIEVE, 31% were female and 65% were non-white. The median CD4 count was 621 cells/mm³, and 98% had a viral load under 400 copies/mL. Enrolled individuals were on stable ART for at least 180 days.

Of trial participants, 78% had never had exposure to abacavir. Of the 22% who had a history of abacavir exposure, 9% had former exposure, with a median duration of 3 years of use. Thirteen percent of participants were currently taking abacavir at trial randomization, with a median duration of 1.47 years of use. Participants had been taking HIV treatment for a median of 9.5 years and the median duration of follow-up was 5.6 years.

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