Can Ziagen Hurt Your Heart?
Research presented at the International AIDS Conference weighs in on the controversy
by Liz Highleyman
In one of the most widely discussed sessions held at the International AIDS Conference in Mexico City, researchers presented data on the link between cardiovascular disease and specific nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs). Cardiovascular disease is a growing concern as HIV-positive people live longer, but the relationships between heart disease, antiretroviral therapy, and HIV infection itself are not yet fully understood. (See story on page 31.)
Earlier this year, researchers studying the large multi-national D:A:D cohort reported that patients who took abacavir (Ziagen, also in the Epzicom and Trizivir combination pills) or ddI (Videx) within the past six months had a significantly greater risk of heart attacks, or myocardial infarction (MI), than people taking other NRTIs. These unexpected results led researchers with the SMART treatment interruption trial to look for a similar pattern in their data (Abstract THAB0305).
SMART included more than 5,000 participants randomly assigned to either stay on continuous HAART or interrupt treatment when their CD4 cell count was above 350. Patients in the treatment interruption arm not only had a higher risk of AIDS-related opportunistic illnesses and death, but also had more serious cardiovascular, liver, and kidney disease.
The researchers went back and analyzed data on cardiovascular events and several blood biomarkers associated with inflammation, blood vessel damage, and coagulation. Current abacavir users had about a four-fold greater risk of MI, nearly twice the risk of major cardiovascular events (including MI, stroke, surgery for coronary artery disease, and cardiovascular-related death), and nearly three times the risk of minor cardiovascular events. Furthermore, levels of high sensitivity C reactive protein (hsCRP) and interleukin-6 (IL-6) were significantly higher among patients taking abacavir (by 27% and 17%, respectively). The researchers concluded that “abacavir was associated with an increased risk of cardiovascular disease,” but they added that this risk only appeared to be clinically relevant for people with traditional cardiovascular risk factors such as older age and smoking.
Abacavir manufacturer GlaxoSmithKline also re-analyzed data from prior clinical trials to look for an association between the drug and cardiovascular disease (Abstract THAB0305). Investigators performed a pooled analysis of more than 14,000 participants in 54 company-sponsored studies, including 12 adult randomized clinical trials. They found that rates of cardiovascular events—both MI and an expanded definition that included atherosclerosis and angina—were similar in patients who took abacavir and those who did not. The overall rates were lower than those observed in D:A:D, and closer to those seen in studies of the general HIV-negative population.
Since these studies were not originally designed to look at cardiovascular outcomes, they did not collect data on traditional risk factors or blood biomarker levels. However, in the company’s HEAT study (Abstract LBPE1138), which compared the fixed-dose Epzicom (abacavir/3TC) and Truvada (tenofovir/emtricitabine) combination pills plus Kaletra (lopinavir/ritonavir), hsCRP and IL-6 levels did not differ significantly in the two arms.
These conflicting results—and uncertainty about what mechanisms might explain an association between abacavir and heart disease—underline the need for further study, including careful analysis of cardiovascular outcomes and biomarkers in future clinical trials. In the meantime, it is important to consider individual cardiovascular risk factors when weighing the benefits and risks of specific antiretroviral drugs. Chicago HIV specialist Renslow Sherer, M.D. said the SMART analysis indicates that there is a real effect of Ziagen on the heart, but the drug is still very useful for people who don’t have the traditional risk factors and are unable to take alternative medications. (Editor’s note: Ziagen’s principle competitor, Viread, is associated with kidney dysfunction in certain susceptible people; see page 13.)
Epzicom versus Truvada
Another pair of conflicting presentations focused on the effectiveness of the Epzicom and Truvada NRTI backbones. Earlier this year, ACTG study A5202 was modified after preliminary data showed that when used with Sustiva (efavirenz) or Norvir-boosted Reyataz (atazanavir), Epzicom did not suppress HIV as well as Truvada in people who started treatment with a high viral load (greater than 100,000). Paul Sax presented un-blinded data from the high viral load patients in Mexico City (Abstract THAB0303); the study is still continuing with the low viral load patients.
A5202 enrolled 1,858 treatment-naïve participants, of whom 797 had a viral load of at least 100,000 copies. About twice as many patients in the Epzicom arm experienced virological failure, which the researchers defined as either a viral load of 1,000 copies or more between 16 and 24 weeks, or else 200 copies or more after 24 weeks (trials usually do not report response before 24 weeks). The time to virological failure was significantly shorter in the Epzicom arm compared with the Truvada arm, but similar proportions in both groups achieved a viral load below 50 copies at 48 weeks (75% vs. 80%, respectively) and CD4 cell gains were comparable.
People taking Epzicom were quicker to experience serious adverse events and were more likely to modify their regimen. The most common side effects were general body aches and blood lipid increases. In both arms, about 7% reported symptoms that might indicate an abacavir hypersensitivity reaction (participants were not screened for genetic susceptibility to hypersensitivity). No heart attacks occurred in either arm, and there were two cases of kidney failure—a potential side effect of Viread (the tenofovir component of Truvada)—in both groups.
Here again, GlaxoSmithKline researchers analyzed data from past studies to search for similar findings (Abstract THAB0304). They looked at 48-week efficacy outcomes from six clinical trials that included a total of 2,940 antiretroviral-naïve patients who took either Epzicom or a comparator NRTI backbone. At 48 weeks, 87% to 95% of participants in both groups maintained a viral load below 50 copies, and there were no significant differences in people with high or low viral load. Safety outcomes were also similar.
Taken together, these studies indicate that despite possible minor differences in speed of response and side effects, both Epzicom and Truvada are highly effective as part of a first-line treatment regimen.
Liz Highleyman (liz@black-rose.com) is a freelance medical writer based in San Francisco.
